干细胞融合与胃癌发生和进展的实验研究
|
摘要
本课题在建立雌雄嵌合体小鼠模型的基础上通过多因素联合攻击法建立嵌合体小鼠胃癌模型并通过Y染色体荧光原位杂交(FISH)检测是否发生细胞融合。通过机械法联合酶消化化学法分离小鼠胃粘膜上皮细胞,并通过免疫磁珠法分选骨髓源干细胞,最终通过化学融合法(聚乙二醇)将此两种细胞进行体外融合实验及培养。同时分离培养脐带血间充质干细胞(CB-MSCs)及人正常胃粘膜上皮细胞系(GES-1)并通过化学融合法(聚乙二醇)将此两种细胞进行体外融合实验并进行相关检测。以研究骨髓源性干细胞融合在小鼠胃癌发生与发展过程中的作用。
第一部分雌雄嵌合体小鼠模型的建立及诱癌实验
目的：通过雌雄嵌合体小鼠胃癌模型了解骨髓源干细胞在胃癌发生及进展过程中的作用。
方法：采用雌性C57BL/6-GFP转基因小鼠为供体、雄性C57BL/6小鼠为受体通过性别交叉骨髓移植建立雌雄嵌合体小鼠。分别于术后1w及4w取嵌合体小鼠骨髓及外周血行流式细胞术鉴定骨髓移植模型是否成功,同时通过荧光显微镜观察骨髓移植后GFP+细胞在不同组织器官中的分布。在雌雄嵌合体小鼠基础上采用多因素联合攻击法建立嵌合体小鼠胃癌模型,并通过HE染色法及CK-18免疫组化法确定小鼠成瘤情况,同时采用Y染色体荧光原位杂交检测是否存在细胞融合。
结果：小鼠骨髓移植术后小鼠存活率100%，流式细胞术结果示骨髓移植术后1周嵌合体小鼠骨髓GFP+细胞为(7.48±1.38)%,术后4周为(73.92±5.57)%。嵌合体小鼠外周血检测T细胞亚群结果显示1wk时仅有少量GFP+细胞且CD8+细胞恢复较CD4+细胞快,4wk时GFP+细胞升高、但CD4+细胞仍较少。嵌合体小鼠经多因素联合攻击法诱癌后总体存活率为72.9%(35/48)。诱癌后18.2%(2/11)小鼠诱发重度不典型增生及25.0%(3/12)小鼠成功诱发胃癌,其中2只腺癌、1只鳞癌。荧光显微镜结果示嵌合体小鼠正常胃组织可见少量GFP表达,而嵌合体小鼠非典型增生胃组织可见大量GFP表达。嵌合体小鼠嵌合体小鼠肾,脑,肝及脾组织中均可见不同程度GFP表达。通过Y染色体FISH检测结果示嵌合体小鼠正常胃组织于间质部位可见少量GFP表达,但均未见GFP及Y染色体双阳性细胞。嵌合体小鼠胃癌癌前病变及胃癌组织中均存在GFP及Y染色体双阳性细胞,但胃癌癌前病变组织中双阳性细胞比例较胃癌组织高。结论：通过性别交叉骨髓移植成功构建雌雄嵌合体小鼠模型,并通过多因素联合攻击法成功诱导小鼠胃部炎症、胃癌前病变及胃癌。骨髓源干细胞参与了不同脏器器官中血管内皮细胞的生成与更新。胃粘膜损伤早期及癌前病变时骨髓源干细胞参与胃粘膜组织的修复且部分细胞与胃粘膜细胞发生融合。当肿瘤发生时大量骨髓源性干细胞参与胃黏膜上皮细胞的修复后可取代原有胃黏膜上皮细胞且细胞融合减少。
第二部分小鼠骨髓源干细胞与胃粘膜上皮细胞体外融合实验
目的：通过小鼠骨髓源性干细胞与原代胃黏膜上皮细胞体外融合探讨骨髓源性干细胞融合参与肿瘤形成的可能机制。
方法：通过机械法联合化学消化法分离胃粘膜上皮细胞并采用免疫荧光法鉴定细胞表型。通过免疫磁珠分离纯化小鼠骨髓谱系抗原阴性细胞,并通过流式细胞术检测细胞纯度。后通过聚乙二醇化学融合法进行小鼠骨髓源性干细胞与小鼠胃黏膜上皮细胞的细胞融合实验并通过流式细胞术检测细胞融合率并进行融合细胞的分选。
结果：通过机械法联合化学消化法分离小鼠胃黏膜上皮细胞,每只小鼠腺胃部分可获得(5.27±2.92×106)个细胞、细胞活力为(97.05±2.20%)。其增殖在7天达到最佳状态,且角蛋白-18(Cytokeratin-18,CK-18)免疫荧光阳性率为(93.21±3.35)%。通过胫骨及股骨可分离出(8.88±4.22×107)个骨髓细胞、细胞活力为(98.35±1.23)%。以(4.43±2.47×107)个骨髓细胞进行免疫磁珠Lin-细胞分选可分出(1.36±1.03×106)个Lin-骨髓细胞。通过FCM检测分选前骨髓细胞Lin+细胞比例为76.21±4.89%、分选后磁珠标记的Lin+细胞比例为(69.23±5.79)%、分选后磁珠未标记Lin-细胞比例为(93.93±3.35)%。胃粘膜上皮细胞通过CFSE绿色荧光染色后可见细胞均表达绿色荧光,Lin-及Lin+骨髓细胞通过PKH26红荧光染色后细胞均表达红色荧光。两种细胞混合培养后未见细胞融合。PEG融合后荧光显微镜观察可见细胞融合,通过流式细胞术检测细胞融合率为(5.77±1.91)%。
结论：通过机械法联合化学消化法成功分离小鼠胃粘膜上皮细胞,且其增殖在第7天达到最佳状态。通过免疫磁珠法成功分离小鼠骨髓Lin-细胞。通过PEG化学融合法成功融合小鼠胃粘膜上皮细胞及小鼠骨髓Lin-细胞。但因小鼠骨髓源干细胞及胃粘膜细胞均为原代细胞,融合后未造成细胞的转化,子代细胞未获得持续增殖的表型,另一方面可能因为融合效率较低,细胞融合致细胞表型改变的效率也较低,即使融合造成少量细胞的转化,在实验系统中未能观察到。
第三部分人脐血间充质干细胞与人胃粘膜上皮细胞体外融合实验
目的：通过人脐血间充质干细胞(CB-MSCs)与人正常胃粘膜上皮细胞系(GES-1)体外融合探讨间充质干细胞融合参与上皮细胞恶性转化的可能及肿瘤干细胞的起源。
方法：体外培养GES-1细胞并通过免疫荧光染色鉴定CK-18在GES-1细胞表达情况。分离脐血单个核细胞进行脐血来源间充质干细胞的培养并探索其培养条件,观察脐血间充质干细胞生长特性。通过流式细胞分析脐血间充质干细胞表型分子Thy-1(CD90)、SH2(CD105)、SH4(CD73)、HLA-ABC、HLA-DR、CD34、CD45等的表达。通过聚乙二醇化学融合法进行CB-MSCs与GES-1的细胞融合实验并通过流式细胞术分选融合细胞。观察融合细胞生长特性,通过免疫荧光鉴定融合细胞CK-18表达情况。通过流式细胞术检测细胞融合率、表面抗原CD90表达情况及DNA倍体分析,通过划痕实验及侵袭实验检测融合细胞的迁移及侵袭能力,并通过MTT细胞增殖实验检测细胞增殖率。BALB/c裸鼠皮下注射融合细胞检测融合细胞成瘤率。
结果：脐带血可分离并培养出CB-MSCs、其第一代形态为圆形及梭形,传代后为纺锤形及多角形且贴壁能力增强、具有很强的自我更新能力,本实验观察其可在体外传至25代。通过流式细胞技术分析CB-MSCs细胞表面免疫表型特征为：SH2(CD105)、SH4(CD73)、HLA-ABC强阳性,CD90弱阳性,、HLA-DR、CD45、CD34阴性。CB-MSCs及GES-1细胞经聚乙二醇体外融合后可通过流式细胞仪分选融合细胞、其融合率为8.7%。融合细胞形态不规则且可见巨大融合细胞,两周后细胞开始增殖、生长迅速且可稳定传代。免疫荧光检测CK-18显示融合细胞胞浆高表达CK-18,且形态发生改变,细胞核增大,胞浆减少,呈现恶性肿瘤细胞特性。流式检测显示融合细胞表达CD90,而DNA倍体分析结果示融合细胞为多倍体及非整倍体细胞且随细胞代数的增长、非整倍体细胞所占比例增加。MTT结果显示融合细胞增殖活性较GES-1明显增强,并获得向基质胶侵袭的能力且其迁移与侵袭能力均有所增强。裸鼠皮下成瘤实验显示融合细胞可形成带有腺体结构的上皮源性肿物。
结论：成功分离并培养出脐带血间充质干细胞,且通过PEG体外与GES-1融合后通过流式细胞成功分选出融合细胞。细胞融合后形态及表型均发生改变,细胞形态呈典型肿瘤细胞且兼具GES-1及MSCs二者的表型、即胞浆表达CK-18且其表面抗原CD90阳性。融合细胞增殖活性较GES-1明显增强,并获得向基质胶侵袭的能力且其迁移与侵袭能力均有所增强。融合细胞与GES-1及MSCs相比可形成皮下肿物。
Role of bone marrow derived stem cells fusion during the development and progression of gastric carcinoma was studied during this experiment. Chimeric mouse model was established through sex mismatch bone marrow transplantation by using female transgenic C57/BL-GFP mouse as donor and male C57/BL mouse as receiver. Then gastric carcinoma was induced by multiple carcinogens attack and cell fusion was assesed through Y chromosome fluorescence in situ hybridization (FISH). Mean while, gastric epithelial cells were isolated from mouse glandular stomach with collagenese digestion, and bone marrow derived stem cells were isolated from mouse bone marrow with MACS separation kit. Then cell fusion with polyethylene glycol (PEG) was performed between these cells. Cord blood mesenchymal stem cells (CB-MSCs) were also isolated and collected from our hospital and in vitro cell fusion was performed between these cells, and fusion cells were sorted with FACSVanture. Then morphology of the fusion cells was observed, and phenotypes of the cells were examined with immunohistochemistry (IHC) and flow cytometry (FCM). Then migration, invasion, and proliferation ability of the fusion cells were also assessed through cell scratch assay, transwell assay, and MTT cell proliferation assay.
Part I Establishment of Chimeric Mouse Model and Induction of Gastric Carcinoma
Objective Role of bone marrow derived stem cell in gastric carcinoma development and progression were still obscured, and through what mechanism it participated in this process was still under debate between transdiffertiation and cell fusion. In the present study, sex mismatch chimeric mouse was used to induce gastric carcinoma, and gastric sample was collected and examined for cancer induce rate and cell fusion, to investigate the role of bone marrow derived stem cells during the development and progression of gastric carcinoma.
Method Chimeric mouse model was established through sex mismatch bone marrow transplantation by using female transgenic C57/BL-GFP mouse as donor and male C57/BL mouse as receiver. Then bone marrow and peripheral blood were collected on week1and week4to examine by FCM, and frozen slide of different organs were also collected to study the distribution of GFP+cells in different organs. Chimeric mouse was then used to induce gastric cancer by multiple carcinogens attack, and stomach samples were collected for pathology study and Y chromosome FISH for examination of tumor induce rate and cell fusion.
Result All the mice underwent bone marrow transplplantation survived, and FCM results showed chimeric mouse bone marrow GFP+cells was7.48±1.38%and73.92±5.57%at week1and week4respectively. In the peripheral blood, only small portion of cells were GFP+on week1and recovery of CD8+cells was faster than that of the CD4+cells, while GFP+cells increased on week4but the amount of CD4+cells was still low.72.9%of chimeric mouse survived after multiple carcinogens attack. For those mice survive through carcinogens attack,18.2%of mice showed precancerous lesion and25.0%of mice were successfully induced with gastric cancer, with2adenocarcinoma and1squamous cell carcinoma. Great amount of GFP expression was detected for stomach sample with severe dysplasia or gastric cancer, and GFP expression was also detected in other different organs such as kidney, brain, liver, and spleen, but no GFP expression was detected in the heart. Great amount of GFP expression was detected for stomach sample with severe dysplasia, and most of the cells showed both GFP and Y-chromosome, which indicated that fusion had occurred (Figure3C). Great amount of GFP expression was also dectected in both adenocarcinoma and squamous cell carcinoma (Figure3D-E). Most of the cells in adenocarcinoma sample showed cells with Y-chromosome in the neucleus and these cells also expressed GFP in the cytoplasm, which indicated that cell fusion had occured. For squamous cell carcinoma, GFP expression was mainly detected in the interstitial or keartine perals, but no sign of fusion was detected. Normal chimeric mouse showed little GFP expression in the interstitial, but no fusion was detected. Great amount of GFP expression was detected for stomach sample with severe dysplasia, and most of the cells showed both GFP and Y-chromosome, which indicated that fusion had occurred.
Conclusion Sex mismatch chimeric mouse model was successfully established. Mouse gastric inflammation, severe dysplasia, and gastric cancer were successfully induced through multiple carcinogens attack. BMSCs involve in the renewal of vessel endothelial cells, and some of the cell participated through cell fusion. BMSCs participated in the renewal of gastric mucosa during gastric inflammation and dysplasia through cell fusion. When tumor occurred, fusion cell or BMSCs have become the main cells in tumor with little amount of fusion cells been detected.
Part Ⅱ Fusion of Mouse Bone Marrow Derived Stem Cells and Gastric Epithelial Cells
Objective Role of cell fusion during tumor development and progression was worth of attention, whereby it might enhance the metastasis ability of tumor cells or potentially be the source of cancer stem cell. In the present study, mouse gastric epithelial cells and mouse BMSCs were isolated and collected. Cells collected were used for in vitro cell fusion to investigate the possibility for BMSCs fusion to be the primary mechanism of neoplasia during the development and progression of gastric tumor.
Method Mouse gastric epithelial cells were isolated and collected with collagenese digestion, and phenotype of isolated cells was examined with IHC. Mouse BMSCs were isolated and collected with MACSs separation kit, and cells were examined with FCM. These cells were used for in vitro PEG cell fusion, and fusion rate were examined with FCM and fusion cells were sorted with FACSVantage.
Result Mouse gastric epithelial cells were successfully isolated with collagenese digestion. For each mouse,5.27±2.92×106cells were isolated from glandular stomach and cell viability was97.05±2.20%. Proliferation of mouse gastric epithelial cells reached climax on7d, and IHC examination showed that93.21±3.35%of cells expressed cytokeratine-18(CK-18).8.88±4.22×107cells were isolated from tibia and femur bone and cell viability was98.35±1.23%.1.36±1.03×106BMSCs (Lin-) cells were isolated from4.43±2.47×107marrow cells. Before MACS separation,76.21±4.89%of marrow cells were Lin+. After MACS separation,69.23±5.79%of marrow cells were Lin+and93.93±3.35%of marrow cells were Lin-. After staining with CFSE or PKH26, mouse gastric epithelial cells and marrow cells (Lin+or Lin-) expressed either green or red fluorescence, and co-culture of these cells showed no sign of cell fusion. After in vitro PEG cell fusion assay, fusion cells can be observed under fluorescence microscope and fusion rate was5.77±1.91%when examined with FCM. Fusion cells showed no proliferation after FCM sorting.
Conclusion Mouse gastric epithelial cells were successfully isolated with collagenese digestion, and proliferation reached climax at7d after isolation. Mouse were successfully isolated from mouse bone marrow with MACS. In vitro PEG cell fusion of these cells was successfully. Proliferation of fusion cells sorted with FCM was unsuccessful, which might be due to that both mouse gastric epithelial cells and BMSCs were of primary culture, therefore the daughter cells after cell fusion did not transformed or gain the phenotype of BMSCs to continuously proliferation. On the other hand, the low fusion rate decreased the chance for fusion cells to go through phenotype transformation or gaining the phenotype of mother cells.
Part III Fusion of Human Cord Blood Mesenchimal Stem Cells and Human Gastric Epithelial Cells
Objective Proliferation of fusion cell between mouse gastric epithelial cells and mouse BMSCs was unsccesful on our previous experiment. In the present study, immortalized human gastric mucosal epithelial cell line (GES-1) and cord bold mesenchymal stem cells (CB-MSCs) were used for in vitro PEG cell fusion to investigate the possibility of epithelial malignant transformation induced by cell fusion and to explore the origin of cancer stem cells.
Method GES-1cells were culture and CK-18expression was determined by IHC. CB-MSCs were isolated from cord blood collected in our hospital, and then the growth characteristics of was monitored. Mesenchymal stem cell-specific phenotype of Thy-1(CD90)、SH2(CD105)、SH4(CD73)、HLA-ABC、HLA-DR、 CD34、CD45were identified by flow cytometry. GES-1cells were labeled with PKH26and CB-MSCs were labeled with CFSE, and fusion of these cellswere induced with PEG. Fusion rate was then determined with FCM and double positive fusion cells were sorted. Then growth characteristics of fusion cells were monitored and CK-18expression was determined by IHC. Cell surface antigen CD90and DNA Ploidy Analysis of fusion cells were determined by FCM. Then migration, invasion, and proliferation ability of fusion cells were assessed by cell scratch test, twanswell assay, and MTT cell proliferative assay. Tumorigenicity of fusion cells were assessed through BALB/c nude mouse subcutaneous injection.
Result CB-MSCs were successfully isolated from cord blood, and the first generation of CB-MSCs obtained an oval or spindle shape. After passaging, cells became polygonal with strong adherent ability and self-renewal capacity, and CB-MSCs could be cultured for25passages in vitro. CB-MSCs showed no expression of hematopoietic marker CD34, CD45, HLA-DR, but expressed the typical MSC marker proteins SH2(CD105), SH4(CD73), HLA-ABC. However, the intensity of expression of CD90was significantly below that of other markers. In vitro cell fusion between CB-MSCs and GES-1was successfully performed, and fusion cells were sorted with FCM with fusion rate of8.7%. CK-18was highly expressed within the cytoplasm of fusion cells. Morphological changes of fusion cells included:greater heterogeneity in the size and shape of cells and nuclei, increased nuclear:cytoplasmic ratio as characteristics of malignant cells. GES-1did not express CD90while the fusion cells acquired the markers of CD90. DNA ploidy analysis showed that fusion cells consisted of polyploid and aneuploid cells and with the increase of passages the proportion of aneuploid cells increased. Proliferation, migration and invasion ability of the fusion cells were increased. Subcutaneous mass was observed after injection of fusion cells, and HE with IHC results showed mass with glandular structure of epithelial origin.
Conclusion CB-MSCs were isolated, collected, and successfully fused with GES-1under PEG stimulation. Fusion cells were morphological different from typical MSCs and GES-1cells, and showed characteristics of both parental cells, such as high expression of CK-18in plasma and is also obtained the surface antigen CD90. Proliferation, migration and invasion ability of the fusion cells were increased, indicating that fusion between MSCs and epithelial cells can result in enhance metastasis ability. Compare to GES-1and MSCs, fusion cells were able to form subcutaneous mass.
第一部分雌雄嵌合体小鼠模型的建立及诱癌实验
目的：通过雌雄嵌合体小鼠胃癌模型了解骨髓源干细胞在胃癌发生及进展过程中的作用。
方法：采用雌性C57BL/6-GFP转基因小鼠为供体、雄性C57BL/6小鼠为受体通过性别交叉骨髓移植建立雌雄嵌合体小鼠。分别于术后1w及4w取嵌合体小鼠骨髓及外周血行流式细胞术鉴定骨髓移植模型是否成功,同时通过荧光显微镜观察骨髓移植后GFP+细胞在不同组织器官中的分布。在雌雄嵌合体小鼠基础上采用多因素联合攻击法建立嵌合体小鼠胃癌模型,并通过HE染色法及CK-18免疫组化法确定小鼠成瘤情况,同时采用Y染色体荧光原位杂交检测是否存在细胞融合。
结果：小鼠骨髓移植术后小鼠存活率100%，流式细胞术结果示骨髓移植术后1周嵌合体小鼠骨髓GFP+细胞为(7.48±1.38)%,术后4周为(73.92±5.57)%。嵌合体小鼠外周血检测T细胞亚群结果显示1wk时仅有少量GFP+细胞且CD8+细胞恢复较CD4+细胞快,4wk时GFP+细胞升高、但CD4+细胞仍较少。嵌合体小鼠经多因素联合攻击法诱癌后总体存活率为72.9%(35/48)。诱癌后18.2%(2/11)小鼠诱发重度不典型增生及25.0%(3/12)小鼠成功诱发胃癌,其中2只腺癌、1只鳞癌。荧光显微镜结果示嵌合体小鼠正常胃组织可见少量GFP表达,而嵌合体小鼠非典型增生胃组织可见大量GFP表达。嵌合体小鼠嵌合体小鼠肾,脑,肝及脾组织中均可见不同程度GFP表达。通过Y染色体FISH检测结果示嵌合体小鼠正常胃组织于间质部位可见少量GFP表达,但均未见GFP及Y染色体双阳性细胞。嵌合体小鼠胃癌癌前病变及胃癌组织中均存在GFP及Y染色体双阳性细胞,但胃癌癌前病变组织中双阳性细胞比例较胃癌组织高。结论：通过性别交叉骨髓移植成功构建雌雄嵌合体小鼠模型,并通过多因素联合攻击法成功诱导小鼠胃部炎症、胃癌前病变及胃癌。骨髓源干细胞参与了不同脏器器官中血管内皮细胞的生成与更新。胃粘膜损伤早期及癌前病变时骨髓源干细胞参与胃粘膜组织的修复且部分细胞与胃粘膜细胞发生融合。当肿瘤发生时大量骨髓源性干细胞参与胃黏膜上皮细胞的修复后可取代原有胃黏膜上皮细胞且细胞融合减少。
第二部分小鼠骨髓源干细胞与胃粘膜上皮细胞体外融合实验
目的：通过小鼠骨髓源性干细胞与原代胃黏膜上皮细胞体外融合探讨骨髓源性干细胞融合参与肿瘤形成的可能机制。
方法：通过机械法联合化学消化法分离胃粘膜上皮细胞并采用免疫荧光法鉴定细胞表型。通过免疫磁珠分离纯化小鼠骨髓谱系抗原阴性细胞,并通过流式细胞术检测细胞纯度。后通过聚乙二醇化学融合法进行小鼠骨髓源性干细胞与小鼠胃黏膜上皮细胞的细胞融合实验并通过流式细胞术检测细胞融合率并进行融合细胞的分选。
结果：通过机械法联合化学消化法分离小鼠胃黏膜上皮细胞,每只小鼠腺胃部分可获得(5.27±2.92×106)个细胞、细胞活力为(97.05±2.20%)。其增殖在7天达到最佳状态,且角蛋白-18(Cytokeratin-18,CK-18)免疫荧光阳性率为(93.21±3.35)%。通过胫骨及股骨可分离出(8.88±4.22×107)个骨髓细胞、细胞活力为(98.35±1.23)%。以(4.43±2.47×107)个骨髓细胞进行免疫磁珠Lin-细胞分选可分出(1.36±1.03×106)个Lin-骨髓细胞。通过FCM检测分选前骨髓细胞Lin+细胞比例为76.21±4.89%、分选后磁珠标记的Lin+细胞比例为(69.23±5.79)%、分选后磁珠未标记Lin-细胞比例为(93.93±3.35)%。胃粘膜上皮细胞通过CFSE绿色荧光染色后可见细胞均表达绿色荧光,Lin-及Lin+骨髓细胞通过PKH26红荧光染色后细胞均表达红色荧光。两种细胞混合培养后未见细胞融合。PEG融合后荧光显微镜观察可见细胞融合,通过流式细胞术检测细胞融合率为(5.77±1.91)%。
结论：通过机械法联合化学消化法成功分离小鼠胃粘膜上皮细胞,且其增殖在第7天达到最佳状态。通过免疫磁珠法成功分离小鼠骨髓Lin-细胞。通过PEG化学融合法成功融合小鼠胃粘膜上皮细胞及小鼠骨髓Lin-细胞。但因小鼠骨髓源干细胞及胃粘膜细胞均为原代细胞,融合后未造成细胞的转化,子代细胞未获得持续增殖的表型,另一方面可能因为融合效率较低,细胞融合致细胞表型改变的效率也较低,即使融合造成少量细胞的转化,在实验系统中未能观察到。
第三部分人脐血间充质干细胞与人胃粘膜上皮细胞体外融合实验
目的：通过人脐血间充质干细胞(CB-MSCs)与人正常胃粘膜上皮细胞系(GES-1)体外融合探讨间充质干细胞融合参与上皮细胞恶性转化的可能及肿瘤干细胞的起源。
方法：体外培养GES-1细胞并通过免疫荧光染色鉴定CK-18在GES-1细胞表达情况。分离脐血单个核细胞进行脐血来源间充质干细胞的培养并探索其培养条件,观察脐血间充质干细胞生长特性。通过流式细胞分析脐血间充质干细胞表型分子Thy-1(CD90)、SH2(CD105)、SH4(CD73)、HLA-ABC、HLA-DR、CD34、CD45等的表达。通过聚乙二醇化学融合法进行CB-MSCs与GES-1的细胞融合实验并通过流式细胞术分选融合细胞。观察融合细胞生长特性,通过免疫荧光鉴定融合细胞CK-18表达情况。通过流式细胞术检测细胞融合率、表面抗原CD90表达情况及DNA倍体分析,通过划痕实验及侵袭实验检测融合细胞的迁移及侵袭能力,并通过MTT细胞增殖实验检测细胞增殖率。BALB/c裸鼠皮下注射融合细胞检测融合细胞成瘤率。
结果：脐带血可分离并培养出CB-MSCs、其第一代形态为圆形及梭形,传代后为纺锤形及多角形且贴壁能力增强、具有很强的自我更新能力,本实验观察其可在体外传至25代。通过流式细胞技术分析CB-MSCs细胞表面免疫表型特征为：SH2(CD105)、SH4(CD73)、HLA-ABC强阳性,CD90弱阳性,、HLA-DR、CD45、CD34阴性。CB-MSCs及GES-1细胞经聚乙二醇体外融合后可通过流式细胞仪分选融合细胞、其融合率为8.7%。融合细胞形态不规则且可见巨大融合细胞,两周后细胞开始增殖、生长迅速且可稳定传代。免疫荧光检测CK-18显示融合细胞胞浆高表达CK-18,且形态发生改变,细胞核增大,胞浆减少,呈现恶性肿瘤细胞特性。流式检测显示融合细胞表达CD90,而DNA倍体分析结果示融合细胞为多倍体及非整倍体细胞且随细胞代数的增长、非整倍体细胞所占比例增加。MTT结果显示融合细胞增殖活性较GES-1明显增强,并获得向基质胶侵袭的能力且其迁移与侵袭能力均有所增强。裸鼠皮下成瘤实验显示融合细胞可形成带有腺体结构的上皮源性肿物。
结论：成功分离并培养出脐带血间充质干细胞,且通过PEG体外与GES-1融合后通过流式细胞成功分选出融合细胞。细胞融合后形态及表型均发生改变,细胞形态呈典型肿瘤细胞且兼具GES-1及MSCs二者的表型、即胞浆表达CK-18且其表面抗原CD90阳性。融合细胞增殖活性较GES-1明显增强,并获得向基质胶侵袭的能力且其迁移与侵袭能力均有所增强。融合细胞与GES-1及MSCs相比可形成皮下肿物。
Role of bone marrow derived stem cells fusion during the development and progression of gastric carcinoma was studied during this experiment. Chimeric mouse model was established through sex mismatch bone marrow transplantation by using female transgenic C57/BL-GFP mouse as donor and male C57/BL mouse as receiver. Then gastric carcinoma was induced by multiple carcinogens attack and cell fusion was assesed through Y chromosome fluorescence in situ hybridization (FISH). Mean while, gastric epithelial cells were isolated from mouse glandular stomach with collagenese digestion, and bone marrow derived stem cells were isolated from mouse bone marrow with MACS separation kit. Then cell fusion with polyethylene glycol (PEG) was performed between these cells. Cord blood mesenchymal stem cells (CB-MSCs) were also isolated and collected from our hospital and in vitro cell fusion was performed between these cells, and fusion cells were sorted with FACSVanture. Then morphology of the fusion cells was observed, and phenotypes of the cells were examined with immunohistochemistry (IHC) and flow cytometry (FCM). Then migration, invasion, and proliferation ability of the fusion cells were also assessed through cell scratch assay, transwell assay, and MTT cell proliferation assay.
Part I Establishment of Chimeric Mouse Model and Induction of Gastric Carcinoma
Objective Role of bone marrow derived stem cell in gastric carcinoma development and progression were still obscured, and through what mechanism it participated in this process was still under debate between transdiffertiation and cell fusion. In the present study, sex mismatch chimeric mouse was used to induce gastric carcinoma, and gastric sample was collected and examined for cancer induce rate and cell fusion, to investigate the role of bone marrow derived stem cells during the development and progression of gastric carcinoma.
Method Chimeric mouse model was established through sex mismatch bone marrow transplantation by using female transgenic C57/BL-GFP mouse as donor and male C57/BL mouse as receiver. Then bone marrow and peripheral blood were collected on week1and week4to examine by FCM, and frozen slide of different organs were also collected to study the distribution of GFP+cells in different organs. Chimeric mouse was then used to induce gastric cancer by multiple carcinogens attack, and stomach samples were collected for pathology study and Y chromosome FISH for examination of tumor induce rate and cell fusion.
Result All the mice underwent bone marrow transplplantation survived, and FCM results showed chimeric mouse bone marrow GFP+cells was7.48±1.38%and73.92±5.57%at week1and week4respectively. In the peripheral blood, only small portion of cells were GFP+on week1and recovery of CD8+cells was faster than that of the CD4+cells, while GFP+cells increased on week4but the amount of CD4+cells was still low.72.9%of chimeric mouse survived after multiple carcinogens attack. For those mice survive through carcinogens attack,18.2%of mice showed precancerous lesion and25.0%of mice were successfully induced with gastric cancer, with2adenocarcinoma and1squamous cell carcinoma. Great amount of GFP expression was detected for stomach sample with severe dysplasia or gastric cancer, and GFP expression was also detected in other different organs such as kidney, brain, liver, and spleen, but no GFP expression was detected in the heart. Great amount of GFP expression was detected for stomach sample with severe dysplasia, and most of the cells showed both GFP and Y-chromosome, which indicated that fusion had occurred (Figure3C). Great amount of GFP expression was also dectected in both adenocarcinoma and squamous cell carcinoma (Figure3D-E). Most of the cells in adenocarcinoma sample showed cells with Y-chromosome in the neucleus and these cells also expressed GFP in the cytoplasm, which indicated that cell fusion had occured. For squamous cell carcinoma, GFP expression was mainly detected in the interstitial or keartine perals, but no sign of fusion was detected. Normal chimeric mouse showed little GFP expression in the interstitial, but no fusion was detected. Great amount of GFP expression was detected for stomach sample with severe dysplasia, and most of the cells showed both GFP and Y-chromosome, which indicated that fusion had occurred.
Conclusion Sex mismatch chimeric mouse model was successfully established. Mouse gastric inflammation, severe dysplasia, and gastric cancer were successfully induced through multiple carcinogens attack. BMSCs involve in the renewal of vessel endothelial cells, and some of the cell participated through cell fusion. BMSCs participated in the renewal of gastric mucosa during gastric inflammation and dysplasia through cell fusion. When tumor occurred, fusion cell or BMSCs have become the main cells in tumor with little amount of fusion cells been detected.
Part Ⅱ Fusion of Mouse Bone Marrow Derived Stem Cells and Gastric Epithelial Cells
Objective Role of cell fusion during tumor development and progression was worth of attention, whereby it might enhance the metastasis ability of tumor cells or potentially be the source of cancer stem cell. In the present study, mouse gastric epithelial cells and mouse BMSCs were isolated and collected. Cells collected were used for in vitro cell fusion to investigate the possibility for BMSCs fusion to be the primary mechanism of neoplasia during the development and progression of gastric tumor.
Method Mouse gastric epithelial cells were isolated and collected with collagenese digestion, and phenotype of isolated cells was examined with IHC. Mouse BMSCs were isolated and collected with MACSs separation kit, and cells were examined with FCM. These cells were used for in vitro PEG cell fusion, and fusion rate were examined with FCM and fusion cells were sorted with FACSVantage.
Result Mouse gastric epithelial cells were successfully isolated with collagenese digestion. For each mouse,5.27±2.92×106cells were isolated from glandular stomach and cell viability was97.05±2.20%. Proliferation of mouse gastric epithelial cells reached climax on7d, and IHC examination showed that93.21±3.35%of cells expressed cytokeratine-18(CK-18).8.88±4.22×107cells were isolated from tibia and femur bone and cell viability was98.35±1.23%.1.36±1.03×106BMSCs (Lin-) cells were isolated from4.43±2.47×107marrow cells. Before MACS separation,76.21±4.89%of marrow cells were Lin+. After MACS separation,69.23±5.79%of marrow cells were Lin+and93.93±3.35%of marrow cells were Lin-. After staining with CFSE or PKH26, mouse gastric epithelial cells and marrow cells (Lin+or Lin-) expressed either green or red fluorescence, and co-culture of these cells showed no sign of cell fusion. After in vitro PEG cell fusion assay, fusion cells can be observed under fluorescence microscope and fusion rate was5.77±1.91%when examined with FCM. Fusion cells showed no proliferation after FCM sorting.
Conclusion Mouse gastric epithelial cells were successfully isolated with collagenese digestion, and proliferation reached climax at7d after isolation. Mouse were successfully isolated from mouse bone marrow with MACS. In vitro PEG cell fusion of these cells was successfully. Proliferation of fusion cells sorted with FCM was unsuccessful, which might be due to that both mouse gastric epithelial cells and BMSCs were of primary culture, therefore the daughter cells after cell fusion did not transformed or gain the phenotype of BMSCs to continuously proliferation. On the other hand, the low fusion rate decreased the chance for fusion cells to go through phenotype transformation or gaining the phenotype of mother cells.
Part III Fusion of Human Cord Blood Mesenchimal Stem Cells and Human Gastric Epithelial Cells
Objective Proliferation of fusion cell between mouse gastric epithelial cells and mouse BMSCs was unsccesful on our previous experiment. In the present study, immortalized human gastric mucosal epithelial cell line (GES-1) and cord bold mesenchymal stem cells (CB-MSCs) were used for in vitro PEG cell fusion to investigate the possibility of epithelial malignant transformation induced by cell fusion and to explore the origin of cancer stem cells.
Method GES-1cells were culture and CK-18expression was determined by IHC. CB-MSCs were isolated from cord blood collected in our hospital, and then the growth characteristics of was monitored. Mesenchymal stem cell-specific phenotype of Thy-1(CD90)、SH2(CD105)、SH4(CD73)、HLA-ABC、HLA-DR、 CD34、CD45were identified by flow cytometry. GES-1cells were labeled with PKH26and CB-MSCs were labeled with CFSE, and fusion of these cellswere induced with PEG. Fusion rate was then determined with FCM and double positive fusion cells were sorted. Then growth characteristics of fusion cells were monitored and CK-18expression was determined by IHC. Cell surface antigen CD90and DNA Ploidy Analysis of fusion cells were determined by FCM. Then migration, invasion, and proliferation ability of fusion cells were assessed by cell scratch test, twanswell assay, and MTT cell proliferative assay. Tumorigenicity of fusion cells were assessed through BALB/c nude mouse subcutaneous injection.
Result CB-MSCs were successfully isolated from cord blood, and the first generation of CB-MSCs obtained an oval or spindle shape. After passaging, cells became polygonal with strong adherent ability and self-renewal capacity, and CB-MSCs could be cultured for25passages in vitro. CB-MSCs showed no expression of hematopoietic marker CD34, CD45, HLA-DR, but expressed the typical MSC marker proteins SH2(CD105), SH4(CD73), HLA-ABC. However, the intensity of expression of CD90was significantly below that of other markers. In vitro cell fusion between CB-MSCs and GES-1was successfully performed, and fusion cells were sorted with FCM with fusion rate of8.7%. CK-18was highly expressed within the cytoplasm of fusion cells. Morphological changes of fusion cells included:greater heterogeneity in the size and shape of cells and nuclei, increased nuclear:cytoplasmic ratio as characteristics of malignant cells. GES-1did not express CD90while the fusion cells acquired the markers of CD90. DNA ploidy analysis showed that fusion cells consisted of polyploid and aneuploid cells and with the increase of passages the proportion of aneuploid cells increased. Proliferation, migration and invasion ability of the fusion cells were increased. Subcutaneous mass was observed after injection of fusion cells, and HE with IHC results showed mass with glandular structure of epithelial origin.
Conclusion CB-MSCs were isolated, collected, and successfully fused with GES-1under PEG stimulation. Fusion cells were morphological different from typical MSCs and GES-1cells, and showed characteristics of both parental cells, such as high expression of CK-18in plasma and is also obtained the surface antigen CD90. Proliferation, migration and invasion ability of the fusion cells were increased, indicating that fusion between MSCs and epithelial cells can result in enhance metastasis ability. Compare to GES-1and MSCs, fusion cells were able to form subcutaneous mass.
引文
[1]李玉林主编.病理学[M].北京：人民卫生出版社,2004.444.
[2]Parkin D M, Bray F, Ferlay J, et al. Global cancer statistics,2002[J]. CA Cancer J Clin,2005,55(2):74-108.
[3]Jemal A, Bray F, Center M M, et al. Global cancer statistics[J]. CA Cancer J Clin,2011,61(2):69-90.
[4]孙秀娣,牧人,周有尚,等.中国1990-1992年胃癌死亡调查分析[J].中华肿瘤杂志,2002,24(1)：4-8.
[5]Shimkin M B. The written word and cancer--some personal involvements, 1940-1977:autobiographical essay[J]. Cancer Res,1978,38(2):241-252.
[6]Wood L D, Parsons D W, Jones S, et al. The genomic landscapes of human breast and colorectal cancers[J]. Science,2007,318(5853):1108-1113.
[7]Sjoblom T, Jones S, Wood L D, et al. The consensus coding sequences of human breast and colorectal cancers[J]. Science,2006,314(5797):268-274.
[8]Duesberg P, Rasnick D. Aneuploidy, the somatic mutation that makes cancer a species of its own[J]. Cell Motil Cytoskeleton,2000,47(2):81-107.
[9]Loeb L A. A mutator phenotype in cancer[J]. Cancer Res,2001,61(8):3230-3239.
[10]Reya T, Morrison S J, Clarke M F, et al. Stem cells, cancer, and cancer stem cells[J]. Nature,2001,414(6859):105-111.
[11]Luebeck E G, Moolgavkar S H. Multistage carcinogenesis and the incidence of colorectal cancer[J]. Proc Natl Acad Sci U S A,2002,99(23):15095-15100.
[12]Serakinci N, Guldberg P, Burns J S, et al. Adult human mesenchymal stem cell as a target for neoplastic transformation[J]. Oncogene,2004,23(29):5095-5098.
[13]Marx J. Cancer research. Mutant stem cells may seed cancer[J]. Science,2003,301(5638):1308-1310.
[14]Rizvi A Z, Swain J R, Davies P S, et al. Bone marrow-derived cells fuse with normal and transformed intestinal stem cells[J]. Proc Natl Acad Sci U S A,2006,103(16):6321-6325.
[15]Houghton J, Stoicov C, Nomura S, et al. Gastric cancer originating from bone marrow-derived cells[J]. Science,2004,306(5701):1568-1571.
[16]王书奎,周振英主编.实用流式细胞术彩色图谱[M].上海：第二军医大学出版社,2004.
[17]张黎,王登山.微量元素Mn,Se对小鼠诱发性胃癌发生的影响[J].甘肃环境研究与监测,1991(2)：36-40.
[18]徐建国,包可杰.甲基胆葸诱发大,小鼠胃癌的实验观察[J].白求恩医科大学学报,1992,18(5)：466-467.
[19]Tatematsu M, Ogawa K, Hoshiya T, et al. Induction of adenocarcinomas in the glandular stomach of BALB/c mice treated with N-methyl-N-nitrosourea[J]. Jpn J Cancer Res,1992,83(9):915-918.
[20]Schauber J, Iffland K, Frisch S, et al. Histone-deacetylase inhibitors induce the cathelicidin LL-37 in gastrointestinal cells[J]. Mol Immunol,2004,41(9):847-854.
[21]Herzog E L, Chai L, Krause D S. Plasticity of marrow-derived stem cells[J]. Blood,2003,102(10):3483-3493.
[22]Barrilleaux B, Phinney D G, Prockop D J, et al. Review:ex vivo engineering of living tissues with adult stem cells[J]. Tissue Eng,2006,12(11):3007-3019.
[23]Mimeault M, Batra S K. Concise review:recent advances on the significance of stem cells in tissue regeneration and cancer therapies[J]. Stem Cells,2006,24(11):2319-2345.
[24]Mimeault M, Hauke R, Batra S K. Stem cells:a revolution in therapeutics-recent advances in stem cell biology and their therapeutic applications in regenerative medicine and cancer therapies[J]. Clin Pharmacol Ther,2007,82(3):252-264.
[25]Mimeault M, Batra S K. Recent progress on tissue-resident adult stem. cell biology and their therapeutic implications[J]. Stem Cell Rev,2008,4(1):27-49.
[26]Sell S. Adult stem cell plasticity:introduction to the first issue of stem cell reviews[J]. Stem Cell Rev,2005,1(1):1-7.
[27]Verstappen J, Katsaros C, Torensma R, et al. A functional model for adult stem cells in epithelial tissues[J]. Wound Repair Regen,2009,17(3):296-305.
[28]Walker M-R, Patel K K, Stappenbeck T S. The stem cell niche[J]. J Pathol,2009,217(2):169-180.
[29]Holden C, Vogel G. Stem cells. Plasticity:time for a reappraisal?[J]. Science,2002,296(5576):2126-2129.
[30]汪瑛,杨葳,郑志红,等.绿色荧光蛋白转基因小鼠模型的建立及胚胎冷冻保种[J].中国比较医学杂志,2007,17(8)：460-462.
[31]Karnoub A E, Dash A B, Vo A P, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis[J]. Nature,2007,449(7162):557-563.
[32]Gordon J W, Scangos G A, Plotkin D J, et al. Genetic transformation of mouse embryos by microinjection of purified DNA[J]. Proc Natl Acad Sci U S A,1980,77(12):7380-7384.
[33]Rakic P. Neurogenesis in adult primate neocortex:an evaluation of the evidence[J]. Nat Rev Neurosci,2002,3(1):65-71.
[34]Theise N D, Krause D S, Sharkis S. Comment on "Little evidence for developmental plasticity of adult hematopoietic stem cells"[J]. Science,2003,299(5611):1317,1317.
[35]Mezey E, Key S, Vogelsang G, et al. Transplanted bone marrow generates new neurons in human brains[J]. Proc Natl Acad Sci U S A,2003,100(3):1364-1369.
[36]Hu M, Krause D, Greaves M, et al. Multilineage gene expression precedes commitment in the hemopoietic system[J]. Genes Dev,1997,11(6):774-785.
[37]Billia F, Barbara M, Mcewen J, et al. Resolution of pluripotential intermediates in murine hematopoietic differentiation by global complementary DNA amplification from single cells:confirmation of assignments by expression profiling of cytokine receptor transcripts[J]. Blood,2001,97(8):2257-2268.
[38]Demura T, Tashiro G, Horiguchi G, et al. Visualization by comprehensive microarray analysis of gene expression programs during transdifferentiation of mesophyll cells into xylem cells[J]. Proc Natl Acad Sci U S A,2002,99(24):15794-15799.
[39]Stocum D L. Development. A tail of transdifferentiation[J]. Science,2002,298(5600):1901-1903.
[40]Shen C N, Horb M E, Slack J M, et al. Transdifferentiation of pancreas to liver[J]. Mech Dev,2003,120(1):107-116.
[41]Shen C N, Slack J M, Tosh D. Molecular basis of transdifferentiation of pancreas to liver[J]. Nat Cell Biol,2000,2(12):879-887.
[42]Tang D G, Tokumoto Y M, Apperly J A, et al. Lack of replicative senescence in cultured rat oligodendrocyte precursor cells[J]. Science,2001,291(5505):868-871.
[43]Hakelien A M, Landsverk H B, Robl J M, et al. Reprogramming fibroblasts to express T-cell functions using cell extracts[J]. Nat Biotechnol,2002,20(5):460-466.
[44]Hardeman E C, Chiu C P, Minty A, et al. The pattern of actin expression in human fibroblast x mouse muscle heterokaryons suggests that human muscle regulatory factors are produced[J]. Cell,1986,47(1):123-130.
[45]Ying Q L, Nichols J, Evans E P, et al. Changing potency by spontaneous fusion[J]. Nature,2002,416(6880):545-548.
[46]Terada N, Hamazaki T, Oka M, et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion[J]. Nature,2002,416(6880):542-545.
[47]Ferrand J, Noel D, Lehours P, et al. Human bone marrow-derived stem cells acquire epithelial characteristics through fusion with gastrointestinal epithelial cells[J]. PLoS One,2011,6(5):e19569.
[48]Bonde S, Pedram M, Stultz R, et al. Cell fusion of bone marrow cells and somatic cell reprogramming by embryonic stem cells[J]. FASEB J,2010,24(2):364-373.
[49]Labarge M A, Blau H M. Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury[J]. Cell,2002,111(4):589-601.
[50]Masuya M, Drake C J, Fleming P A, et al. Hematopoietic origin of glomerular mesangial cells[J]. Blood,2003,101(6):2215-2218.
[51]Blau H M. A twist of fate[J]. Nature,2002,419(6906):437.
[52]Blau H M, Blakely B T. Plasticity of cell fate:insights from heterokaryons[J]. Semin Cell Dev Biol,1999,10(3):267-272.
[53]Sugimura T, Fujimura S, Baba T. Tumor production in the glandular stomach and alimentary tract of the rat by N-methyl-N'-nitro-N-nitrosoguanidine[J]. Cancer Res,1970,30(2):455-465.
[54]Sugiyama A, Maruta F, Ikeno T, et al. Helicobacter pylori infection enhances N-methyl-N-nitrosourea-induced stomach carcinogenesis in the Mongolian gerbil[J]. Cancer Res,1998,58(10):2067-2069.
[55]周本杰,陈蔚文,王建华,等.硝酸结合MNNG攻击大鼠胃癌模型与评价[J]. 中国药理学通报,2001(1)：111-112.
[56]Sugiyama T, Hige S, Asaka M. Development of an H. pylori-infected animal model and gastric cancer:recent progress and issues[J]. J Gastroenterol,2002,37 Suppl 13:6-9.
[57]徐晶莹,李益民,李玉兰,等.MNNG诱导大鼠胃癌模型的建立[J].哈尔滨医科大学学报,2003,37(02).
[58]Tsukamoto T, Mizoshita T, Tatematsu M. Animal models of stomach carcinogenesis[J]. Toxicol Pathol,2007,35(5):636-648.
[59]许翼麟,何向辉,喻志革,等.小鼠胃癌模型的建立及T细胞免疫功能的变化[J].中华实验外科杂志,2010,27(04).
[60]Ianus A, Holz G G, Theise N D, et al. In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion[J]. J Clin Invest,2003,111(6):843-850.
[61]Harris R G, Herzog E L, Bruscia E M, et al. Lack of a fusion requirement for development of bone marrow-derived epithelia[J]. Science,2004,305(5680):90-93.
[62]Wang X, Willenbring H, Akkari Y, et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes[J]. Nature,2003,422(6934):897-901.
[63]Vassilopoulos G, Wang P R, Russell D W. Transplanted bone marrow regenerates liver by cell fusion[J]. Nature,2003,422(6934):901-904.
[64]Krause D S, Theise N D, Collector M I, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell[J]. Cell,2001,105(3):369-377.
[65]Jiang Y, Jahagirdar B N, Reinhardt R L, et al. Pluripotency of mesenchymal stem cells derived from adult marrow[J]. Nature,2002,418(6893):41-49.
[66]Korbling M, Katz R L, Khanna A, et al. Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells[J]. N Engl J Med,2002,346(10):738-746.
[67]Zhang S, Wang D, Estrov Z, et al. Both cell fusion and transdifferentiation account for the transformation of human peripheral blood CD-34-positive cells into cardiomyocytes in vivo[J]. Circulation,2004,110(25):3803-3807.
[68]Nygren J M, Jovinge S, Breitbach M, et al. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation[J]. Nat Med,2004,10(5):494-501.
[69]Murry C E, Soonpaa M H, Reinecke H, et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts[J]. Nature,2004,428(6983):664-668.
[70]Alvarez-Dolado M, Pardal R, Garcia-Verdugo J M, et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes.[J].Nature,2003,425(6961):968-973.
[71]Brittan M, Hunt T, Jeffery R, et al. Bone marrow derivation of pericryptal myofibroblasts in the mouse and human small intestine and colon[J]. Gut,2002,50(6):752-757.
[72]Okamoto R, Yajima T, Yamazaki M, et al. Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract[J]. Nat Med,2002,8(9):1011-1017.
[73]Davies P S, Powell A E, Swain J R, et al. Inflammation and proliferation act together to mediate intestinal cell fusion[J]. PLoS One,2009,4(8):e6530.
[74]Worthley D L, Ruszkiewicz A, Davies R, et al. Human gastrointestinal neoplasia-associated myofibroblasts can develop from bone marrow-derived cells following allogeneic stem cell transplantation[J]. Stem Cells,2009,27(6):1463-1468.
[75]Powell A E, Anderson E C, Davies P S, et al. Fusion between Intestinal epithelial cells and macrophages in a cancer context results in nuclear reprogramming[J]. Cancer Res,2011,71(4):1497-1505.
[76]Fukamachi H, Mizuno T, Takayama S. Epithelial-mesenchymal interactions in differentiation of stomach epithelium in fetal mice[J]. Anat Embryol (Berl),1979,157(2):151-160.
[77]Nowell P C. The clonal evolution of tumor cell populations[J]. Science,1976,194(4260):23-28.
[78]Grander D. How do mutated oncogenes and tumor suppressor genes cause cancer?[J]. Med Oncol,1998,15(1):20-26.
[79]Heppner G H, Miller F R. The cellular basis of tumor progression[J]. Int Rev Cytol,1998,177:1-56.
[80]Hanahan D, Weinberg R A. The hallmarks of cancer[J]. Cell,2000,100(1):57-70.
[81]李志芳,林庚金,蔡定芳.改良成人胃粘膜上皮细胞原代培养[J].胃肠病学,2000(1)：34-35.
[82]程永波,房殿春,郭立萍,等.一种简便的人正常胃黏膜上皮细胞原代培养方法[J].胃肠病学,2007,12(1)：31-35.
[83]Kinoshita Y, Hassan S, Nakata H, et al. Establishment of primary epithelial cell culture from elutriated rat gastric mucosal cell[J]. J Gastroenterol,1995,30(2):135-141.
[84]Chen M C, Lee A T, Soll A H. Mitogenic response of canine fundic epithelial cells in short-term culture to transforming growth factor alpha and insulinlike growth factor I[J]. J Clin Invest,1991,87(5):1716-1723.
[85]Karam S M, Alexander G, Farook V, et al. Characterization of the rabbit gastric epithelial lineage progenitors in short-term culture[J]. Cell Tissue Res,2001,306(1):65-74.
[86]Rhodes D, Revis D, Lacy E R. Extracellular matrix constituents affect superficial gastric epithelial cell adhesion[J]. J Gastroenterol Hepatol,1994,9 Suppl 1:S72-S77.
[87]Koike T, Yasugi S. In vitro analysis of mesenchymal influences on the differentiation of stomach epithelial cells of the chicken embryo[J]. Differentiation,1999,65(1):13-25.
[88]Fujiwara Y, Arakawa T, Fukuda T, et al. Role of extracellular matrix in attachment, migration, and repair of wounded rabbit cultured.gastric cells[J]. J Clin Gastroenterol,1995,21 Suppl 1:S125-S130.
[89]Wolf N S, Kone A, Priestley G V, et al. In vivo and in vitro characterization of long-term repopulating primitive hematopoietic cells isolated by sequential Hoechst 33342-rhodamine 123 FACS selection[J]. Exp Hematol,1993,21 (5):614-622.
[90]Krause D S, Ito T, Fackler M J, et al. Characterization of murine CD34, a marker for hematopoietic progenitor and stem cells[J]. Blood,1994,84(3):691-701.
[91]Fleming W H, Alpern E J, Uchida N, et al. Functional heterogeneity is associated with the cell cycle status of murine hematopoietic stem cells[J]. J Cell Biol,1993,122(4):897-902.
[92]Donnelly D S, Zelterman D, Sharkis S, et al. Functional activity of murine CD34+ and CD34- hematopoietic stem cell populations[J]. Exp Hematol, 999,27(5):788-796.
[93]Goodell M A, Rosenzweig M, Kim H, et al. Dye efflux, studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species[J]. Nat Med,1997,3(12):1337-1345.
[94]Scharenberg C W, Harkey M A, Torok-Storb B. The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors[J]. Blood,2002,99(2):507-512.
[95]Seale P, Asakura A, Rudnicki M A. The potential of muscle stem cells[J]. Dev Cell,2001,1(3):333-342.
[96]Mckinney-Freeman S L, Jackson K A, Camargo F D, et al. Muscle-derived hematopoietic stem cells are hematopoietic in origin[J]. Proc Natl Acad Sci U S A,2002,99(3):1341-1346.
[97]Kawada H, Ogawa M. Bone marrow origin of hematopoietic progenitors and stem cells in murine muscle[J]. Blood,2001,98(7):2008-2013.
[98]Majka S M, Jackson K A, Kienstra K A, et al. Distinct progenitor populations in skeletal muscle are bone marrow derived and exhibit different cell fates during vascular regeneration[J].J Clin Invest,2003,111(1):71-79.
[99]Lanzkron S M, Collector M I, Sharkis S J. Hematopoietic stem cell tracking in vivo:a comparison of short-term and long-term repopulating cells[J]. Blood,1999,93(6):1916-1921.
[100]Wagers A J, Weissman I L. Plasticity of adult stem cells.[J]. Cell,2004,116(5):639-648.
[101]Camargo F D, Chambers S M, Goodell M A. Stem cell plasticity:from transdifferentiation to macrophage fusion.[J]. Cell Prolif,2004,37(1):55-65.
[102]O'Malley K, Scott E W. Stem cell fusion confusion.[J]. Exp Hematol,2004,32(2):131-134.
[103]Pomerantz J, Blau H M. Nuclear reprogramming:a key to stem cell function in regenerative medicine.[J]. Nat Cell Biol,2004,6(9):810-816.
[104]Weimann J M, Johansson C B, Trejo A, et al. Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant.[J]. Nat Cell Biol,2003,5(11):959-966.
[105]Takagi Y, Takahashi J, Saiki H, et al. Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model[J]. J Clin Invest,2005,115(1):102-109.
[106]Shemer G, Podbilewicz B. The story of cell fusion:big lessons from little worms.[J].Bioessays,2003,25(7):672-682.
[107]Ogle B M, Cascalho M, Platt J L. Biological implications of cell fusion.[J]. Nat Rev Mol Cell Biol,2005,6(7):567-575.
[108]Aractingi S, Kanitakis J, Euvrard S, et al. Skin carcinoma arising from donor cells in a kidney transplant recipient.[J]. Cancer Res,2005,65(5):1755-1760.
[109]Wockel L, Ketelsen U P, Stotter M, et al. Abundant minute myotubes in a patient who later developed centronuclear myopathy[J]. Acta Neuropathol,1998,95(5):547-551.
[110]Redman C W, Sargent I L. Placental debris, oxidative stress and pre-eclampsia[J]. Placenta,2000,21(7):597-602.
[111]Miyamoto T, Suda T. Differentiation and function of osteoclasts.[J]. Keio J Med,2003,52(1):1-7.
[112]Bjerregaard B, Holck S, Christensen I J, et al. Syncytin is involved in breast cancer-endothelial cell fusions[J]. Cell Mol Life Sci,2006,63(16):1906-1911.
[113]Bjerkvig R, Tysnes B B, Aboody K S, et al. Opinion:the origin of the cancer stem cell:current controversies and new insights[J]. Nat Rev Cancer,2005,5(11):899-904.
[114]Farkas-Bargeton E, Barbet J P, Dancea S, et al. Immaturity of muscle fibers in the congenital form of myotonic dystrophy:its consequences and its origin[J]. J Neurol Sci,1988,83(2-3):145-159.
[115]Wongsurawat V J, Finley J C, Galipeau P C, et al. Genetic mechanisms of TP53 loss of heterozygosity in Barrett's esophagus:implications for biomarker validation[J]. Cancer Epidemiol Biomarkers Prev,2006,15(3):509-516.
[116]Barrett M T, Pritchard D, Palanca-Wessels C, et al. Molecular phenotype of spontaneously arising 4N (G2-tetraploid) intermediates of neoplastic progression in Barrett's esophagus[J]. Cancer Res,2003,63(14):4211-4217.
[117]Levine D S, Rabinovitch P S, Haggitt R C, et al. Distribution of aneuploid cell populations in ulcerative colitis with dysplasia or cancer[J]. Gastroenterology,1991,101 (5):1198-1210.
[118]Olaharski A J, Eastmond D A. Elevated levels of tetraploid cervical cells in human papillomavirus-positive Papanicolaou smears diagnosed as atypical squamous cells of undetermined significance[J]. Cancer,2004,102(3):192-199.
[119]Chen K A, Laywell E D, Marshall G, et al. Fusion of neural stem cells in culture[J]. Exp Neurol,2006,198(1):129-135.
[120]Roumier T, Valent A, Perfettini J L, et al. A cellular machine generating apoptosis-prone aneuploid cells[J]. Cell Death Differ,2005,12(1):91-93.
[121]Grace V M, Shalini J V, Lekha T T, et al. Co-overexpression of p53 and bcl-2 proteins in HPV-induced squamous cell carcinoma of the uterine cervix[J]. Gynecol Oncol,2003,91(1):51-58.
[122]Yilmaz Y, Lazova R, Qumsiyeh M, et al. Donor Y chromosome in renal carcinoma cells of a female BMT recipient:visualization of putative BMT-tumor hybrids by FISH[J]. Bone Marrow Transplant,2005,35(10):1021-1024.
[123]Chakraborty A, Lazova R, Davies S, et al. Donor DNA in a renal cell carcinoma metastasis from a bone marrow transplant recipient[J]. Bone Marrow Transplant,2004,34(2):183-186.
[124]Saikawa Y, Fukuda K, Takahashi T, et al. Gastric carcinogenesis and the cancer stem cell hypothesis[J]. Gastric Cancer,2010,13(1):11-24.
[125]Al-Hajj M, Clarke M F. Self-renewal and solid tumor stem cells.[J]. Oncogene,2004,23(43):7274-7282.
[126]Al-Hajj M, Wicha M S, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells[J]. Proc Natl Acad Sci U S A,2003,100(7):3983-3988.
[127]Singh S K, Clarke I D, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors[J]. Cancer Res,2003,63(18):5821-5828.
[128]Galli R, Binda E, Orfanelli U, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma[J]. Cancer Res,2004,64(19):7011-7021.
[129]Krause D S, Theise N D, Collector M I, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell[J]. Cell,2001,105(3):369-377.
[130]Peters B A, Diaz L A, Polyak K, et al. Contribution of bone marrow-derived endothelial cells to human tumor vasculature[J]. Nat Med,2005,11(3):261-262.
[131]Ding D C, Shyu W C, Chiang M F, et al. Enhancement of neuroplasticity through upregulation of betal-integrin in human umbilical cord-derived stromal cell implanted stroke model[J]. Neurobiol Dis,2007,27(3):339-353.
[132]申艳,虞容豪,黄怀,等.脐带间充质干细胞移植治疗持续性植物状态患者的护理[J].护理学报,2009,16(09).
[133]Baksh D, Song L, Tuan R S. Adult mesenchymal stem cells:characterization, differentiation, and application in cell and gene therapy[J]. J Cell Mol Med,2004,8(3):301-316.
[134]Mankani M H, Kuznetsov S A, Shannon B, et al. Canine cranial reconstruction using autologous bone marrow stromal cells[J]. Am J Pathol,2006,168(2):542-550.
[135]杨立业,刘相名,惠国桢,等.丹参诱导鼠骨髓间充质细胞向神经元分化[J].中华神经外科疾病研究杂志,2003,2(01).
[136]Li C, Zhang W, Jiang X, et al. Human-placenta-derived mesenchymal stem cells inhibit proliferation and function of allogeneic immune cells[J]. Cell Tissue Res,2007,330(3):437-446.
[137]Tian Y, Deng Y B, Huang Y J, et al. Bone marrow-derived mesenchymal stem cells decrease acute graft-versus-host disease after allogeneic hematopoietic stem cells transplantation[J]. Immunol Invest,2008,37(1):29-42.
[138]柯杨,宁涛,王冰,等.人胃粘膜上皮细胞系GES—1的建立及其生物学特性[J].中华肿瘤杂志,1994(1)：7-10.
[139]Friedenstein A J, Deriglasova U F, Kulagina N N, et al. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method[J]. Exp Hematol,1974,2(2):83-92.
[140]Friedenstein A J, Gorskaja J F, Kulagina N N. Fibroblast precursors in normal and irradiated mouse hematopoietic organs[J]. Exp Hematol,1976,4(5):267-274.
[141]Erices A, Conget P, Minguell J J. Mesenchymal progenitor cells in human umbilical cord blood[J]. Br J Haematol,2000,109(1):235-242.
[142]Romanov Y A, Svintsitskaya V A, Smirnov V N. Searching for alternative sources of postnatal human mesenchymal stem cells:candidate MSC-like cells from umbilical cord[J]. Stem Cells.2003,21(1):105-110.
[143]Fukuchi Y, Nakajima H, Sugiyama D, et al. Human placenta-derived cells have mesenchymal stem/progenitor cell potential[J]. Stem Cells,2004,22(5):649-658.
[144]Pittenger M F, Mackay A M, Beck S C, et al. Multilineage potential of adult human mesenchymal stem cells[J]. Science,1999,284(5411):143-147.
[145]Burdzinska A, Gala K, Paczek L. Myogenic stem cells[J]. Folia Histochem Cytobiol,2008,46(4):401-412.
[146]Taha M F, Hedayati V. Isolation, identification and multipotential differentiation of mouse adipose tissue-derived stem cells[J]. Tissue Cell,2010,42(4):211-216.
[147]Zeddou M, Briquet A, Relic B, et al. The umbilical cord matrix is a better source of mesenchymal stem cells (MSC) than the umbilical cord blood[J]. Cell Biol Int,2010,34(7):693-701.
[148]Laitinen A, Nystedt J, Laitinen S. The isolation and culture of human cord blood-derived mesenchymal stem cells under low oxygen conditions[J]. Methods Mol Biol,2011,698:63-73.
[149]Zvaifler N J, Marinova-Mutafchieva L, Adams G, et al. Mesenchymal precursor cells in the blood of normal individuals[J]. Arthritis Res,2000,2(6):477-488.
[150]Sapir A, Avinoam O, Podbilewicz B, et al. Viral and developmental cell fusion mechanisms:conservation and divergence.[J]. Dev Cell,2008,14(1):11-21.
[151]Chen E H, Olson E N. Unveiling the mechanisms of cell-cell fusion.[J]. Science,2005,308(5720):369-373.
[152]Vignery A. Macrophage fusion:the making of osteoclasts and giant cells.[J]. J Exp Med,2005,202(3):337-340.
[153]Vignery A. Macrophage fusion:are somatic and cancer cells possible partners?[J]. Trends Cell Biol,2005,15(4):188-193.
[154]Chen E H, Grote E, Mohler W, et al. Cell-cell fusion.[J]. FEBS Lett,2007,581(11):2181-2193.
[155]Davidson R L, Ephrussi B, Yamamoto K. Regulation of pigment synthesis in mammalian cells, as studied by somatic hybridization[J]. Proc Natl Acad Sci U S A,1966,56(5):1437-1440.
[156]Harris H. The analysis of malignancy by cell fusion:the position in 1988[J]. Cancer Res,1988,48(12):3302-3306.
[157]Sabin A B. Suppression of malignancy in human cancer cells:issues and challenges[J]. Proc Natl Acad Sci U S A,1981,78(11):7129-7133.
[158]Lu X, Kang Y. Cell fusion as a hidden force in tumor progression[J]. Cancer Res,2009,69(22):8536-8539.
[159]Pawelek J M, Chakraborty A K. Fusion of tumour cells with bone marrow-derived cells:a unifying explanation for metastasis. [J]. Nat Rev Cancer,2008,8(5):377-386.
[160]Duelli D, Lazebnik Y. Cell fusion:a hidden enemy? [J]. Cancer Cell,2003,3(5):445-448.
[161]Powers T P, Davidson R L. Coordinate extinction of melanocyte-specific gene expression in hybrid cells[J]. Somat Cell Mol Genet,1996,22(1):41-56.
[162]Powers T P, Shows T B, Davidson R L. Pigment-cell-specific genes from fibroblasts are transactivated after chromosomal transfer into melanoma cells[J]. Mol Cell Biol,1994,14(2):1179-1190.
[163]Makino S. The role of tumor stem-cells in regrowth of the tumor following drastic applications[J]. Acta Unio Int Contra Cancrum,1959,15(Suppl 1):196-198.
[164]Bruce W R, VAN DER Gaag H. A QUANTITATIVE ASSAY FOR THE NUMBER OF MURINE LYMPHOMA CELLS CAPABLE OF PROLIFERATION IN VIVO[J]. Nature,1963,199:79-80.
[165]Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice[J]. Nature,1994,367(6464):645-648.
[166]Bonnet D, Dick J E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell[J]. Nat Med,1997,3(7):730-737.
[167]Welte Y, Adjaye J, Lehrach H R, et al. Cancer stem cells in solid tumors: elusive or illusive?[J]. Cell Commun Signal,2010,8(1):6.
[168]Matsui W, Huff C A, Wang Q, et al. Characterization of clonogenic multiple myeloma cells[J]. Blood,2004,103(6):2332-2336.
[169]Xiao L, Yuan X, Sharkis S J. Activin A maintains self-renewal and regulates fibroblast growth factor, Wnt, and bone morphogenic protein pathways in human embryonic stem cells[J]. Stem Cells,2006,24(6):1476-1486.
[170]Alexson T O, Hitoshi S, Coles B L, et al. Notch signaling is required to maintain all neural stem cell populations--irrespective of spatial or temporal niche[J]. Dev Neurosci,2006,28(1-2):34-48.
[171]Fang D, Nguyen T K, Leishear K, et al. A tumorigenic subpopulation with stem cell properties in melanomas[J]. Cancer Res,2005,65(20):9328-9337.
[172]Matsumura H, Tada T. Cell fusion-mediated nuclear reprogramming of somatic cells[J]. Reprod Biomed Online,2008,16(1):51-56.
[173]Hanahan D, Weinberg R A. Hallmarks of cancer:the next generation[J]. Cell,2011,144(5):646-674.
[174]Hanahan D, Weinberg R A. The hallmarks of cancer[J]. Cell,2000,100(1):57-70.
[175]Bissell M J, Radisky D. Putting tumours in context[J]. Nat Rev Cancer,2001,1(1):46-54.
[176]Bissell M J, Labarge M A. Context, tissue plasticity, and cancer:are tumor stem cells also regulated by the microenvironment?[J]. Cancer Cell,2005,7(1):17-23.
[177]Bhowmick N A, Neilson E G, Moses H L. Stromal fibroblasts in cancer initiation and progression[J]. Nature,2004,432(7015):332-337.
[178]Mcallister S S, Gifford A M, Greiner A L, et al. Systemic endocrine instigation of indolent tumor growth requires osteopontin[J]. Cell,2008,133(6):994-1005.
[179]Yu J, Vodyanik M A, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells[J]. Science,2007,318(5858):1917-1920.
[180]Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors[J]. Cell,2007,131(5):861-872.
[181]Hugo H, Ackland M L, Blick T, et al. Epithelial--mesenchymal and mesenchymal--epithelial transitions in carcinoma progression[J]. J Cell Physiol,2007,213(2):374-383.
[182]Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression:an alliance against the epithelial phenotype?[J]. Nat Rev Cancer,2007,7(6):415-428.
[183]Gupta P B, Mani S, Yang J, et al. The evolving portrait of cancer metastasis[J]. Cold Spring Harb Symp Quant Biol,2005,70:291-297.
[184]Yang J, Mani S A, Weinberg R A. Exploring a new twist on tumor metastasis[J]. Cancer Res,2006,66(9):4549-4552.
[185]Thiery J P, Acloque H, Huang R Y, et al. Epithelial-mesenchymal transitions in development and disease[J]. Cell,2009,139(5):871-890.
[186]Yilmaz M, Christofori G. EMT, the cytoskeleton, and cancer cell invasion[J]. Cancer Metastasis Rev,2009,28(1-2):15-33.
[187]Yang J, Weinberg R A. Epithelial-mesenchymal transition:at the crossroads of development and tumor metastasis[J]. Dev Cell,2008,14(6):818-829.
[188]Kang Y, Massague J. Epithelial-mesenchymal transitions:twist in development and metastasis[J]. Cell,2004,118(3):277-279.
[189]Hendrix M J, Seftor R E, Seftor E A, et al. Transendothelial function of human metastatic melanoma cells:role of the microenvironment in cell-fate determination[J]. Cancer Res,2002,62(3):665-668.
[190]Hess A R, Margaryan N V, Seftor E A, et al. Deciphering the signaling events that promote melanoma tumor cell vasculogenic mimicry and their link to embryonic vasculogenesis:role of the Eph receptors[J]. Dev Dyn,2007,236(12):3283-3296.
[191]Sipos F, Galamb O. Epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions in the colon[J]. World J Gastroenterol,2012,18(7):601-608.
[192]Tellez C S, Juri D E, Do K, et al. EMT and stem cell-like properties associated with miR-205 and miR-200 epigenetic silencing are early manifestations during carcinogen-induced transformation of human lung epithelial cells[J]. Cancer Res,2011,71(8):3087-3097.
[193]Singh A, Settleman J. EMT, cancer stem cells and drug resistance:an emerging axis of evil in the war on cancer[J]. Oncogene,2010,29(34):4741-4751.
[194]Kalluri R, Weinberg R A. The basics of epithelial-mesenchymal transition[J]. J Clin Invest,2009,119(6):1420-1428.
[195]Acloque H, Adams M S, Fishwick K, et al. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease[J]. J Clin Invest,2009,119(6):1438-1449.
[196]Haslehurst A M, Koti M, Dharsee M, et al. EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer[J]. BMC Cancer,2012,12(1):91.
[197]Liu Y, Liu B A. Enhanced proliferation, invasion, and epithelial-mesenchymal transition of nicotine-promoted gastric cancer by periostin[J]. World J Gastroenterol,2011,17(21):2674-2680.
[198]Barriere G, Riouallon A, Renaudie J, et al. Mesenchymal and sternness circulating tumor cells in early breast cancer diagnosis[J]. BMC Cancer,2012,12(1):114.
[199]Ozel C, Seidel J, Meyer-Staeckling S, et al. Hybrid cells derived from breast epithelial cell/ breast cancer cell fusion events show a differential RAF-AKT crosstalk[J]. Cell Commun Signal,2012,10(1):10.
[200]Ohta H, Aoyagi K, Fukaya M, et al. Cross talk between hedgehog and epithelial-mesenchymal transition pathways in gastric pit cells and in diffuse-type gastric cancers[J]. Br J Cancer,2009,100(2):389-398.
[201]Lee J, Kim J C, Lee S E, et al. STAT3 (Signal Transducer and Activator of Transcription 3) suppresses adenoma to carcinoma transition In Apcmin/+ mice via regulation of SNAI (Snail-1) stability[J]. J Biol Chem,2012.
[202]Yoon C H, Kim M J, Lee H, et al. PTTG1 promotes tumor malignancy via epithelial to mesenchymal transition and expansion of cancer stem cell population[J]. J Biol Chem,2012.
[203]Nam S, Park T. Pathway-Based Evaluation in Early Onset Colorectal Cancer Suggests Focal Adhesion and Immunosuppression along with Epithelial-Mesenchymal Transition[J]. PLoS One,2012,7(3):e31685.
[204]Momin E N, Vela G, Zaidi H A, et al. The Oncogenic Potential of Mesenchymal Stem Cells in the Treatment of Cancer:Directions for Future Research[J]. Curr Immunol Rev,2010,6(2):137-148.
[205]Lazennec G, Jorgensen C. Concise review:adult multipotent stromal cells and cancer:risk or benefit?[J]. Stem Cells,2008,26(6):1387-1394.
[206]Teicher B A, Bagley R G. Stem cells and cancer[M]. Totowa, N.J.:Humana,2009.334.
[207]Correa P, Houghton J. Carcinogenesis of Helicobacter pylori[J]. Gastroenterology,2007,133(2):659-672.
[208]Sarosi G, Brown G, Jaiswal K, et al. Bone marrow progenitor cells contribute to esophageal regeneration and metaplasia in a rat model of Barrett's esophagus[J]. Dis Esophagus,2008,21(1):43-50.
[209]Hayashi Y, Tsuji S, Tsujii M, et al. Topical transplantation of mesenchymal stem cells accelerates gastric ulcer healing in rats[J]. Am J Physiol Gastrointest Liver Physiol,2008,294(3):G778-G786.
[210]Kahler C M, Wechselberger J, Hilbe W, et al. Peripheral infusion of rat bone marrow derived endothelial progenitor cells leads to homing in acute lung injury[J]. Respir Res,2007,8:50.
[211]Serikov V B, Popov B, Mikhailov V M, et al. Evidence of temporary airway epithelial repopulation and rare clonal formation by BM-derived cells following naphthalene injury in mice[J]. Anat Rec (Hoboken),2007,290(9):1033-1045.
[212]Suzuki M, Mchugh J, Tork C, et al. Direct muscle delivery of GDNF with human mesenchymal stem cells improves motor neuron survival and function in a rat model of familial ALS[J]. Mol Ther,2008,16(12):2002-2010.
[213]Ruan K, Bao S, Ouyang G. The multifaceted role of periostin in tumorigenesis[J]. Cell Mol Life Sci,2009,66(14):2219-2230.
[214]Ruan K, Song G, Ouyang G. Role of hypoxia in the hallmarks of human cancer[J]. J Cell Biochem,2009,107(6):1053-1062.
[215]Ouyang G, Wang Z, Fang X, et al. Molecular signaling of the epithelial to mesenchymal transition in generating and maintaining cancer stem cells [J]. Cell Mol Life Sci,2010,67(15):2605-2618.
[216]Taube J H, Herschkowitz J I, Komurov K, et al. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes[J]. Proc Natl Acad Sci U S A,2010,107(35):15449-15454.
[217]Mani S A, Guo W, Liao M J, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells[J]. Cell,2008,133(4):704-715.
[218]Mccoy E L, Iwanaga R, Jedlicka P, et al. Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition[J]. J Clin Invest,2009,119(9):2663-2677.
[219]Morel A P, Lievre M, Thomas C, et al. Generation of breast cancer stem cells through epithelial-mesenchymal transition[J]. PLoS One,2008,3(8):e2888.
[220]Iliopoulos D, Polytarchou C, Hatziapostolou M, et al. MicroRNAs differentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells[J]. Sci Signal,2009,2(92):a62.
[221]Evdokimova V, Tognon C, Ng T, et al. Translational activation of snaill and other developmentally regulated transcription factors by YB-1 promotes an epithelial-mesenchymal transition[J]. Cancer Cell,2009,15(5):402-415.
[222]Polyak K, Weinberg R A. Transitions between epithelial and mesenchymal states:acquisition of malignant and stem cell traits[J]. Nat Rev Cancer,2009,9(4):265-273.
[223]Wellner U, Schubert J, Burk U C, et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs[J]. Nat Cell Biol,2009,11(12):1487-1495.
[224]Yu M, Smolen G A, Zhang J, et al. A developmentally regulated inducer of EMT, LBX1,contributes to breast cancer progression[J]. Genes Dev,2009,23(15):1737-1742.
[225]Gupta P B, Chaffer C L, Weinberg R A. Cancer stem cells:mirage or reality?[J]. Nat Med,2009,15(9):1010-1012.
[226]Gupta P B, Onder T T, Jiang G, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening[J]. Cell,2009,138(4):645-659.
[227]Lu X, Kang Y. Efficient acquisition of dual metastasis organotropism to bone and lung through stable spontaneous fusion between MDA-MB-231 variants[J]. Proc Natl Acad Sci U S A,2009,106(23):9385-9390.
[1]李玉林主编.病理学[M].北京：人民卫生出版社,2004.444.
[2]Shimkin M B. The written word and cancer--some personal involvements, 1940-1977:autobiographical essay[J]. Cancer Res,1978,38(2):241-252.
[3]Wood L D, Parsons D W, Jones S, et al. The genomic landscapes of human breast and colorectal cancers[J]. Science,2007,318(5853):1108-1113.
[4]Sjoblom T, Jones S, Wood L D, et al. The consensus coding sequences of human breast and colorectal cancers[J]. Science,2006,314(5797):268-274.
[5]Duesberg P, Rasnick D. Aneuploidy, the somatic mutation that makes cancer a species of its own[J]. Cell Motil Cytoskeleton,2000,47(2):81-107.
[6]Loeb L A. A mutator phenotype in cancer[J]. Cancer Res,2001,61(8):3230-3239.
[7]Reya T, Morrison S J, Clarke M F, et al. Stem cells, cancer, and cancer stem cells[J].Nature,2001,414(6859):105-111.
[8]Barrilleaux B, Phinney D G, Prockop D J, et al. Review:ex vivo engineering of living tissues with adult stem cells[J]. Tissue Eng,2006,12(11):3007-3019.
[9]Mimeault M, Batra S K. Concise review:recent advances on the significance of stem cells in tissue regeneration and cancer therapies[J]. Stem Cells,2006,24(11):2319-2345.
[10]Mimeault M, Batra S K. Recent progress on tissue-resident adult stem cell biology and their therapeutic implications[J]. Stem Cell Rev,2008,4(1):27-49.
[11]Mimeault M, Hauke R, Batra S K. Stem cells:a revolution in therapeutics-recent advances in stem cell biology and their therapeutic applications in regenerative medicine and cancer therapies[J]. Clin Pharmacol Ther,2007,82(3):252-264.
[12]Sell S. Adult stem cell plasticity:introduction to the first issue of stem cell reviews[J]. Stem Cell Rev,2005,1(1):1-7.
[13]Verstappen J, Katsaros C, Torensma R, et al. A functional model for adult stem cells in epithelial tissues[J]. Wound Repair Regen,2009,17(3):296-305.
[14]Walker M R, Patel K K, Stappenbeck T S. The stem cell niche[J]. J Pathol,2009,217(2):169-180.
[15]Herzog E L, Chai L, Krause D S. Plasticity of marrow-derived stem cells[J]. Blood,2003,102(10):3483-3493.
[16]Holden C, Vogel G. Stem cells. Plasticity:time for a reappraisal?[J]. Science,2002,296(5576):2126-2129.
[17]Wolf N S, Kone A, Priestley G V, et al. In vivo and in vitro characterization of long-term repopulating primitive hematopoietic cells isolated by sequential Hoechst 33342-rhodamine 123 FACS selection[J]. Exp Hematol,1993,21(5):614-622.
[18]Krause D S, Ito T, Fackler M J, et al. Characterization of murine CD34, a marker for hematopoietic progenitor and stem cells[J]. Blood,1994,84(3):691-701.
[19]Fleming W H, Alpern E J, Uchida N, et al. Functional heterogeneity is associated with the cell cycle status of murine hematopoietic stem cells[J]. J Cell Biol,1993,122(4):897-902.
[20]Donnelly D S, Zelterman D, Sharkis S, et al. Functional activity of murine CD34+ and CD34- hematopoietic stem cell populations[J]. Exp Hematol,1999,27(5):788-796.
[21]Goodell M A, Rosenzweig M, Kim H, et al. Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species[J]. Nat Med,1997,3(12):1337-1345.
[22]Scharenberg C W, Harkey M A, Torok-Storb B. The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors[J]. Blood,2002,99(2):507-512.
[23]Seale P, Asakura A, Rudnicki M A. The potential of muscle stem cells[J]. Dev Cell,2001,1(3):333-342.
[24]Mckinney-Freeman S L, Jackson K A, Camargo F D, et al. Muscle-derived hematopoietic stem cells are hematopoietic in origin[J]. Proc Natl Acad Sci U S A,2002,99(3):1341-1346.
[25]Kawada H, Ogawa M. Bone marrow origin of hematopoietic progenitors and stem cells in murine muscle[J]. Blood,2001,98(7):2008-2013.
[26]Majka S M, Jackson K A, Kienstra K A, et al. Distinct progenitor populations in skeletal muscle are bone marrow derived and exhibit different cell fates during vascular regeneration[J]. J Clin Invest,2003,111(1):71-79.
[27]Lanzkron S M, Collector M I, Sharkis S J. Hematopoietic stem cell tracking in vivo:a comparison of short-term and long-term repopulating cells[J]. Blood,1999,93(6):1916-1921.
[28]Krause D S, Theise N D, Collector M I, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell[J]. Cell,2001,105(3):369-377.
[29]Simmons P J, Gronthos S, Zannettino A, et al. Isolation, characterization and functional activity of human marrow stromal progenitors in hemopoiesis[J]. Prog Clin Biol Res,1994,389:271-280.
[30]Simmons P J, Torok-Storb B. Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1[J]. Blood,1991,78(1):55-62.
[31]Gronthos S, Zannettino A C, Hay S J, et al. Molecular and cellular characterisation of highly purified stromal stem cells derived from human bone marrow[J]. J Cell Sci,2003,116(Pt 9):1827-1835.
[32]Pittenger M F, Mackay A M, Beck S C, et al. Multilineage potential of adult human mesenchymal stem cells[J]. Science,1999,284(5411):143-147.
[33]Azizi S A, Stokes D, Augelli B J, et al. Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats--similarities to astrocyte grafts[J]. Proc Natl Acad Sci U S A,1998,95(7):3908-3913.
[34]Jiang Y, Vaessen B, Lenvik T, et al. Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain[J]. Exp Hematol,2002,30(8):896-904.
[35]Jiang Y, Jahagirdar B N, Reinhardt R L, et al. Pluripotency of mesenchymal stem cells derived from adult marrow[J]. Nature,2002,418(6893):41-49.
[36]Morrison S J, Prowse K R, Ho P, et al. Telomerase activity in hematopoietic cells is associated with self-renewal potential[J]. Immunity,1996,5(3):207-216.
[37]Rakic P. Neurogenesis in adult primate neocortex:an evaluation of the evidence[J]. Nat Rev Neurosci,2002,3(1):65-71.
[38]Harris R G, Herzog E L, Bruscia E M, et al. Lack of a fusion requirement for development of bone marrow-derived epithelia[J]. Science,2004,305(5680):90-93.
[39]Theise N D, Krause D S, Sharkis S. Comment on "Little evidence for developmental plasticity of adult hematopoietic stem cells"[J]. Science,2003,299(5611):1317,1317.
[40]Mezey E, Key S, Vogelsang G, et al. Transplanted bone marrow generates new neurons in human brains[J]. Proc Natl Acad Sci U S A,2003,100(3):1364-1369.
[41]Hu M, Krause D, Greaves M, et al. Multilineage gene expression precedes commitment in the hemopoietic system[J]. Genes Dev,1997,11(6):774-785.
[42]Billia F, Barbara M, Mcewen J, et al. Resolution of pluripotential intermediates in murine hematopoietic differentiation by global complementary DNA amplification from single cells:confirmation of assignments by expression profiling of cytokine receptor transcripts[J]. Blood,2001,97(8):2257-2268.
[43]Petersen B E, Bowen W C, Patrene K D, et al. Bone marrow as a potential source of hepatic oval cells[J]. Science,1999,284(5417):1168-1170.
[44]Theise N D, Badve S, Saxena R, et al. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation[J]. Hepatology,2000,31 (1):235-240.
[45]Alison M R, Poulsom R, Jeffery R, et al. Hepatocytes from non-hepatic adult stem cells[J]. Nature,2000,406(6793):257.
[46]Theise N D, Nimmakayalu M, Gardner R, et al. Liver from bone marrow in humans[J].Hepatology,2000,32(1):11-16.
[47]Austin T W, Lagasse E. Hepatic regeneration from hematopoietic stem cells[J]. Mech Dev,2003,120(1):131-135.
[48]Evarts R P, Nagy P, Nakatsukasa H, et al. In vivo differentiation of rat liver oval cells into hepatocytes[J]. Cancer Res,1989,49(6):1541-1547.
[49]Lagasse E, Connors H, Al-Dhalimy M, et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo[J]. Nat Med,2000,6(11):1229-1234.
[50]Wang X, Willenbring H, Akkari Y, et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes[J]. Nature,2003,422(6934):897-901.
[51]Jorquera R, Tanguay R M. Fumarylacetoacetate, the metabolite accumulating in hereditary tyrosinemia, activates the ERK pathway and induces mitotic abnormalities and genomic instability[J]. Hum Mol Genet,2001,10(17):1741-1752.
[52]Jang Y Y, Collector M I, Baylin S B, et al. Hematopoietic stem cells convert into liver cells within days without fusion[J]. Nat Cell Biol,2004,6(6):532-539.
[53]Korbling M, Katz R L, Khanna A, et al. Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells[J]. N Engl J Med,2002,346(10):738-746.
[54]Dalakas E, Newsome P N, Boyle S, et al. Bone marrow stem cells contribute to alcohol liver fibrosis in humans[J]. Stem Cells Dev,2010,19(9):1417-1425.
[55]Srour E F, Jetmore A, Wolber F M, et al. Homing, cell cycle kinetics and fate of transplanted hematopoietic stem cells[J]. Leukemia,2001,15(11):1681-1684.
[56]Heissig B, Hattori K, Dias S, et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand[J]. Cell,2002,109(5):625-637.
[57]Wright D E, Bowman E P, Wagers A J, et al. Hematopoietic stem cells are uniquely selective in their migratory response to chemokines[J]. J Exp Med,2002,195(9):1145-1154.
[58]Hatch H M, Zheng D, Jorgensen M L, et al. SDF-1alpha/CXCR4:a mechanism for hepatic oval cell activation and bone marrow stem cell recruitment to the injured liver of rats[J]. Cloning Stem Cells,2002,4(4):339-351.
[59]Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium[J].Nature,2001,410(6829):701-705.
[60]Orlic D, Kajstura J, Chimenti S, et al. Mobilized bone marrow cells repair the infarcted heart, improving function and survival[J]. Proc Natl Acad Sci U S A,2001,98(18):10344-10349.
[61]Quaini F, Urbanek K, Beltrami A P, et al. Chimerism of the transplanted heart[J]. N Engl J Med,2002,346(1):5-15.
[62]Thiele J, Varus E, Wickenhauser C, et al. Regeneration of heart muscle tissue: quantification of chimeric cardiomyocytes and endothelial cells following transplantation[J]. Histol Histopathol,2004,19(1):201-209.
[63]Tse H F, Kwong Y L, Chan J K, et al. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation[J]. Lancet,2003,361(9351):47-49.
[64]Stamm C, Westphal B, Kleine H D, et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration[J]. Lancet,2003,361(9351):45-46.
[65]Rota M, Kajstura J, Hosoda T, et al. Bone marrow cells adopt the cardiomyogenic fate in vivo[J]. Proc Natl Acad Sci U S A,2007,104(45):17783-17788.
[66]Assmus B, Fischer-Rasokat U, Honold J, et al. Transcoronary transplantation of functionally competent BMCs is associated with a decrease in natriuretic peptide serum levels and improved survival of patients with chronic postinfarction heart failure:results of the TOPCARE-CHD Registry[J]. Circ Res,2007,100(8):1234-1241.
[67]Schachinger V, Tonn T, Dimmeler S, et al. Bone-marrow-derived progenitor cell therapy in need of proof of concept:design of the REP AIR-AMI trial[J]. Nat Clin Pract Cardiovasc Med,2006,3 Suppl 1:S23-S28.
[68]Abdel-Latif A, Bolli R, Tleyjeh I M, et al. Adult bone marrow-derived cells for cardiac repair:a systematic review and meta-analysis[J]. Arch Intern Med,2007,167(10):989-997.
[69]Martin-Rendon E, Brunskill S J, Hyde C J, et al. Autologous bone marrow stem cells to treat acute myocardial infarction:a systematic review[J]. Eur Heart J,2008,29(15):1807-1818.
[70]Gersh B J, Simari R D, Behfar A, et al. Cardiac cell repair therapy:a clinical perspective[J]. Mayo Clin Proc,2009,84(10):876-892.
[71]Leri A, Kajstura J, Anversa P. Cardiac stem cells and mechanisms of myocardial regeneration[J]. Physiol Rev,2005,85(4):1373-1416.
[72]Bearzi C, Rota M, Hosoda T, et al. Human cardiac stem cells[J]. Proc Natl Acad Sci U S A,2007,104(35):14068-14073.
[73]Anversa P, Kajstura J, Leri A, et al. Life and death of cardiac stem cells:a paradigm shift in cardiac biology[J]. Circulation,2006,113(11):1451-1463.
[74]Dimmeler S, Burchfield J, Zeiher A M. Cell-based therapy of myocardial infarction[J]. Arterioscler Thromb Vasc Biol,2008,28(2):208-216.
[75]Anversa P, Leri A, Rota M, et al. Concise review:stem cells, myocardial regeneration, and methodological artifacts[J]. Stem Cells,2007,25(3):589-601.
[76]Ferrari G, Cusella-De A G, Coletta M, et al. Muscle regeneration by bone marrow-derived myogenic progenitors[J]. Science,1998,279(5356):1528-1530.
[77]Yoshimoto M, Chang H, Shiota M, et al. Two different roles of purified CD45+c-Kit+Sca-1+Lin-cells after transplantation in muscles[J]. Stem Cells,2005,23(5):610-618.
[78]Labarge M A, Blau H M. Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury[J]. Cell,2002,111(4):589-601.
[79]Abedi M, Foster B M, Wood K D, et al. Haematopoietic stem cells participate in muscle regeneration[J]. Br J Haematol,2007,138(6):792-801.
[80]Gussoni E, Soneoka Y, Strickland C D, et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation[J]. Nature,1999,401 (6751):390-394.
[81]Brazelton T R, Nystrom M, Blau H M. Significant differences among skeletal muscles in the incorporation of bone marrow-derived cells[J]. Dev Biol,2003,262(1):64-74.
[82]Gussoni E, Bennett R R, Muskiewicz K R, et al. Long-term persistence of donor nuclei in a Duchenne muscular dystrophy patient receiving bone marrow transplantation[J]. J Clin Invest,2002,110(6):807-814.
[83]Hess D C, Borlongan C V. Stem cells and neurological diseases[J]. Cell Prolif,2008,41 Suppl 1:94-114.
[84]Li Y, Chopp M. Marrow stromal cell transplantation in stroke and traumatic brain injury[J]. Neurosci Lett,2009,456(3):120-123.
[85]Mezey E. Bone marrow-derived stem cells in neurological diseases:stones or masons?[J]. Regen Med,2007,2(1):37-49.
[86]Phinney D G, Isakova I. Plasticity and therapeutic potential of mesenchymal stem cells in the nervous system[J]. Curr Pharm Des,2005,11(10):1255-1265.
[87]Sadan O, Melamed E, Offen D. Bone-marrow-derived mesenchymal stem cell therapy for neurodegenerative diseases[J]. Expert Opin Biol Ther,2009,9(12):1487-1497.
[88]Brazelton T R, Rossi F M, Keshet G I, et al. From marrow to brain:expression of neuronal phenotypes in adult mice[J]. Science,2000,290(5497):1775-1779.
[89]Mezey E, Chandross K J, Harta G, et al. Turning blood into brain:cells bearing neuronal antigens generated in vivo from bone marrow[J]. Science,2000,290(5497):1779-1782.
[90]Jin H K, Carter J E, Huntley G W, et al. Intracerebral transplantation of mesenchymal stem cells into acid sphingomyelinase-deficient mice delays the onset of neurological abnormalities and extends their life span[J]. J Clin Invest,2002,109(9):1183-1191.
[91]Woodbury D, Schwarz E J, Prockop D J, et al. Adult rat and human bone marrow stromal cells differentiate into neurons[J]. J Neurosci Res,2000,61(4):364-370.
[92]Akiyama Y, Radtke C, Kocsis J D. Remyelination of the rat spinal cord by transplantation of identified bone marrow stromal cells[J]. J Neurosci,2002,22(15):6623-6630.
[93]Akiyama Y, Radtke C, Honmou O, et al. Remyelination of the spinal cord following intravenous delivery of bone marrow cells[J]. Glia,2002,39(3):229-236.
[94]Chopp M, Zhang X H, Li Y, et al. Spinal cord injury in rat:treatment with bone marrow stromal cell transplantation[J]. Neuroreport,2000,11(13):3001-3005.
[95]Gupta S, Verfaillie C, Chmielewski D, et al. A role for extrarenal cells in the regeneration following acute renal failure[J]. Kidney Int,2002,62(4):1285-1290.
[96]Poulsom R, Forbes S J, Hodivala-Dilke K, et al. Bone marrow contributes to renal parenchymal turnover and regeneration[J]. J Pathol,2001,195(2):229-235.
[97]Grimm P C, Nickerson P, Jeffery J, et al. Neointimal and tubulointerstitial infiltration by recipient mesenchymal cells in chronic renal-allograft rejection[J]. N Engl J Med,2001,345(2):93-97.
[98]Ito T, Suzuki A, Imai E, et al. Bone marrow is a reservoir of repopulating mesangial cells during glomerular remodeling[J]. J Am Soc Nephrol,2001,12(12):2625-2635.
[99]Cornacchia F, Fornoni A, Plati A R, et al. Glomerulosclerosis is transmitted by bone marrow-derived mesangial cell progenitors[J]. J Clin Invest,2001,108(11):1649-1656.
[100]Kale S, Karihaloo A, Clark P R, et al. Bone marrow stem cells contribute to repair of the ischemically injured renal tubule[J].J Clin Invest,2003,112(1):42-49.
[101]Gupta S, Rosenberg M E. Do stem cells exist in the adult kidney?[J]. Am J Nephrol,2008,28(4):607-613.
[102]Krause D, Cantley L G. Bone marrow plasticity revisited:protection or differentiation in the kidney tubule?[J]. J Clin Invest,2005,115(7):1705-1708.
[103]Baer P C, Geiger H. Mesenchymal stem cell interactions with growth factors on kidney repair[J]. Curr Opin Nephrol Hypertens,2010,19(1):1-6.
[104]Camussi G, Deregibus M C, Tetta C. Paracrine/endocrine mechanism of stem cells on kidney repair:role of microvesicle-mediated transfer of genetic information[J]. Curr Opin Nephrol Hypertens,2010,19(1):7-12.
[105]Ianus A, Holz G G, Theise N D, et al. In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion[J]. J Clin Invest,2003,111(6):843-850.
[106]Hess D, Li L, Martin M, et al. Bone marrow-derived stem cells initiate pancreatic regeneration[J]. Nat Biotechnol,2003,21(7):763-770.
[107]Theise N D, Henegariu O, Grove J, et al. Radiation pneumonitis in mice:a severe injury model for pneumocyte engraftment from bone marrow[J]. Exp Hematol,2002,30(11):1333-1338.
[108]Krause D S. Bone marrow-derived cells and stem cells in lung repair[J]. Proc Am Thorac Soc,2008,5(3):323-327.
[109]Trempus C S, Morris R J, Bortner C D, et al. Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34[J]. J Invest Dermatol,2003,120(4):501-511.
[110]Hoang M P, Keady M, Mahalingam M. Stem cell markers (cytokeratin 15, CD34 and nestin) in primary scarring and nonscarring alopecia[J]. Br J Dermatol,2009,160(3):609-615.
[111]Kloepper J E, Tiede S, Brinckmann J, et al. Immunophenotyping of the human bulge region:the quest to define useful in situ markers for human epithelial hair follicle stem cells and their niche[J]. Exp Dermatol,2008,17(7):592-609.
[112]Poblet E, Jimenez F, Godinez J M, et al. The immunohistochemical expression of CD34 in human hair follicles:a comparative study with the bulge marker CK15[J]. Clin Exp Dermatol,2006,31(6):807-812.
[113]Abbas O, Mahalingam M. Epidermal stem cells:practical perspectives and potential uses[J]. Br J Dermatol,2009,161(2):228-236.
[114]Blanpain C, Fuchs E. Epidermal homeostasis:a balancing act of stem cells in the skin[J]. Nat Rev Mol Cell Biol,2009,10(3):207-217.
[115]Fuchs E. Finding one's niche in the skin[J]. Cell Stem Cell,2009,4(6):499-502.
[116]Badiavas E V, Abedi M, Butmarc J, et al. Participation of bone marrow derived cells in cutaneous wound healing[J]. J Cell Physiol,2003,196(2):245-250.
[117]Okamoto R, Yajima T, Yamazaki M, et al. Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract[J]. Nat Med,2002,8(9):1011-1017.
[118]Demura T, Tashiro G, Horiguchi G, et al. Visualization by comprehensive microarray analysis of gene expression programs during transdifferentiation of mesophyll cells into xylem cells[J]. Proc Natl Acad Sci U S A,2002,99(24):15794-15799.
[119]Stocum D L. Development. A tail of transdifferentiation[J]. Science,2002,298(5600):1901-1903.
[120]Shen C N, Horb M E, Slack J M, et al. Transdifferentiation of pancreas to liver[J]. Mech Dev,2003,120(1):107-116.
[121]Shen C N, Slack J M, Tosh D. Molecular basis of transdifferentiation of pancreas to liver[J]. Nat Cell Biol,2000,2(12):879-887.
[122]Tang D G, Tokumoto Y M, Apperly J A, et al. Lack of replicative senescence in cultured rat oligodendrocyte precursor cells[J]. Science,2001,291(5505):868-871.
[123]Hakelien A M, Landsverk H B, Robl J M, et al. Reprogramming fibroblasts to express T-cell functions using cell extracts[J]. Nat Biotechnol,2002,20(5):460-466.
[124]Hardeman E C, Chiu C P, Minty A, et al. The pattern of actin expression in human fibroblast x mouse muscle heterokaryons suggests that human muscle regulatory factors are produced[J]. Cell,1986,47(1):123-130.
[125]Ying Q L, Nichols J, Evans E P, et al. Changing potency by spontaneous fusion[J].Nature,2002,416(6880):545-548.
[126]Terada N, Hamazaki T, Oka M, et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion[J]. Nature,2002,416(6880):542-545.
[127]Masuya M, Drake C J, Fleming P A, et al. Hematopoietic origin of glomerular mesangial cells[J]. Blood,2003,101(6):2215-2218.
[128]Vassilopoulos G, Wang P R, Russell D W. Transplanted bone marrow regenerates liver by cell fusion[J]. Nature,2003,422(6934):901-904.
[129]Zhang S, Wang D, Estrov Z, et al. Both cell fusion and transdifferentiation account for the transformation of human peripheral blood CD34-positive cells into cardiomyocytes in vivo[J]. Circulation,2004,110(25):3803-3807.
[130]Nygren J M, Jovinge S, Breitbach M, et al. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation[J]. Nat Med,2004,10(5):494-501.
[131]Murry C E, Soonpaa M H, Reinecke H, et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts[J]. Nature,2004,428(6983):664-668.
[132]Blau H M.A twist of fate[J]. Nature,2002,419(6906):437.
[133]Blau H M, Blakely B T. Plasticity of cell fate:insights from heterokaryons[J]. Semin Cell Dev Biol,1999,10(3):267-272.
[134]Wagers A J, Sherwood R I, Christensen J L, et al. Little evidence for developmental plasticity of adult hematopoietic stem cells[J]. Science,2002,297(5590):2256-2259.
[135]Pawliuk R, Westerman K A, Fabry M E, et al. Correction of sickle cell disease in transgenic mouse models by gene therapy[J]. Science,2001,294(5550):2368-2371.
[136]Matzner U, Hartmann D, Lullmann-Rauch R, et al. Bone marrow stem cell-based gene transfer in a mouse model for metachromatic leukodystrophy:effects on visceral and nervous system disease manifestations[J]. Gene Ther,2002,9(1):53-63.
[137]Siatskas C, Medin J A. Gene therapy for Fabry disease[J]. J Inherit Metab Dis,2001,24 Suppl 2:25-41,11-12.
[138]Grove J E, Lutzko C, Priller J, et al. Marrow-derived cells as vehicles for delivery of gene therapy to pulmonary epithelium[J]. Am J Respir Cell Mol Biol,2002,27(6):645-651.
[139]Priller J, Flugel A, Wehner T, et al. Targeting gene-modified hematopoietic cells to the central nervous system:use of green fluorescent protein uncovers microglial engraftment[J]. Nat Med,2001,7(12):1356-1361.
[140]Waterland R A. Epigenetic mechanisms and gastrointestinal development[J]. J Pediatr,2006,149(5 Suppl):S137-S142.
[141]Nowell P C. Foundations in cancer research. Chromosomes and cancer:the evolution of an idea[J]. Adv Cancer Res,1993,62:1-17.
[142]Clarke M F, Dick J E, Dirks P B, et al. Cancer stem cells--perspectives on current status and future directions:AACR Workshop on cancer stem cells [J]. Cancer Res,2006,66(19):9339-9344.
[143]Vogelstein B, Kinzler K W. The multistep nature of cancer[J]. Trends Genet,1993,9(4):138-141.
[144]Hickman E S, Moroni M C, Helin K. The role of p53 and pRB in apoptosis and cancer[J]. Curr Opin Genet Dev,2002,12(1):60-66.
[145]Malumbres M, Barbacid M. RAS oncogenes:the first 30 years[J]. Nat Rev Cancer,2003,3(6):459-465.
[146]Calin G A, Croce C M. MicroRNAs and chromosomal abnormalities in cancer cells[J].Oncogene,2006,25(46):6202-6210.
[147]Sancar A, Lindsey-Boltz L A, Unsal-Kacmaz K, et al. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints[J]. Annu Rev Biochem,2004,73:39-85.
[148]Wicha M S, Liu S, Dontu G. Cancer stem cells:an old idea--a paradigm shift[J]. Cancer Res,2006,66(4):1883-1890,1895-1896.
[149]Song L L, Miele L. Cancer stem cells-an old idea that's new again: implications for the diagnosis and treatment of breast cancer[J]. Expert Opin Biol Ther,2007,7(4):431-438.
[150]Pardal R, Clarke M F, Morrison S J. Applying the principles of stem-cell biology to cancer[J]. Nat Rev Cancer,2003,3(12):895-902.
[151]Bixby S, Kruger G M, Mosher J T, et al. Cell-intrinsic differences between stem cells from different regions of the peripheral nervous system regulate the generation of neural diversity[J]. Neuron,2002,35(4):643-656.
[152]Sagar J, Chaib B, Sales K, et al. Role of stem cells in cancer therapy and cancer stem cells:a review[J]. Cancer Cell Int,2007,7:9.
[153]Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice[J]. Nature,1994,367(6464):645-648.
[154]Bonnet D, Dick J E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell[J]. Nat Med,1997,3(7):730-737.
[155]Hemmati H D, Nakano I, Lazareff J A, et al. Cancerous stem cells can arise from pediatric brain tumors[J]. Proc Natl Acad Sci U S A,2003,100(25):15178-15183.
[156]Singh S K, Clarke I D, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors[J]. Cancer Res,2003,63(18):5821-5828.
[157]Singh S K, Hawkins C, Clarke I D, et al. Identification of human brain tumour initiating cells[J]. Nature,2004,432(7015):396-401.
[158]Seigel G M, Hackam A S, Ganguly A, et al. Human embryonic and neuronal stem cell markers in retinoblastoma[J]. Mol Vis,2007,13:823-832.
[159]O'Brien C A, Pollett A, Gallinger S, et al. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice[J]. Nature,2007,445(7123):106-110.
[160]Ricci-Vitiani L, Lombardi D G, Pilozzi E, et al. Identification and expansion of human colon-cancer-initiating cells[J]. Nature,2007,445(7123):111-115.
[161]Haraguchi N, Ohkuma M, Sakashita H, et al. CD133+CD44+ population efficiently enriches colon cancer initiating cells[J]. Ann Surg Oncol,2008,15(10):2927-2933.
[162]Puglisi M A, Sgambato A, Saulnier N, et al. Isolation and characterization of CD133+ cell population within human primary and metastatic colon cancer[J]. Eur Rev Med Pharmacol Sci,2009,13 Suppl 1:55-62.
[163]Fang D D, Kim Y J, Lee C N, et al. Expansion of CD133(+) colon cancer cultures retaining stem cell properties to enable cancer stem cell target discovery[J]. Br J Cancer,2010,102(8):1265-1275.
[164]Haraguchi N, Inoue H, Tanaka F, et al. Cancer stem cells in human gastrointestinal cancers[J]. Hum Cell,2006,19(1):24-29.
[165]Prince M E, Sivanandan R, Kaczorowski A, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma[J]. Proc Natl Acad Sci U S A,2007,104(3):973-978.
[166]Wang J, Guo L P, Chen L Z, et al. Identification of cancer stem cell-like side population cells in human nasopharyngeal carcinoma cell line[J]. Cancer Res,2007,67(8):3716-3724.
[167]Schatton T, Murphy G F, Frank N Y, et al. Identification of cells initiating human melanomas[J]. Nature,2008,451(7176):345-349.
[168]Fang D, Nguyen T K, Leishear K, et al. A tumorigenic subpopulation with stem cell properties in melanomas[J]. Cancer Res,2005,65(20):9328-9337.
[169]Held M A, Curley D P, Dankort D, et al. Characterization of melanoma cells capable of propagating tumors from a single cell[J]. Cancer Res,2010,70(1):388-397.
[170]Wright M H, Calcagno A M, Salcido C D, et al. Brcal breast tumors contain distinct CD44+/CD24- and CD133+ cells with cancer stem cell characteristics[J]. Breast Cancer Res,2008,10(1):R10.
[171]Al-Hajj M, Wicha M S, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells[J]. Proc Natl Acad Sci U S A,2003,100(7):3983-3988.
[172]Curley M D, Therrien V A, Cummings C L, et al. CD 133 expression defines a tumor initiating cell population in primary human ovarian cancer[J]. Stem Cells,2009,27(12):2875-2883.
[173]Olempska M, Eisenach P A, Ammerpohl O, et al. Detection of tumor stem cell markers in pancreatic carcinoma cell lines[J]. Hepatobiliary Pancreat Dis Int,2007,6(1):92-97.
[174]Tirino V, Camerlingo R, Franco R, et al. The role of CD 133 in the identification and characterisation of tumour-initiating cells in non-small-cell lung cancer[J]. Eur J Cardiothorac Surg,2009,36(3):446-453.
[175]Bertolini G, Roz L, Perego P, et al. Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment[J]. Proc Natl Acad Sci U S A,2009,106(38):16281-16286.
[176]Ho M M, Ng A V, Lam S, et al. Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells[J]. Cancer Res,2007,67(10):4827-4833.
[177]Tirino V, Desiderio V, D'Aquino R, et al. Detection and characterization of CD133+ cancer stem cells in human solid tumours[J]. PLoS One,2008,3(10):e3469.
[178]Tomuleasa C, Soritau O, Rus-Ciuca D, et al. Isolation and characterization of hepatic cancer cells with stem-like properties from hepatocellular carcinoma[J]. J Gastrointestin Liver Dis,2010,19(1):61-67.
[179]Zhu Z, Hao X, Yan M, et al. Cancer stem/progenitor cells are highly enriched in CD133+CD44+ population in hepatocellular carcinoma[J]. Int J Cancer,2010,126(9):2067-2078.
[180]Zen Y, Fujii T, Yoshikawa S, et al. Histological and culture studies with respect to ABCG2 expression support the existence of a cancer cell hierarchy in human hepatocellular carcinoma[J]. Am J Pathol.2007,170(5):1750-1762.
[181]Dalerba P, Dylla S J, Park I K, et al. Phenotypic characterization of human colorectal cancer stem cells[J]. Proc Natl Acad Sci U S A,2007,104(24):10158-10163.
[182]Kondo T. Stem cell-like cancer cells in cancer cell lines[J]. Cancer Biomark,2007,3(4-5):245-250.
[183]Setoguchi T, Taga T, Kondo T. Cancer stem cells persist in many cancer cell lines[J]. Cell Cycle,2004,3(4):414-415.
[184]Collins A T, Berry P A, Hyde C, et al. Prospective identification of tumorigenic prostate cancer stem cells[J]. Cancer Res,2005,65(23):10946-10951.
[185]Yu J, Vodyanik M A, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells[J]. Science,2007,318(5858):1917-1920.
[186]Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors[J]. Cell,2007,131(5):861-872.
[187]Hugo H, Ackland M L, Blick T, et al. Epithelial--mesenchymal and mesenchymal--epithelial transitions in carcinoma progression[J]. J Cell Physiol,2007,213(2):374-383.
[188]Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression:an alliance against the epithelial phenotype?[J]. Nat Rev Cancer,2007,7(6):415-428.
[189]Gupta P B, Mani S, Yang J, et al. The evolving portrait of cancer metastasis[J]. Cold Spring Harb Symp Quant Biol,2005,70:291-297.
[190]Yang J, Mani S A, Weinberg R A. Exploring a new twist on tumor metastasis [J]. Cancer Res,2006,66(9):4549-4552.
[191]Hendrix M J, Seftor R E, Seftor E A, et al. Transendothelial function of human metastatic melanoma cells:role of the microenvironment in cell-fate determination[J]. Cancer Res,2002,62(3):665-668.
[192]Hess A R, Margaryan N V, Seftor E A, et al. Deciphering the signaling events that promote melanoma tumor cell vasculogenic mimicry and their link to embryonic vasculogenesis:role of the Eph receptors[J]. Dev Dyn,2007,236(12):3283-3296.
[193]Read T A, Fogarty M P, Markant S L, et al. Identification of CD 15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma[J]. Cancer Cell,2009,15(2):135-147.
[194]Son M J, Woolard K, Nam D H, et al. SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma[J]. Cell Stem Cell,2009,4(5):440-452.
[195]Ward R J, Lee L, Graham K, et al. Multipotent CD15+ cancer stem cells in patched-1-deficient mouse medulloblastoma[J]. Cancer Res,2009,69(11):4682-4690.
[196]Du L, Wang H, He L, et al. CD44 is of functional importance for colorectal cancer stem cells[J]. Clin Cancer Res,2008,14(21):6751-6760.
[197]Chu P, Clanton D J, Snipas T S, et al. Characterization of a subpopulation of colon cancer cells with stem cell-like properties[J]. Int J Cancer,2009,124(6):1312-1321.
[198]Li C, Heidt D G, Dalerba P, et al. Identification of pancreatic cancer stem cells[J]. Cancer Res,2007,67(3):1030-1037.
[199]Zhou S, Schuetz J D, Bunting K D, et al. The ABC transporter Bcrpl/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype[J]. Nat Med,2001,7(9):1028-1034.
[200]Hirschmann-Jax C, Foster A E, Wulf G G, et al. A distinct "side population" of cells with high drug efflux capacity in human tumor cells[J]. Proc Natl Acad Sci U S A,2004,101(39):14228-14233.
[201]Komuro H, Saihara R, Shinya M, et al. Identification of side population cells (stem-like cell population) in pediatric solid tumor cell lines[J]. J Pediatr Surg,2007,42(12):2040-2045.
[202]Wang Y H, Li F, Luo B, et al. A side population of cells from a human pancreatic carcinoma cell line harbors cancer stem cell characteristics^]. Neoplasma,2009,56(5):371-378.
[203]Yao J, Cai H H, Wei J S, et al. Side population in the pancreatic cancer cell lines SW1990 and CFPAC-1 is enriched with cancer stem-like cells[J]. Oncol Rep,2010,23(5):1375-1382.
[204]Ginestier C, Hur M H, Charafe-Jauffret E, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome[J]. Cell Stem Cell,2007,1(5):555-567.
[205]Huang E H, Hynes M J, Zhang T, et al. Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis[J]. Cancer Res,2009,69(8):3382-3389.
[206]Kelly P N, Dakic A, Adams J M, et al. Tumor growth need not be driven by rare cancer stem cells[J]. Science,2007,317(5836):337.
[207]Hill R P. Identifying cancer stem cells in solid tumors:case not proven[J]. Cancer Res,2006,66(4):1891-1895,1890.
[208]Kuperwasser C, Chavarria T, Wu M, et al. Reconstruction of functionally normal and malignant human breast tissues in mice[J]. Proc Natl Acad Sci U S A,2004,101(14):4966-4971.
[209]Scadden D T. The stem cell niche in health and leukemic disease[J]. Best Pract Res Clin Haematol,2007,20(1):19-27.
[210]Gilbertson R J, Rich J N. Making a tumour's bed:glioblastoma stem cells and the vascular niche[J]. Nat Rev Cancer,2007,7(10):733-736.
[211]Baguley B C. Tumor stem cell niches:a new functional framework for the action of anticancer drugs[J]. Recent Pat Anticancer Drug Discov,2006,1(1):121-127.
[212]Yang Z J, Wechsler-Reya R J. Hit 'em where they live:targeting the cancer stem cell niche[J]. Cancer Cell,2007,11(1):3-5.
[213]Hoelzinger D B, Demuth T, Berens M E. Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment[J]. J Natl Cancer Inst,2007,99(21):1583-1593.
[214]Fodde R, Brabletz T. Wnt/beta-catenin signaling in cancer sternness and malignant behavior[J]. Curr Opin Cell Biol,2007,19(2):150-158.
[215]Dontu G, Wicha M S. Survival of mammary stem cells in suspension culture: implications for stem cell biology and neoplasia[J]. J Mammary Gland Biol Neoplasia,2005,10(1):75-86.
[216]Liu S, Dontu G, Wicha M S. Mammary stem cells, self-renewal pathways, and carcinogenesis[J]. Breast Cancer Res,2005,7(3):86-95.
[217]Hosen N, Park C Y, Tatsumi N, et al. CD96 is a leukemic stem cell-specific marker in human acute myeloid leukemia[J]. Proc Natl Acad Sci U S A,2007,104(26):11008-11013.
[218]Katoh M. Networking of WNT, FGF, Notch, BMP, and Hedgehog signaling pathways during carcinogenesis[J]. Stem Cell Rev,2007,3(1):30-38.
[219]Tung D C, Chao K S. Targeting hedgehog in cancer stem cells:how a paradigm shift can improve treatment response[J]. Future Oncol,2007,3(5):569-574.
[220]Cho R W, Wang X, Diehn M, et al. Isolation and molecular characterization of cancer stem cells in MMTV-Wnt-1 murine breast tumors[J]. Stem Cells,2008,26(2):364-371.
[221]Korkaya H, Wicha M S. Selective targeting of cancer stem cells:a new concept in cancer therapeutics [J]. BioDrugs,2007,21(5):299-310.
[222]Dontu G, Jackson K W, Mcnicholas E, et al. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells[J]. Breast Cancer Res,2004,6(6):R605-R615.
[223]Bailey J M, Singh P K, Hollingsworth M A. Cancer metastasis facilitated by developmental pathways:Sonic hedgehog, Notch, and bone morphogenic proteins[J]. J Cell Biochem,2007,102(4):829-839.
[224]Rizzo P, Osipo C, Foreman K, et al. Rational targeting of Notch signaling in cancer[J].Oncogene,2008,27(38):5124-5131.
[225]Shih A H, Holland E C. Notch signaling enhances nestin expression in gliomas[J]. Neoplasia,2006,8(12):1072-1082.
[226]Phillips H S, Kharbanda S, Chen R, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis[J]. Cancer Cell,2006,9(3):157-173.
[227]Fan X, Matsui W, Khaki L, et al. Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors[J]. Cancer Res,2006,66(15):7445-7452.
[228]Reedijk M, Odorcic S, Chang L, et al. High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival[J]. Cancer Res,2005,65(18):8530-8537.
[229]Dickson B C, Mulligan A M, Zhang H, et al. High-level JAG1 mRNA and protein predict poor outcome in breast cancer[J]. Mod Pathol,2007,20(6):685-693.
[230]Farnie G, Clarke R B, Spence K, et al. Novel cell culture technique for primary ductal carcinoma in situ:role of Notch and epidermal growth factor receptor signaling pathways[J]. J Natl Cancer Inst,2007,99(8):616-627.
[2]Parkin D M, Bray F, Ferlay J, et al. Global cancer statistics,2002[J]. CA Cancer J Clin,2005,55(2):74-108.
[3]Jemal A, Bray F, Center M M, et al. Global cancer statistics[J]. CA Cancer J Clin,2011,61(2):69-90.
[4]孙秀娣,牧人,周有尚,等.中国1990-1992年胃癌死亡调查分析[J].中华肿瘤杂志,2002,24(1)：4-8.
[5]Shimkin M B. The written word and cancer--some personal involvements, 1940-1977:autobiographical essay[J]. Cancer Res,1978,38(2):241-252.
[6]Wood L D, Parsons D W, Jones S, et al. The genomic landscapes of human breast and colorectal cancers[J]. Science,2007,318(5853):1108-1113.
[7]Sjoblom T, Jones S, Wood L D, et al. The consensus coding sequences of human breast and colorectal cancers[J]. Science,2006,314(5797):268-274.
[8]Duesberg P, Rasnick D. Aneuploidy, the somatic mutation that makes cancer a species of its own[J]. Cell Motil Cytoskeleton,2000,47(2):81-107.
[9]Loeb L A. A mutator phenotype in cancer[J]. Cancer Res,2001,61(8):3230-3239.
[10]Reya T, Morrison S J, Clarke M F, et al. Stem cells, cancer, and cancer stem cells[J]. Nature,2001,414(6859):105-111.
[11]Luebeck E G, Moolgavkar S H. Multistage carcinogenesis and the incidence of colorectal cancer[J]. Proc Natl Acad Sci U S A,2002,99(23):15095-15100.
[12]Serakinci N, Guldberg P, Burns J S, et al. Adult human mesenchymal stem cell as a target for neoplastic transformation[J]. Oncogene,2004,23(29):5095-5098.
[13]Marx J. Cancer research. Mutant stem cells may seed cancer[J]. Science,2003,301(5638):1308-1310.
[14]Rizvi A Z, Swain J R, Davies P S, et al. Bone marrow-derived cells fuse with normal and transformed intestinal stem cells[J]. Proc Natl Acad Sci U S A,2006,103(16):6321-6325.
[15]Houghton J, Stoicov C, Nomura S, et al. Gastric cancer originating from bone marrow-derived cells[J]. Science,2004,306(5701):1568-1571.
[16]王书奎,周振英主编.实用流式细胞术彩色图谱[M].上海：第二军医大学出版社,2004.
[17]张黎,王登山.微量元素Mn,Se对小鼠诱发性胃癌发生的影响[J].甘肃环境研究与监测,1991(2)：36-40.
[18]徐建国,包可杰.甲基胆葸诱发大,小鼠胃癌的实验观察[J].白求恩医科大学学报,1992,18(5)：466-467.
[19]Tatematsu M, Ogawa K, Hoshiya T, et al. Induction of adenocarcinomas in the glandular stomach of BALB/c mice treated with N-methyl-N-nitrosourea[J]. Jpn J Cancer Res,1992,83(9):915-918.
[20]Schauber J, Iffland K, Frisch S, et al. Histone-deacetylase inhibitors induce the cathelicidin LL-37 in gastrointestinal cells[J]. Mol Immunol,2004,41(9):847-854.
[21]Herzog E L, Chai L, Krause D S. Plasticity of marrow-derived stem cells[J]. Blood,2003,102(10):3483-3493.
[22]Barrilleaux B, Phinney D G, Prockop D J, et al. Review:ex vivo engineering of living tissues with adult stem cells[J]. Tissue Eng,2006,12(11):3007-3019.
[23]Mimeault M, Batra S K. Concise review:recent advances on the significance of stem cells in tissue regeneration and cancer therapies[J]. Stem Cells,2006,24(11):2319-2345.
[24]Mimeault M, Hauke R, Batra S K. Stem cells:a revolution in therapeutics-recent advances in stem cell biology and their therapeutic applications in regenerative medicine and cancer therapies[J]. Clin Pharmacol Ther,2007,82(3):252-264.
[25]Mimeault M, Batra S K. Recent progress on tissue-resident adult stem. cell biology and their therapeutic implications[J]. Stem Cell Rev,2008,4(1):27-49.
[26]Sell S. Adult stem cell plasticity:introduction to the first issue of stem cell reviews[J]. Stem Cell Rev,2005,1(1):1-7.
[27]Verstappen J, Katsaros C, Torensma R, et al. A functional model for adult stem cells in epithelial tissues[J]. Wound Repair Regen,2009,17(3):296-305.
[28]Walker M-R, Patel K K, Stappenbeck T S. The stem cell niche[J]. J Pathol,2009,217(2):169-180.
[29]Holden C, Vogel G. Stem cells. Plasticity:time for a reappraisal?[J]. Science,2002,296(5576):2126-2129.
[30]汪瑛,杨葳,郑志红,等.绿色荧光蛋白转基因小鼠模型的建立及胚胎冷冻保种[J].中国比较医学杂志,2007,17(8)：460-462.
[31]Karnoub A E, Dash A B, Vo A P, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis[J]. Nature,2007,449(7162):557-563.
[32]Gordon J W, Scangos G A, Plotkin D J, et al. Genetic transformation of mouse embryos by microinjection of purified DNA[J]. Proc Natl Acad Sci U S A,1980,77(12):7380-7384.
[33]Rakic P. Neurogenesis in adult primate neocortex:an evaluation of the evidence[J]. Nat Rev Neurosci,2002,3(1):65-71.
[34]Theise N D, Krause D S, Sharkis S. Comment on "Little evidence for developmental plasticity of adult hematopoietic stem cells"[J]. Science,2003,299(5611):1317,1317.
[35]Mezey E, Key S, Vogelsang G, et al. Transplanted bone marrow generates new neurons in human brains[J]. Proc Natl Acad Sci U S A,2003,100(3):1364-1369.
[36]Hu M, Krause D, Greaves M, et al. Multilineage gene expression precedes commitment in the hemopoietic system[J]. Genes Dev,1997,11(6):774-785.
[37]Billia F, Barbara M, Mcewen J, et al. Resolution of pluripotential intermediates in murine hematopoietic differentiation by global complementary DNA amplification from single cells:confirmation of assignments by expression profiling of cytokine receptor transcripts[J]. Blood,2001,97(8):2257-2268.
[38]Demura T, Tashiro G, Horiguchi G, et al. Visualization by comprehensive microarray analysis of gene expression programs during transdifferentiation of mesophyll cells into xylem cells[J]. Proc Natl Acad Sci U S A,2002,99(24):15794-15799.
[39]Stocum D L. Development. A tail of transdifferentiation[J]. Science,2002,298(5600):1901-1903.
[40]Shen C N, Horb M E, Slack J M, et al. Transdifferentiation of pancreas to liver[J]. Mech Dev,2003,120(1):107-116.
[41]Shen C N, Slack J M, Tosh D. Molecular basis of transdifferentiation of pancreas to liver[J]. Nat Cell Biol,2000,2(12):879-887.
[42]Tang D G, Tokumoto Y M, Apperly J A, et al. Lack of replicative senescence in cultured rat oligodendrocyte precursor cells[J]. Science,2001,291(5505):868-871.
[43]Hakelien A M, Landsverk H B, Robl J M, et al. Reprogramming fibroblasts to express T-cell functions using cell extracts[J]. Nat Biotechnol,2002,20(5):460-466.
[44]Hardeman E C, Chiu C P, Minty A, et al. The pattern of actin expression in human fibroblast x mouse muscle heterokaryons suggests that human muscle regulatory factors are produced[J]. Cell,1986,47(1):123-130.
[45]Ying Q L, Nichols J, Evans E P, et al. Changing potency by spontaneous fusion[J]. Nature,2002,416(6880):545-548.
[46]Terada N, Hamazaki T, Oka M, et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion[J]. Nature,2002,416(6880):542-545.
[47]Ferrand J, Noel D, Lehours P, et al. Human bone marrow-derived stem cells acquire epithelial characteristics through fusion with gastrointestinal epithelial cells[J]. PLoS One,2011,6(5):e19569.
[48]Bonde S, Pedram M, Stultz R, et al. Cell fusion of bone marrow cells and somatic cell reprogramming by embryonic stem cells[J]. FASEB J,2010,24(2):364-373.
[49]Labarge M A, Blau H M. Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury[J]. Cell,2002,111(4):589-601.
[50]Masuya M, Drake C J, Fleming P A, et al. Hematopoietic origin of glomerular mesangial cells[J]. Blood,2003,101(6):2215-2218.
[51]Blau H M. A twist of fate[J]. Nature,2002,419(6906):437.
[52]Blau H M, Blakely B T. Plasticity of cell fate:insights from heterokaryons[J]. Semin Cell Dev Biol,1999,10(3):267-272.
[53]Sugimura T, Fujimura S, Baba T. Tumor production in the glandular stomach and alimentary tract of the rat by N-methyl-N'-nitro-N-nitrosoguanidine[J]. Cancer Res,1970,30(2):455-465.
[54]Sugiyama A, Maruta F, Ikeno T, et al. Helicobacter pylori infection enhances N-methyl-N-nitrosourea-induced stomach carcinogenesis in the Mongolian gerbil[J]. Cancer Res,1998,58(10):2067-2069.
[55]周本杰,陈蔚文,王建华,等.硝酸结合MNNG攻击大鼠胃癌模型与评价[J]. 中国药理学通报,2001(1)：111-112.
[56]Sugiyama T, Hige S, Asaka M. Development of an H. pylori-infected animal model and gastric cancer:recent progress and issues[J]. J Gastroenterol,2002,37 Suppl 13:6-9.
[57]徐晶莹,李益民,李玉兰,等.MNNG诱导大鼠胃癌模型的建立[J].哈尔滨医科大学学报,2003,37(02).
[58]Tsukamoto T, Mizoshita T, Tatematsu M. Animal models of stomach carcinogenesis[J]. Toxicol Pathol,2007,35(5):636-648.
[59]许翼麟,何向辉,喻志革,等.小鼠胃癌模型的建立及T细胞免疫功能的变化[J].中华实验外科杂志,2010,27(04).
[60]Ianus A, Holz G G, Theise N D, et al. In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion[J]. J Clin Invest,2003,111(6):843-850.
[61]Harris R G, Herzog E L, Bruscia E M, et al. Lack of a fusion requirement for development of bone marrow-derived epithelia[J]. Science,2004,305(5680):90-93.
[62]Wang X, Willenbring H, Akkari Y, et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes[J]. Nature,2003,422(6934):897-901.
[63]Vassilopoulos G, Wang P R, Russell D W. Transplanted bone marrow regenerates liver by cell fusion[J]. Nature,2003,422(6934):901-904.
[64]Krause D S, Theise N D, Collector M I, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell[J]. Cell,2001,105(3):369-377.
[65]Jiang Y, Jahagirdar B N, Reinhardt R L, et al. Pluripotency of mesenchymal stem cells derived from adult marrow[J]. Nature,2002,418(6893):41-49.
[66]Korbling M, Katz R L, Khanna A, et al. Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells[J]. N Engl J Med,2002,346(10):738-746.
[67]Zhang S, Wang D, Estrov Z, et al. Both cell fusion and transdifferentiation account for the transformation of human peripheral blood CD-34-positive cells into cardiomyocytes in vivo[J]. Circulation,2004,110(25):3803-3807.
[68]Nygren J M, Jovinge S, Breitbach M, et al. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation[J]. Nat Med,2004,10(5):494-501.
[69]Murry C E, Soonpaa M H, Reinecke H, et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts[J]. Nature,2004,428(6983):664-668.
[70]Alvarez-Dolado M, Pardal R, Garcia-Verdugo J M, et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes.[J].Nature,2003,425(6961):968-973.
[71]Brittan M, Hunt T, Jeffery R, et al. Bone marrow derivation of pericryptal myofibroblasts in the mouse and human small intestine and colon[J]. Gut,2002,50(6):752-757.
[72]Okamoto R, Yajima T, Yamazaki M, et al. Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract[J]. Nat Med,2002,8(9):1011-1017.
[73]Davies P S, Powell A E, Swain J R, et al. Inflammation and proliferation act together to mediate intestinal cell fusion[J]. PLoS One,2009,4(8):e6530.
[74]Worthley D L, Ruszkiewicz A, Davies R, et al. Human gastrointestinal neoplasia-associated myofibroblasts can develop from bone marrow-derived cells following allogeneic stem cell transplantation[J]. Stem Cells,2009,27(6):1463-1468.
[75]Powell A E, Anderson E C, Davies P S, et al. Fusion between Intestinal epithelial cells and macrophages in a cancer context results in nuclear reprogramming[J]. Cancer Res,2011,71(4):1497-1505.
[76]Fukamachi H, Mizuno T, Takayama S. Epithelial-mesenchymal interactions in differentiation of stomach epithelium in fetal mice[J]. Anat Embryol (Berl),1979,157(2):151-160.
[77]Nowell P C. The clonal evolution of tumor cell populations[J]. Science,1976,194(4260):23-28.
[78]Grander D. How do mutated oncogenes and tumor suppressor genes cause cancer?[J]. Med Oncol,1998,15(1):20-26.
[79]Heppner G H, Miller F R. The cellular basis of tumor progression[J]. Int Rev Cytol,1998,177:1-56.
[80]Hanahan D, Weinberg R A. The hallmarks of cancer[J]. Cell,2000,100(1):57-70.
[81]李志芳,林庚金,蔡定芳.改良成人胃粘膜上皮细胞原代培养[J].胃肠病学,2000(1)：34-35.
[82]程永波,房殿春,郭立萍,等.一种简便的人正常胃黏膜上皮细胞原代培养方法[J].胃肠病学,2007,12(1)：31-35.
[83]Kinoshita Y, Hassan S, Nakata H, et al. Establishment of primary epithelial cell culture from elutriated rat gastric mucosal cell[J]. J Gastroenterol,1995,30(2):135-141.
[84]Chen M C, Lee A T, Soll A H. Mitogenic response of canine fundic epithelial cells in short-term culture to transforming growth factor alpha and insulinlike growth factor I[J]. J Clin Invest,1991,87(5):1716-1723.
[85]Karam S M, Alexander G, Farook V, et al. Characterization of the rabbit gastric epithelial lineage progenitors in short-term culture[J]. Cell Tissue Res,2001,306(1):65-74.
[86]Rhodes D, Revis D, Lacy E R. Extracellular matrix constituents affect superficial gastric epithelial cell adhesion[J]. J Gastroenterol Hepatol,1994,9 Suppl 1:S72-S77.
[87]Koike T, Yasugi S. In vitro analysis of mesenchymal influences on the differentiation of stomach epithelial cells of the chicken embryo[J]. Differentiation,1999,65(1):13-25.
[88]Fujiwara Y, Arakawa T, Fukuda T, et al. Role of extracellular matrix in attachment, migration, and repair of wounded rabbit cultured.gastric cells[J]. J Clin Gastroenterol,1995,21 Suppl 1:S125-S130.
[89]Wolf N S, Kone A, Priestley G V, et al. In vivo and in vitro characterization of long-term repopulating primitive hematopoietic cells isolated by sequential Hoechst 33342-rhodamine 123 FACS selection[J]. Exp Hematol,1993,21 (5):614-622.
[90]Krause D S, Ito T, Fackler M J, et al. Characterization of murine CD34, a marker for hematopoietic progenitor and stem cells[J]. Blood,1994,84(3):691-701.
[91]Fleming W H, Alpern E J, Uchida N, et al. Functional heterogeneity is associated with the cell cycle status of murine hematopoietic stem cells[J]. J Cell Biol,1993,122(4):897-902.
[92]Donnelly D S, Zelterman D, Sharkis S, et al. Functional activity of murine CD34+ and CD34- hematopoietic stem cell populations[J]. Exp Hematol, 999,27(5):788-796.
[93]Goodell M A, Rosenzweig M, Kim H, et al. Dye efflux, studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species[J]. Nat Med,1997,3(12):1337-1345.
[94]Scharenberg C W, Harkey M A, Torok-Storb B. The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors[J]. Blood,2002,99(2):507-512.
[95]Seale P, Asakura A, Rudnicki M A. The potential of muscle stem cells[J]. Dev Cell,2001,1(3):333-342.
[96]Mckinney-Freeman S L, Jackson K A, Camargo F D, et al. Muscle-derived hematopoietic stem cells are hematopoietic in origin[J]. Proc Natl Acad Sci U S A,2002,99(3):1341-1346.
[97]Kawada H, Ogawa M. Bone marrow origin of hematopoietic progenitors and stem cells in murine muscle[J]. Blood,2001,98(7):2008-2013.
[98]Majka S M, Jackson K A, Kienstra K A, et al. Distinct progenitor populations in skeletal muscle are bone marrow derived and exhibit different cell fates during vascular regeneration[J].J Clin Invest,2003,111(1):71-79.
[99]Lanzkron S M, Collector M I, Sharkis S J. Hematopoietic stem cell tracking in vivo:a comparison of short-term and long-term repopulating cells[J]. Blood,1999,93(6):1916-1921.
[100]Wagers A J, Weissman I L. Plasticity of adult stem cells.[J]. Cell,2004,116(5):639-648.
[101]Camargo F D, Chambers S M, Goodell M A. Stem cell plasticity:from transdifferentiation to macrophage fusion.[J]. Cell Prolif,2004,37(1):55-65.
[102]O'Malley K, Scott E W. Stem cell fusion confusion.[J]. Exp Hematol,2004,32(2):131-134.
[103]Pomerantz J, Blau H M. Nuclear reprogramming:a key to stem cell function in regenerative medicine.[J]. Nat Cell Biol,2004,6(9):810-816.
[104]Weimann J M, Johansson C B, Trejo A, et al. Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant.[J]. Nat Cell Biol,2003,5(11):959-966.
[105]Takagi Y, Takahashi J, Saiki H, et al. Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model[J]. J Clin Invest,2005,115(1):102-109.
[106]Shemer G, Podbilewicz B. The story of cell fusion:big lessons from little worms.[J].Bioessays,2003,25(7):672-682.
[107]Ogle B M, Cascalho M, Platt J L. Biological implications of cell fusion.[J]. Nat Rev Mol Cell Biol,2005,6(7):567-575.
[108]Aractingi S, Kanitakis J, Euvrard S, et al. Skin carcinoma arising from donor cells in a kidney transplant recipient.[J]. Cancer Res,2005,65(5):1755-1760.
[109]Wockel L, Ketelsen U P, Stotter M, et al. Abundant minute myotubes in a patient who later developed centronuclear myopathy[J]. Acta Neuropathol,1998,95(5):547-551.
[110]Redman C W, Sargent I L. Placental debris, oxidative stress and pre-eclampsia[J]. Placenta,2000,21(7):597-602.
[111]Miyamoto T, Suda T. Differentiation and function of osteoclasts.[J]. Keio J Med,2003,52(1):1-7.
[112]Bjerregaard B, Holck S, Christensen I J, et al. Syncytin is involved in breast cancer-endothelial cell fusions[J]. Cell Mol Life Sci,2006,63(16):1906-1911.
[113]Bjerkvig R, Tysnes B B, Aboody K S, et al. Opinion:the origin of the cancer stem cell:current controversies and new insights[J]. Nat Rev Cancer,2005,5(11):899-904.
[114]Farkas-Bargeton E, Barbet J P, Dancea S, et al. Immaturity of muscle fibers in the congenital form of myotonic dystrophy:its consequences and its origin[J]. J Neurol Sci,1988,83(2-3):145-159.
[115]Wongsurawat V J, Finley J C, Galipeau P C, et al. Genetic mechanisms of TP53 loss of heterozygosity in Barrett's esophagus:implications for biomarker validation[J]. Cancer Epidemiol Biomarkers Prev,2006,15(3):509-516.
[116]Barrett M T, Pritchard D, Palanca-Wessels C, et al. Molecular phenotype of spontaneously arising 4N (G2-tetraploid) intermediates of neoplastic progression in Barrett's esophagus[J]. Cancer Res,2003,63(14):4211-4217.
[117]Levine D S, Rabinovitch P S, Haggitt R C, et al. Distribution of aneuploid cell populations in ulcerative colitis with dysplasia or cancer[J]. Gastroenterology,1991,101 (5):1198-1210.
[118]Olaharski A J, Eastmond D A. Elevated levels of tetraploid cervical cells in human papillomavirus-positive Papanicolaou smears diagnosed as atypical squamous cells of undetermined significance[J]. Cancer,2004,102(3):192-199.
[119]Chen K A, Laywell E D, Marshall G, et al. Fusion of neural stem cells in culture[J]. Exp Neurol,2006,198(1):129-135.
[120]Roumier T, Valent A, Perfettini J L, et al. A cellular machine generating apoptosis-prone aneuploid cells[J]. Cell Death Differ,2005,12(1):91-93.
[121]Grace V M, Shalini J V, Lekha T T, et al. Co-overexpression of p53 and bcl-2 proteins in HPV-induced squamous cell carcinoma of the uterine cervix[J]. Gynecol Oncol,2003,91(1):51-58.
[122]Yilmaz Y, Lazova R, Qumsiyeh M, et al. Donor Y chromosome in renal carcinoma cells of a female BMT recipient:visualization of putative BMT-tumor hybrids by FISH[J]. Bone Marrow Transplant,2005,35(10):1021-1024.
[123]Chakraborty A, Lazova R, Davies S, et al. Donor DNA in a renal cell carcinoma metastasis from a bone marrow transplant recipient[J]. Bone Marrow Transplant,2004,34(2):183-186.
[124]Saikawa Y, Fukuda K, Takahashi T, et al. Gastric carcinogenesis and the cancer stem cell hypothesis[J]. Gastric Cancer,2010,13(1):11-24.
[125]Al-Hajj M, Clarke M F. Self-renewal and solid tumor stem cells.[J]. Oncogene,2004,23(43):7274-7282.
[126]Al-Hajj M, Wicha M S, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells[J]. Proc Natl Acad Sci U S A,2003,100(7):3983-3988.
[127]Singh S K, Clarke I D, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors[J]. Cancer Res,2003,63(18):5821-5828.
[128]Galli R, Binda E, Orfanelli U, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma[J]. Cancer Res,2004,64(19):7011-7021.
[129]Krause D S, Theise N D, Collector M I, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell[J]. Cell,2001,105(3):369-377.
[130]Peters B A, Diaz L A, Polyak K, et al. Contribution of bone marrow-derived endothelial cells to human tumor vasculature[J]. Nat Med,2005,11(3):261-262.
[131]Ding D C, Shyu W C, Chiang M F, et al. Enhancement of neuroplasticity through upregulation of betal-integrin in human umbilical cord-derived stromal cell implanted stroke model[J]. Neurobiol Dis,2007,27(3):339-353.
[132]申艳,虞容豪,黄怀,等.脐带间充质干细胞移植治疗持续性植物状态患者的护理[J].护理学报,2009,16(09).
[133]Baksh D, Song L, Tuan R S. Adult mesenchymal stem cells:characterization, differentiation, and application in cell and gene therapy[J]. J Cell Mol Med,2004,8(3):301-316.
[134]Mankani M H, Kuznetsov S A, Shannon B, et al. Canine cranial reconstruction using autologous bone marrow stromal cells[J]. Am J Pathol,2006,168(2):542-550.
[135]杨立业,刘相名,惠国桢,等.丹参诱导鼠骨髓间充质细胞向神经元分化[J].中华神经外科疾病研究杂志,2003,2(01).
[136]Li C, Zhang W, Jiang X, et al. Human-placenta-derived mesenchymal stem cells inhibit proliferation and function of allogeneic immune cells[J]. Cell Tissue Res,2007,330(3):437-446.
[137]Tian Y, Deng Y B, Huang Y J, et al. Bone marrow-derived mesenchymal stem cells decrease acute graft-versus-host disease after allogeneic hematopoietic stem cells transplantation[J]. Immunol Invest,2008,37(1):29-42.
[138]柯杨,宁涛,王冰,等.人胃粘膜上皮细胞系GES—1的建立及其生物学特性[J].中华肿瘤杂志,1994(1)：7-10.
[139]Friedenstein A J, Deriglasova U F, Kulagina N N, et al. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method[J]. Exp Hematol,1974,2(2):83-92.
[140]Friedenstein A J, Gorskaja J F, Kulagina N N. Fibroblast precursors in normal and irradiated mouse hematopoietic organs[J]. Exp Hematol,1976,4(5):267-274.
[141]Erices A, Conget P, Minguell J J. Mesenchymal progenitor cells in human umbilical cord blood[J]. Br J Haematol,2000,109(1):235-242.
[142]Romanov Y A, Svintsitskaya V A, Smirnov V N. Searching for alternative sources of postnatal human mesenchymal stem cells:candidate MSC-like cells from umbilical cord[J]. Stem Cells.2003,21(1):105-110.
[143]Fukuchi Y, Nakajima H, Sugiyama D, et al. Human placenta-derived cells have mesenchymal stem/progenitor cell potential[J]. Stem Cells,2004,22(5):649-658.
[144]Pittenger M F, Mackay A M, Beck S C, et al. Multilineage potential of adult human mesenchymal stem cells[J]. Science,1999,284(5411):143-147.
[145]Burdzinska A, Gala K, Paczek L. Myogenic stem cells[J]. Folia Histochem Cytobiol,2008,46(4):401-412.
[146]Taha M F, Hedayati V. Isolation, identification and multipotential differentiation of mouse adipose tissue-derived stem cells[J]. Tissue Cell,2010,42(4):211-216.
[147]Zeddou M, Briquet A, Relic B, et al. The umbilical cord matrix is a better source of mesenchymal stem cells (MSC) than the umbilical cord blood[J]. Cell Biol Int,2010,34(7):693-701.
[148]Laitinen A, Nystedt J, Laitinen S. The isolation and culture of human cord blood-derived mesenchymal stem cells under low oxygen conditions[J]. Methods Mol Biol,2011,698:63-73.
[149]Zvaifler N J, Marinova-Mutafchieva L, Adams G, et al. Mesenchymal precursor cells in the blood of normal individuals[J]. Arthritis Res,2000,2(6):477-488.
[150]Sapir A, Avinoam O, Podbilewicz B, et al. Viral and developmental cell fusion mechanisms:conservation and divergence.[J]. Dev Cell,2008,14(1):11-21.
[151]Chen E H, Olson E N. Unveiling the mechanisms of cell-cell fusion.[J]. Science,2005,308(5720):369-373.
[152]Vignery A. Macrophage fusion:the making of osteoclasts and giant cells.[J]. J Exp Med,2005,202(3):337-340.
[153]Vignery A. Macrophage fusion:are somatic and cancer cells possible partners?[J]. Trends Cell Biol,2005,15(4):188-193.
[154]Chen E H, Grote E, Mohler W, et al. Cell-cell fusion.[J]. FEBS Lett,2007,581(11):2181-2193.
[155]Davidson R L, Ephrussi B, Yamamoto K. Regulation of pigment synthesis in mammalian cells, as studied by somatic hybridization[J]. Proc Natl Acad Sci U S A,1966,56(5):1437-1440.
[156]Harris H. The analysis of malignancy by cell fusion:the position in 1988[J]. Cancer Res,1988,48(12):3302-3306.
[157]Sabin A B. Suppression of malignancy in human cancer cells:issues and challenges[J]. Proc Natl Acad Sci U S A,1981,78(11):7129-7133.
[158]Lu X, Kang Y. Cell fusion as a hidden force in tumor progression[J]. Cancer Res,2009,69(22):8536-8539.
[159]Pawelek J M, Chakraborty A K. Fusion of tumour cells with bone marrow-derived cells:a unifying explanation for metastasis. [J]. Nat Rev Cancer,2008,8(5):377-386.
[160]Duelli D, Lazebnik Y. Cell fusion:a hidden enemy? [J]. Cancer Cell,2003,3(5):445-448.
[161]Powers T P, Davidson R L. Coordinate extinction of melanocyte-specific gene expression in hybrid cells[J]. Somat Cell Mol Genet,1996,22(1):41-56.
[162]Powers T P, Shows T B, Davidson R L. Pigment-cell-specific genes from fibroblasts are transactivated after chromosomal transfer into melanoma cells[J]. Mol Cell Biol,1994,14(2):1179-1190.
[163]Makino S. The role of tumor stem-cells in regrowth of the tumor following drastic applications[J]. Acta Unio Int Contra Cancrum,1959,15(Suppl 1):196-198.
[164]Bruce W R, VAN DER Gaag H. A QUANTITATIVE ASSAY FOR THE NUMBER OF MURINE LYMPHOMA CELLS CAPABLE OF PROLIFERATION IN VIVO[J]. Nature,1963,199:79-80.
[165]Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice[J]. Nature,1994,367(6464):645-648.
[166]Bonnet D, Dick J E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell[J]. Nat Med,1997,3(7):730-737.
[167]Welte Y, Adjaye J, Lehrach H R, et al. Cancer stem cells in solid tumors: elusive or illusive?[J]. Cell Commun Signal,2010,8(1):6.
[168]Matsui W, Huff C A, Wang Q, et al. Characterization of clonogenic multiple myeloma cells[J]. Blood,2004,103(6):2332-2336.
[169]Xiao L, Yuan X, Sharkis S J. Activin A maintains self-renewal and regulates fibroblast growth factor, Wnt, and bone morphogenic protein pathways in human embryonic stem cells[J]. Stem Cells,2006,24(6):1476-1486.
[170]Alexson T O, Hitoshi S, Coles B L, et al. Notch signaling is required to maintain all neural stem cell populations--irrespective of spatial or temporal niche[J]. Dev Neurosci,2006,28(1-2):34-48.
[171]Fang D, Nguyen T K, Leishear K, et al. A tumorigenic subpopulation with stem cell properties in melanomas[J]. Cancer Res,2005,65(20):9328-9337.
[172]Matsumura H, Tada T. Cell fusion-mediated nuclear reprogramming of somatic cells[J]. Reprod Biomed Online,2008,16(1):51-56.
[173]Hanahan D, Weinberg R A. Hallmarks of cancer:the next generation[J]. Cell,2011,144(5):646-674.
[174]Hanahan D, Weinberg R A. The hallmarks of cancer[J]. Cell,2000,100(1):57-70.
[175]Bissell M J, Radisky D. Putting tumours in context[J]. Nat Rev Cancer,2001,1(1):46-54.
[176]Bissell M J, Labarge M A. Context, tissue plasticity, and cancer:are tumor stem cells also regulated by the microenvironment?[J]. Cancer Cell,2005,7(1):17-23.
[177]Bhowmick N A, Neilson E G, Moses H L. Stromal fibroblasts in cancer initiation and progression[J]. Nature,2004,432(7015):332-337.
[178]Mcallister S S, Gifford A M, Greiner A L, et al. Systemic endocrine instigation of indolent tumor growth requires osteopontin[J]. Cell,2008,133(6):994-1005.
[179]Yu J, Vodyanik M A, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells[J]. Science,2007,318(5858):1917-1920.
[180]Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors[J]. Cell,2007,131(5):861-872.
[181]Hugo H, Ackland M L, Blick T, et al. Epithelial--mesenchymal and mesenchymal--epithelial transitions in carcinoma progression[J]. J Cell Physiol,2007,213(2):374-383.
[182]Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression:an alliance against the epithelial phenotype?[J]. Nat Rev Cancer,2007,7(6):415-428.
[183]Gupta P B, Mani S, Yang J, et al. The evolving portrait of cancer metastasis[J]. Cold Spring Harb Symp Quant Biol,2005,70:291-297.
[184]Yang J, Mani S A, Weinberg R A. Exploring a new twist on tumor metastasis[J]. Cancer Res,2006,66(9):4549-4552.
[185]Thiery J P, Acloque H, Huang R Y, et al. Epithelial-mesenchymal transitions in development and disease[J]. Cell,2009,139(5):871-890.
[186]Yilmaz M, Christofori G. EMT, the cytoskeleton, and cancer cell invasion[J]. Cancer Metastasis Rev,2009,28(1-2):15-33.
[187]Yang J, Weinberg R A. Epithelial-mesenchymal transition:at the crossroads of development and tumor metastasis[J]. Dev Cell,2008,14(6):818-829.
[188]Kang Y, Massague J. Epithelial-mesenchymal transitions:twist in development and metastasis[J]. Cell,2004,118(3):277-279.
[189]Hendrix M J, Seftor R E, Seftor E A, et al. Transendothelial function of human metastatic melanoma cells:role of the microenvironment in cell-fate determination[J]. Cancer Res,2002,62(3):665-668.
[190]Hess A R, Margaryan N V, Seftor E A, et al. Deciphering the signaling events that promote melanoma tumor cell vasculogenic mimicry and their link to embryonic vasculogenesis:role of the Eph receptors[J]. Dev Dyn,2007,236(12):3283-3296.
[191]Sipos F, Galamb O. Epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions in the colon[J]. World J Gastroenterol,2012,18(7):601-608.
[192]Tellez C S, Juri D E, Do K, et al. EMT and stem cell-like properties associated with miR-205 and miR-200 epigenetic silencing are early manifestations during carcinogen-induced transformation of human lung epithelial cells[J]. Cancer Res,2011,71(8):3087-3097.
[193]Singh A, Settleman J. EMT, cancer stem cells and drug resistance:an emerging axis of evil in the war on cancer[J]. Oncogene,2010,29(34):4741-4751.
[194]Kalluri R, Weinberg R A. The basics of epithelial-mesenchymal transition[J]. J Clin Invest,2009,119(6):1420-1428.
[195]Acloque H, Adams M S, Fishwick K, et al. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease[J]. J Clin Invest,2009,119(6):1438-1449.
[196]Haslehurst A M, Koti M, Dharsee M, et al. EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer[J]. BMC Cancer,2012,12(1):91.
[197]Liu Y, Liu B A. Enhanced proliferation, invasion, and epithelial-mesenchymal transition of nicotine-promoted gastric cancer by periostin[J]. World J Gastroenterol,2011,17(21):2674-2680.
[198]Barriere G, Riouallon A, Renaudie J, et al. Mesenchymal and sternness circulating tumor cells in early breast cancer diagnosis[J]. BMC Cancer,2012,12(1):114.
[199]Ozel C, Seidel J, Meyer-Staeckling S, et al. Hybrid cells derived from breast epithelial cell/ breast cancer cell fusion events show a differential RAF-AKT crosstalk[J]. Cell Commun Signal,2012,10(1):10.
[200]Ohta H, Aoyagi K, Fukaya M, et al. Cross talk between hedgehog and epithelial-mesenchymal transition pathways in gastric pit cells and in diffuse-type gastric cancers[J]. Br J Cancer,2009,100(2):389-398.
[201]Lee J, Kim J C, Lee S E, et al. STAT3 (Signal Transducer and Activator of Transcription 3) suppresses adenoma to carcinoma transition In Apcmin/+ mice via regulation of SNAI (Snail-1) stability[J]. J Biol Chem,2012.
[202]Yoon C H, Kim M J, Lee H, et al. PTTG1 promotes tumor malignancy via epithelial to mesenchymal transition and expansion of cancer stem cell population[J]. J Biol Chem,2012.
[203]Nam S, Park T. Pathway-Based Evaluation in Early Onset Colorectal Cancer Suggests Focal Adhesion and Immunosuppression along with Epithelial-Mesenchymal Transition[J]. PLoS One,2012,7(3):e31685.
[204]Momin E N, Vela G, Zaidi H A, et al. The Oncogenic Potential of Mesenchymal Stem Cells in the Treatment of Cancer:Directions for Future Research[J]. Curr Immunol Rev,2010,6(2):137-148.
[205]Lazennec G, Jorgensen C. Concise review:adult multipotent stromal cells and cancer:risk or benefit?[J]. Stem Cells,2008,26(6):1387-1394.
[206]Teicher B A, Bagley R G. Stem cells and cancer[M]. Totowa, N.J.:Humana,2009.334.
[207]Correa P, Houghton J. Carcinogenesis of Helicobacter pylori[J]. Gastroenterology,2007,133(2):659-672.
[208]Sarosi G, Brown G, Jaiswal K, et al. Bone marrow progenitor cells contribute to esophageal regeneration and metaplasia in a rat model of Barrett's esophagus[J]. Dis Esophagus,2008,21(1):43-50.
[209]Hayashi Y, Tsuji S, Tsujii M, et al. Topical transplantation of mesenchymal stem cells accelerates gastric ulcer healing in rats[J]. Am J Physiol Gastrointest Liver Physiol,2008,294(3):G778-G786.
[210]Kahler C M, Wechselberger J, Hilbe W, et al. Peripheral infusion of rat bone marrow derived endothelial progenitor cells leads to homing in acute lung injury[J]. Respir Res,2007,8:50.
[211]Serikov V B, Popov B, Mikhailov V M, et al. Evidence of temporary airway epithelial repopulation and rare clonal formation by BM-derived cells following naphthalene injury in mice[J]. Anat Rec (Hoboken),2007,290(9):1033-1045.
[212]Suzuki M, Mchugh J, Tork C, et al. Direct muscle delivery of GDNF with human mesenchymal stem cells improves motor neuron survival and function in a rat model of familial ALS[J]. Mol Ther,2008,16(12):2002-2010.
[213]Ruan K, Bao S, Ouyang G. The multifaceted role of periostin in tumorigenesis[J]. Cell Mol Life Sci,2009,66(14):2219-2230.
[214]Ruan K, Song G, Ouyang G. Role of hypoxia in the hallmarks of human cancer[J]. J Cell Biochem,2009,107(6):1053-1062.
[215]Ouyang G, Wang Z, Fang X, et al. Molecular signaling of the epithelial to mesenchymal transition in generating and maintaining cancer stem cells [J]. Cell Mol Life Sci,2010,67(15):2605-2618.
[216]Taube J H, Herschkowitz J I, Komurov K, et al. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes[J]. Proc Natl Acad Sci U S A,2010,107(35):15449-15454.
[217]Mani S A, Guo W, Liao M J, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells[J]. Cell,2008,133(4):704-715.
[218]Mccoy E L, Iwanaga R, Jedlicka P, et al. Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition[J]. J Clin Invest,2009,119(9):2663-2677.
[219]Morel A P, Lievre M, Thomas C, et al. Generation of breast cancer stem cells through epithelial-mesenchymal transition[J]. PLoS One,2008,3(8):e2888.
[220]Iliopoulos D, Polytarchou C, Hatziapostolou M, et al. MicroRNAs differentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells[J]. Sci Signal,2009,2(92):a62.
[221]Evdokimova V, Tognon C, Ng T, et al. Translational activation of snaill and other developmentally regulated transcription factors by YB-1 promotes an epithelial-mesenchymal transition[J]. Cancer Cell,2009,15(5):402-415.
[222]Polyak K, Weinberg R A. Transitions between epithelial and mesenchymal states:acquisition of malignant and stem cell traits[J]. Nat Rev Cancer,2009,9(4):265-273.
[223]Wellner U, Schubert J, Burk U C, et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs[J]. Nat Cell Biol,2009,11(12):1487-1495.
[224]Yu M, Smolen G A, Zhang J, et al. A developmentally regulated inducer of EMT, LBX1,contributes to breast cancer progression[J]. Genes Dev,2009,23(15):1737-1742.
[225]Gupta P B, Chaffer C L, Weinberg R A. Cancer stem cells:mirage or reality?[J]. Nat Med,2009,15(9):1010-1012.
[226]Gupta P B, Onder T T, Jiang G, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening[J]. Cell,2009,138(4):645-659.
[227]Lu X, Kang Y. Efficient acquisition of dual metastasis organotropism to bone and lung through stable spontaneous fusion between MDA-MB-231 variants[J]. Proc Natl Acad Sci U S A,2009,106(23):9385-9390.
[1]李玉林主编.病理学[M].北京：人民卫生出版社,2004.444.
[2]Shimkin M B. The written word and cancer--some personal involvements, 1940-1977:autobiographical essay[J]. Cancer Res,1978,38(2):241-252.
[3]Wood L D, Parsons D W, Jones S, et al. The genomic landscapes of human breast and colorectal cancers[J]. Science,2007,318(5853):1108-1113.
[4]Sjoblom T, Jones S, Wood L D, et al. The consensus coding sequences of human breast and colorectal cancers[J]. Science,2006,314(5797):268-274.
[5]Duesberg P, Rasnick D. Aneuploidy, the somatic mutation that makes cancer a species of its own[J]. Cell Motil Cytoskeleton,2000,47(2):81-107.
[6]Loeb L A. A mutator phenotype in cancer[J]. Cancer Res,2001,61(8):3230-3239.
[7]Reya T, Morrison S J, Clarke M F, et al. Stem cells, cancer, and cancer stem cells[J].Nature,2001,414(6859):105-111.
[8]Barrilleaux B, Phinney D G, Prockop D J, et al. Review:ex vivo engineering of living tissues with adult stem cells[J]. Tissue Eng,2006,12(11):3007-3019.
[9]Mimeault M, Batra S K. Concise review:recent advances on the significance of stem cells in tissue regeneration and cancer therapies[J]. Stem Cells,2006,24(11):2319-2345.
[10]Mimeault M, Batra S K. Recent progress on tissue-resident adult stem cell biology and their therapeutic implications[J]. Stem Cell Rev,2008,4(1):27-49.
[11]Mimeault M, Hauke R, Batra S K. Stem cells:a revolution in therapeutics-recent advances in stem cell biology and their therapeutic applications in regenerative medicine and cancer therapies[J]. Clin Pharmacol Ther,2007,82(3):252-264.
[12]Sell S. Adult stem cell plasticity:introduction to the first issue of stem cell reviews[J]. Stem Cell Rev,2005,1(1):1-7.
[13]Verstappen J, Katsaros C, Torensma R, et al. A functional model for adult stem cells in epithelial tissues[J]. Wound Repair Regen,2009,17(3):296-305.
[14]Walker M R, Patel K K, Stappenbeck T S. The stem cell niche[J]. J Pathol,2009,217(2):169-180.
[15]Herzog E L, Chai L, Krause D S. Plasticity of marrow-derived stem cells[J]. Blood,2003,102(10):3483-3493.
[16]Holden C, Vogel G. Stem cells. Plasticity:time for a reappraisal?[J]. Science,2002,296(5576):2126-2129.
[17]Wolf N S, Kone A, Priestley G V, et al. In vivo and in vitro characterization of long-term repopulating primitive hematopoietic cells isolated by sequential Hoechst 33342-rhodamine 123 FACS selection[J]. Exp Hematol,1993,21(5):614-622.
[18]Krause D S, Ito T, Fackler M J, et al. Characterization of murine CD34, a marker for hematopoietic progenitor and stem cells[J]. Blood,1994,84(3):691-701.
[19]Fleming W H, Alpern E J, Uchida N, et al. Functional heterogeneity is associated with the cell cycle status of murine hematopoietic stem cells[J]. J Cell Biol,1993,122(4):897-902.
[20]Donnelly D S, Zelterman D, Sharkis S, et al. Functional activity of murine CD34+ and CD34- hematopoietic stem cell populations[J]. Exp Hematol,1999,27(5):788-796.
[21]Goodell M A, Rosenzweig M, Kim H, et al. Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species[J]. Nat Med,1997,3(12):1337-1345.
[22]Scharenberg C W, Harkey M A, Torok-Storb B. The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors[J]. Blood,2002,99(2):507-512.
[23]Seale P, Asakura A, Rudnicki M A. The potential of muscle stem cells[J]. Dev Cell,2001,1(3):333-342.
[24]Mckinney-Freeman S L, Jackson K A, Camargo F D, et al. Muscle-derived hematopoietic stem cells are hematopoietic in origin[J]. Proc Natl Acad Sci U S A,2002,99(3):1341-1346.
[25]Kawada H, Ogawa M. Bone marrow origin of hematopoietic progenitors and stem cells in murine muscle[J]. Blood,2001,98(7):2008-2013.
[26]Majka S M, Jackson K A, Kienstra K A, et al. Distinct progenitor populations in skeletal muscle are bone marrow derived and exhibit different cell fates during vascular regeneration[J]. J Clin Invest,2003,111(1):71-79.
[27]Lanzkron S M, Collector M I, Sharkis S J. Hematopoietic stem cell tracking in vivo:a comparison of short-term and long-term repopulating cells[J]. Blood,1999,93(6):1916-1921.
[28]Krause D S, Theise N D, Collector M I, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell[J]. Cell,2001,105(3):369-377.
[29]Simmons P J, Gronthos S, Zannettino A, et al. Isolation, characterization and functional activity of human marrow stromal progenitors in hemopoiesis[J]. Prog Clin Biol Res,1994,389:271-280.
[30]Simmons P J, Torok-Storb B. Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1[J]. Blood,1991,78(1):55-62.
[31]Gronthos S, Zannettino A C, Hay S J, et al. Molecular and cellular characterisation of highly purified stromal stem cells derived from human bone marrow[J]. J Cell Sci,2003,116(Pt 9):1827-1835.
[32]Pittenger M F, Mackay A M, Beck S C, et al. Multilineage potential of adult human mesenchymal stem cells[J]. Science,1999,284(5411):143-147.
[33]Azizi S A, Stokes D, Augelli B J, et al. Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats--similarities to astrocyte grafts[J]. Proc Natl Acad Sci U S A,1998,95(7):3908-3913.
[34]Jiang Y, Vaessen B, Lenvik T, et al. Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain[J]. Exp Hematol,2002,30(8):896-904.
[35]Jiang Y, Jahagirdar B N, Reinhardt R L, et al. Pluripotency of mesenchymal stem cells derived from adult marrow[J]. Nature,2002,418(6893):41-49.
[36]Morrison S J, Prowse K R, Ho P, et al. Telomerase activity in hematopoietic cells is associated with self-renewal potential[J]. Immunity,1996,5(3):207-216.
[37]Rakic P. Neurogenesis in adult primate neocortex:an evaluation of the evidence[J]. Nat Rev Neurosci,2002,3(1):65-71.
[38]Harris R G, Herzog E L, Bruscia E M, et al. Lack of a fusion requirement for development of bone marrow-derived epithelia[J]. Science,2004,305(5680):90-93.
[39]Theise N D, Krause D S, Sharkis S. Comment on "Little evidence for developmental plasticity of adult hematopoietic stem cells"[J]. Science,2003,299(5611):1317,1317.
[40]Mezey E, Key S, Vogelsang G, et al. Transplanted bone marrow generates new neurons in human brains[J]. Proc Natl Acad Sci U S A,2003,100(3):1364-1369.
[41]Hu M, Krause D, Greaves M, et al. Multilineage gene expression precedes commitment in the hemopoietic system[J]. Genes Dev,1997,11(6):774-785.
[42]Billia F, Barbara M, Mcewen J, et al. Resolution of pluripotential intermediates in murine hematopoietic differentiation by global complementary DNA amplification from single cells:confirmation of assignments by expression profiling of cytokine receptor transcripts[J]. Blood,2001,97(8):2257-2268.
[43]Petersen B E, Bowen W C, Patrene K D, et al. Bone marrow as a potential source of hepatic oval cells[J]. Science,1999,284(5417):1168-1170.
[44]Theise N D, Badve S, Saxena R, et al. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation[J]. Hepatology,2000,31 (1):235-240.
[45]Alison M R, Poulsom R, Jeffery R, et al. Hepatocytes from non-hepatic adult stem cells[J]. Nature,2000,406(6793):257.
[46]Theise N D, Nimmakayalu M, Gardner R, et al. Liver from bone marrow in humans[J].Hepatology,2000,32(1):11-16.
[47]Austin T W, Lagasse E. Hepatic regeneration from hematopoietic stem cells[J]. Mech Dev,2003,120(1):131-135.
[48]Evarts R P, Nagy P, Nakatsukasa H, et al. In vivo differentiation of rat liver oval cells into hepatocytes[J]. Cancer Res,1989,49(6):1541-1547.
[49]Lagasse E, Connors H, Al-Dhalimy M, et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo[J]. Nat Med,2000,6(11):1229-1234.
[50]Wang X, Willenbring H, Akkari Y, et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes[J]. Nature,2003,422(6934):897-901.
[51]Jorquera R, Tanguay R M. Fumarylacetoacetate, the metabolite accumulating in hereditary tyrosinemia, activates the ERK pathway and induces mitotic abnormalities and genomic instability[J]. Hum Mol Genet,2001,10(17):1741-1752.
[52]Jang Y Y, Collector M I, Baylin S B, et al. Hematopoietic stem cells convert into liver cells within days without fusion[J]. Nat Cell Biol,2004,6(6):532-539.
[53]Korbling M, Katz R L, Khanna A, et al. Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells[J]. N Engl J Med,2002,346(10):738-746.
[54]Dalakas E, Newsome P N, Boyle S, et al. Bone marrow stem cells contribute to alcohol liver fibrosis in humans[J]. Stem Cells Dev,2010,19(9):1417-1425.
[55]Srour E F, Jetmore A, Wolber F M, et al. Homing, cell cycle kinetics and fate of transplanted hematopoietic stem cells[J]. Leukemia,2001,15(11):1681-1684.
[56]Heissig B, Hattori K, Dias S, et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand[J]. Cell,2002,109(5):625-637.
[57]Wright D E, Bowman E P, Wagers A J, et al. Hematopoietic stem cells are uniquely selective in their migratory response to chemokines[J]. J Exp Med,2002,195(9):1145-1154.
[58]Hatch H M, Zheng D, Jorgensen M L, et al. SDF-1alpha/CXCR4:a mechanism for hepatic oval cell activation and bone marrow stem cell recruitment to the injured liver of rats[J]. Cloning Stem Cells,2002,4(4):339-351.
[59]Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium[J].Nature,2001,410(6829):701-705.
[60]Orlic D, Kajstura J, Chimenti S, et al. Mobilized bone marrow cells repair the infarcted heart, improving function and survival[J]. Proc Natl Acad Sci U S A,2001,98(18):10344-10349.
[61]Quaini F, Urbanek K, Beltrami A P, et al. Chimerism of the transplanted heart[J]. N Engl J Med,2002,346(1):5-15.
[62]Thiele J, Varus E, Wickenhauser C, et al. Regeneration of heart muscle tissue: quantification of chimeric cardiomyocytes and endothelial cells following transplantation[J]. Histol Histopathol,2004,19(1):201-209.
[63]Tse H F, Kwong Y L, Chan J K, et al. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation[J]. Lancet,2003,361(9351):47-49.
[64]Stamm C, Westphal B, Kleine H D, et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration[J]. Lancet,2003,361(9351):45-46.
[65]Rota M, Kajstura J, Hosoda T, et al. Bone marrow cells adopt the cardiomyogenic fate in vivo[J]. Proc Natl Acad Sci U S A,2007,104(45):17783-17788.
[66]Assmus B, Fischer-Rasokat U, Honold J, et al. Transcoronary transplantation of functionally competent BMCs is associated with a decrease in natriuretic peptide serum levels and improved survival of patients with chronic postinfarction heart failure:results of the TOPCARE-CHD Registry[J]. Circ Res,2007,100(8):1234-1241.
[67]Schachinger V, Tonn T, Dimmeler S, et al. Bone-marrow-derived progenitor cell therapy in need of proof of concept:design of the REP AIR-AMI trial[J]. Nat Clin Pract Cardiovasc Med,2006,3 Suppl 1:S23-S28.
[68]Abdel-Latif A, Bolli R, Tleyjeh I M, et al. Adult bone marrow-derived cells for cardiac repair:a systematic review and meta-analysis[J]. Arch Intern Med,2007,167(10):989-997.
[69]Martin-Rendon E, Brunskill S J, Hyde C J, et al. Autologous bone marrow stem cells to treat acute myocardial infarction:a systematic review[J]. Eur Heart J,2008,29(15):1807-1818.
[70]Gersh B J, Simari R D, Behfar A, et al. Cardiac cell repair therapy:a clinical perspective[J]. Mayo Clin Proc,2009,84(10):876-892.
[71]Leri A, Kajstura J, Anversa P. Cardiac stem cells and mechanisms of myocardial regeneration[J]. Physiol Rev,2005,85(4):1373-1416.
[72]Bearzi C, Rota M, Hosoda T, et al. Human cardiac stem cells[J]. Proc Natl Acad Sci U S A,2007,104(35):14068-14073.
[73]Anversa P, Kajstura J, Leri A, et al. Life and death of cardiac stem cells:a paradigm shift in cardiac biology[J]. Circulation,2006,113(11):1451-1463.
[74]Dimmeler S, Burchfield J, Zeiher A M. Cell-based therapy of myocardial infarction[J]. Arterioscler Thromb Vasc Biol,2008,28(2):208-216.
[75]Anversa P, Leri A, Rota M, et al. Concise review:stem cells, myocardial regeneration, and methodological artifacts[J]. Stem Cells,2007,25(3):589-601.
[76]Ferrari G, Cusella-De A G, Coletta M, et al. Muscle regeneration by bone marrow-derived myogenic progenitors[J]. Science,1998,279(5356):1528-1530.
[77]Yoshimoto M, Chang H, Shiota M, et al. Two different roles of purified CD45+c-Kit+Sca-1+Lin-cells after transplantation in muscles[J]. Stem Cells,2005,23(5):610-618.
[78]Labarge M A, Blau H M. Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury[J]. Cell,2002,111(4):589-601.
[79]Abedi M, Foster B M, Wood K D, et al. Haematopoietic stem cells participate in muscle regeneration[J]. Br J Haematol,2007,138(6):792-801.
[80]Gussoni E, Soneoka Y, Strickland C D, et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation[J]. Nature,1999,401 (6751):390-394.
[81]Brazelton T R, Nystrom M, Blau H M. Significant differences among skeletal muscles in the incorporation of bone marrow-derived cells[J]. Dev Biol,2003,262(1):64-74.
[82]Gussoni E, Bennett R R, Muskiewicz K R, et al. Long-term persistence of donor nuclei in a Duchenne muscular dystrophy patient receiving bone marrow transplantation[J]. J Clin Invest,2002,110(6):807-814.
[83]Hess D C, Borlongan C V. Stem cells and neurological diseases[J]. Cell Prolif,2008,41 Suppl 1:94-114.
[84]Li Y, Chopp M. Marrow stromal cell transplantation in stroke and traumatic brain injury[J]. Neurosci Lett,2009,456(3):120-123.
[85]Mezey E. Bone marrow-derived stem cells in neurological diseases:stones or masons?[J]. Regen Med,2007,2(1):37-49.
[86]Phinney D G, Isakova I. Plasticity and therapeutic potential of mesenchymal stem cells in the nervous system[J]. Curr Pharm Des,2005,11(10):1255-1265.
[87]Sadan O, Melamed E, Offen D. Bone-marrow-derived mesenchymal stem cell therapy for neurodegenerative diseases[J]. Expert Opin Biol Ther,2009,9(12):1487-1497.
[88]Brazelton T R, Rossi F M, Keshet G I, et al. From marrow to brain:expression of neuronal phenotypes in adult mice[J]. Science,2000,290(5497):1775-1779.
[89]Mezey E, Chandross K J, Harta G, et al. Turning blood into brain:cells bearing neuronal antigens generated in vivo from bone marrow[J]. Science,2000,290(5497):1779-1782.
[90]Jin H K, Carter J E, Huntley G W, et al. Intracerebral transplantation of mesenchymal stem cells into acid sphingomyelinase-deficient mice delays the onset of neurological abnormalities and extends their life span[J]. J Clin Invest,2002,109(9):1183-1191.
[91]Woodbury D, Schwarz E J, Prockop D J, et al. Adult rat and human bone marrow stromal cells differentiate into neurons[J]. J Neurosci Res,2000,61(4):364-370.
[92]Akiyama Y, Radtke C, Kocsis J D. Remyelination of the rat spinal cord by transplantation of identified bone marrow stromal cells[J]. J Neurosci,2002,22(15):6623-6630.
[93]Akiyama Y, Radtke C, Honmou O, et al. Remyelination of the spinal cord following intravenous delivery of bone marrow cells[J]. Glia,2002,39(3):229-236.
[94]Chopp M, Zhang X H, Li Y, et al. Spinal cord injury in rat:treatment with bone marrow stromal cell transplantation[J]. Neuroreport,2000,11(13):3001-3005.
[95]Gupta S, Verfaillie C, Chmielewski D, et al. A role for extrarenal cells in the regeneration following acute renal failure[J]. Kidney Int,2002,62(4):1285-1290.
[96]Poulsom R, Forbes S J, Hodivala-Dilke K, et al. Bone marrow contributes to renal parenchymal turnover and regeneration[J]. J Pathol,2001,195(2):229-235.
[97]Grimm P C, Nickerson P, Jeffery J, et al. Neointimal and tubulointerstitial infiltration by recipient mesenchymal cells in chronic renal-allograft rejection[J]. N Engl J Med,2001,345(2):93-97.
[98]Ito T, Suzuki A, Imai E, et al. Bone marrow is a reservoir of repopulating mesangial cells during glomerular remodeling[J]. J Am Soc Nephrol,2001,12(12):2625-2635.
[99]Cornacchia F, Fornoni A, Plati A R, et al. Glomerulosclerosis is transmitted by bone marrow-derived mesangial cell progenitors[J]. J Clin Invest,2001,108(11):1649-1656.
[100]Kale S, Karihaloo A, Clark P R, et al. Bone marrow stem cells contribute to repair of the ischemically injured renal tubule[J].J Clin Invest,2003,112(1):42-49.
[101]Gupta S, Rosenberg M E. Do stem cells exist in the adult kidney?[J]. Am J Nephrol,2008,28(4):607-613.
[102]Krause D, Cantley L G. Bone marrow plasticity revisited:protection or differentiation in the kidney tubule?[J]. J Clin Invest,2005,115(7):1705-1708.
[103]Baer P C, Geiger H. Mesenchymal stem cell interactions with growth factors on kidney repair[J]. Curr Opin Nephrol Hypertens,2010,19(1):1-6.
[104]Camussi G, Deregibus M C, Tetta C. Paracrine/endocrine mechanism of stem cells on kidney repair:role of microvesicle-mediated transfer of genetic information[J]. Curr Opin Nephrol Hypertens,2010,19(1):7-12.
[105]Ianus A, Holz G G, Theise N D, et al. In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion[J]. J Clin Invest,2003,111(6):843-850.
[106]Hess D, Li L, Martin M, et al. Bone marrow-derived stem cells initiate pancreatic regeneration[J]. Nat Biotechnol,2003,21(7):763-770.
[107]Theise N D, Henegariu O, Grove J, et al. Radiation pneumonitis in mice:a severe injury model for pneumocyte engraftment from bone marrow[J]. Exp Hematol,2002,30(11):1333-1338.
[108]Krause D S. Bone marrow-derived cells and stem cells in lung repair[J]. Proc Am Thorac Soc,2008,5(3):323-327.
[109]Trempus C S, Morris R J, Bortner C D, et al. Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34[J]. J Invest Dermatol,2003,120(4):501-511.
[110]Hoang M P, Keady M, Mahalingam M. Stem cell markers (cytokeratin 15, CD34 and nestin) in primary scarring and nonscarring alopecia[J]. Br J Dermatol,2009,160(3):609-615.
[111]Kloepper J E, Tiede S, Brinckmann J, et al. Immunophenotyping of the human bulge region:the quest to define useful in situ markers for human epithelial hair follicle stem cells and their niche[J]. Exp Dermatol,2008,17(7):592-609.
[112]Poblet E, Jimenez F, Godinez J M, et al. The immunohistochemical expression of CD34 in human hair follicles:a comparative study with the bulge marker CK15[J]. Clin Exp Dermatol,2006,31(6):807-812.
[113]Abbas O, Mahalingam M. Epidermal stem cells:practical perspectives and potential uses[J]. Br J Dermatol,2009,161(2):228-236.
[114]Blanpain C, Fuchs E. Epidermal homeostasis:a balancing act of stem cells in the skin[J]. Nat Rev Mol Cell Biol,2009,10(3):207-217.
[115]Fuchs E. Finding one's niche in the skin[J]. Cell Stem Cell,2009,4(6):499-502.
[116]Badiavas E V, Abedi M, Butmarc J, et al. Participation of bone marrow derived cells in cutaneous wound healing[J]. J Cell Physiol,2003,196(2):245-250.
[117]Okamoto R, Yajima T, Yamazaki M, et al. Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract[J]. Nat Med,2002,8(9):1011-1017.
[118]Demura T, Tashiro G, Horiguchi G, et al. Visualization by comprehensive microarray analysis of gene expression programs during transdifferentiation of mesophyll cells into xylem cells[J]. Proc Natl Acad Sci U S A,2002,99(24):15794-15799.
[119]Stocum D L. Development. A tail of transdifferentiation[J]. Science,2002,298(5600):1901-1903.
[120]Shen C N, Horb M E, Slack J M, et al. Transdifferentiation of pancreas to liver[J]. Mech Dev,2003,120(1):107-116.
[121]Shen C N, Slack J M, Tosh D. Molecular basis of transdifferentiation of pancreas to liver[J]. Nat Cell Biol,2000,2(12):879-887.
[122]Tang D G, Tokumoto Y M, Apperly J A, et al. Lack of replicative senescence in cultured rat oligodendrocyte precursor cells[J]. Science,2001,291(5505):868-871.
[123]Hakelien A M, Landsverk H B, Robl J M, et al. Reprogramming fibroblasts to express T-cell functions using cell extracts[J]. Nat Biotechnol,2002,20(5):460-466.
[124]Hardeman E C, Chiu C P, Minty A, et al. The pattern of actin expression in human fibroblast x mouse muscle heterokaryons suggests that human muscle regulatory factors are produced[J]. Cell,1986,47(1):123-130.
[125]Ying Q L, Nichols J, Evans E P, et al. Changing potency by spontaneous fusion[J].Nature,2002,416(6880):545-548.
[126]Terada N, Hamazaki T, Oka M, et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion[J]. Nature,2002,416(6880):542-545.
[127]Masuya M, Drake C J, Fleming P A, et al. Hematopoietic origin of glomerular mesangial cells[J]. Blood,2003,101(6):2215-2218.
[128]Vassilopoulos G, Wang P R, Russell D W. Transplanted bone marrow regenerates liver by cell fusion[J]. Nature,2003,422(6934):901-904.
[129]Zhang S, Wang D, Estrov Z, et al. Both cell fusion and transdifferentiation account for the transformation of human peripheral blood CD34-positive cells into cardiomyocytes in vivo[J]. Circulation,2004,110(25):3803-3807.
[130]Nygren J M, Jovinge S, Breitbach M, et al. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation[J]. Nat Med,2004,10(5):494-501.
[131]Murry C E, Soonpaa M H, Reinecke H, et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts[J]. Nature,2004,428(6983):664-668.
[132]Blau H M.A twist of fate[J]. Nature,2002,419(6906):437.
[133]Blau H M, Blakely B T. Plasticity of cell fate:insights from heterokaryons[J]. Semin Cell Dev Biol,1999,10(3):267-272.
[134]Wagers A J, Sherwood R I, Christensen J L, et al. Little evidence for developmental plasticity of adult hematopoietic stem cells[J]. Science,2002,297(5590):2256-2259.
[135]Pawliuk R, Westerman K A, Fabry M E, et al. Correction of sickle cell disease in transgenic mouse models by gene therapy[J]. Science,2001,294(5550):2368-2371.
[136]Matzner U, Hartmann D, Lullmann-Rauch R, et al. Bone marrow stem cell-based gene transfer in a mouse model for metachromatic leukodystrophy:effects on visceral and nervous system disease manifestations[J]. Gene Ther,2002,9(1):53-63.
[137]Siatskas C, Medin J A. Gene therapy for Fabry disease[J]. J Inherit Metab Dis,2001,24 Suppl 2:25-41,11-12.
[138]Grove J E, Lutzko C, Priller J, et al. Marrow-derived cells as vehicles for delivery of gene therapy to pulmonary epithelium[J]. Am J Respir Cell Mol Biol,2002,27(6):645-651.
[139]Priller J, Flugel A, Wehner T, et al. Targeting gene-modified hematopoietic cells to the central nervous system:use of green fluorescent protein uncovers microglial engraftment[J]. Nat Med,2001,7(12):1356-1361.
[140]Waterland R A. Epigenetic mechanisms and gastrointestinal development[J]. J Pediatr,2006,149(5 Suppl):S137-S142.
[141]Nowell P C. Foundations in cancer research. Chromosomes and cancer:the evolution of an idea[J]. Adv Cancer Res,1993,62:1-17.
[142]Clarke M F, Dick J E, Dirks P B, et al. Cancer stem cells--perspectives on current status and future directions:AACR Workshop on cancer stem cells [J]. Cancer Res,2006,66(19):9339-9344.
[143]Vogelstein B, Kinzler K W. The multistep nature of cancer[J]. Trends Genet,1993,9(4):138-141.
[144]Hickman E S, Moroni M C, Helin K. The role of p53 and pRB in apoptosis and cancer[J]. Curr Opin Genet Dev,2002,12(1):60-66.
[145]Malumbres M, Barbacid M. RAS oncogenes:the first 30 years[J]. Nat Rev Cancer,2003,3(6):459-465.
[146]Calin G A, Croce C M. MicroRNAs and chromosomal abnormalities in cancer cells[J].Oncogene,2006,25(46):6202-6210.
[147]Sancar A, Lindsey-Boltz L A, Unsal-Kacmaz K, et al. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints[J]. Annu Rev Biochem,2004,73:39-85.
[148]Wicha M S, Liu S, Dontu G. Cancer stem cells:an old idea--a paradigm shift[J]. Cancer Res,2006,66(4):1883-1890,1895-1896.
[149]Song L L, Miele L. Cancer stem cells-an old idea that's new again: implications for the diagnosis and treatment of breast cancer[J]. Expert Opin Biol Ther,2007,7(4):431-438.
[150]Pardal R, Clarke M F, Morrison S J. Applying the principles of stem-cell biology to cancer[J]. Nat Rev Cancer,2003,3(12):895-902.
[151]Bixby S, Kruger G M, Mosher J T, et al. Cell-intrinsic differences between stem cells from different regions of the peripheral nervous system regulate the generation of neural diversity[J]. Neuron,2002,35(4):643-656.
[152]Sagar J, Chaib B, Sales K, et al. Role of stem cells in cancer therapy and cancer stem cells:a review[J]. Cancer Cell Int,2007,7:9.
[153]Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice[J]. Nature,1994,367(6464):645-648.
[154]Bonnet D, Dick J E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell[J]. Nat Med,1997,3(7):730-737.
[155]Hemmati H D, Nakano I, Lazareff J A, et al. Cancerous stem cells can arise from pediatric brain tumors[J]. Proc Natl Acad Sci U S A,2003,100(25):15178-15183.
[156]Singh S K, Clarke I D, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors[J]. Cancer Res,2003,63(18):5821-5828.
[157]Singh S K, Hawkins C, Clarke I D, et al. Identification of human brain tumour initiating cells[J]. Nature,2004,432(7015):396-401.
[158]Seigel G M, Hackam A S, Ganguly A, et al. Human embryonic and neuronal stem cell markers in retinoblastoma[J]. Mol Vis,2007,13:823-832.
[159]O'Brien C A, Pollett A, Gallinger S, et al. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice[J]. Nature,2007,445(7123):106-110.
[160]Ricci-Vitiani L, Lombardi D G, Pilozzi E, et al. Identification and expansion of human colon-cancer-initiating cells[J]. Nature,2007,445(7123):111-115.
[161]Haraguchi N, Ohkuma M, Sakashita H, et al. CD133+CD44+ population efficiently enriches colon cancer initiating cells[J]. Ann Surg Oncol,2008,15(10):2927-2933.
[162]Puglisi M A, Sgambato A, Saulnier N, et al. Isolation and characterization of CD133+ cell population within human primary and metastatic colon cancer[J]. Eur Rev Med Pharmacol Sci,2009,13 Suppl 1:55-62.
[163]Fang D D, Kim Y J, Lee C N, et al. Expansion of CD133(+) colon cancer cultures retaining stem cell properties to enable cancer stem cell target discovery[J]. Br J Cancer,2010,102(8):1265-1275.
[164]Haraguchi N, Inoue H, Tanaka F, et al. Cancer stem cells in human gastrointestinal cancers[J]. Hum Cell,2006,19(1):24-29.
[165]Prince M E, Sivanandan R, Kaczorowski A, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma[J]. Proc Natl Acad Sci U S A,2007,104(3):973-978.
[166]Wang J, Guo L P, Chen L Z, et al. Identification of cancer stem cell-like side population cells in human nasopharyngeal carcinoma cell line[J]. Cancer Res,2007,67(8):3716-3724.
[167]Schatton T, Murphy G F, Frank N Y, et al. Identification of cells initiating human melanomas[J]. Nature,2008,451(7176):345-349.
[168]Fang D, Nguyen T K, Leishear K, et al. A tumorigenic subpopulation with stem cell properties in melanomas[J]. Cancer Res,2005,65(20):9328-9337.
[169]Held M A, Curley D P, Dankort D, et al. Characterization of melanoma cells capable of propagating tumors from a single cell[J]. Cancer Res,2010,70(1):388-397.
[170]Wright M H, Calcagno A M, Salcido C D, et al. Brcal breast tumors contain distinct CD44+/CD24- and CD133+ cells with cancer stem cell characteristics[J]. Breast Cancer Res,2008,10(1):R10.
[171]Al-Hajj M, Wicha M S, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells[J]. Proc Natl Acad Sci U S A,2003,100(7):3983-3988.
[172]Curley M D, Therrien V A, Cummings C L, et al. CD 133 expression defines a tumor initiating cell population in primary human ovarian cancer[J]. Stem Cells,2009,27(12):2875-2883.
[173]Olempska M, Eisenach P A, Ammerpohl O, et al. Detection of tumor stem cell markers in pancreatic carcinoma cell lines[J]. Hepatobiliary Pancreat Dis Int,2007,6(1):92-97.
[174]Tirino V, Camerlingo R, Franco R, et al. The role of CD 133 in the identification and characterisation of tumour-initiating cells in non-small-cell lung cancer[J]. Eur J Cardiothorac Surg,2009,36(3):446-453.
[175]Bertolini G, Roz L, Perego P, et al. Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment[J]. Proc Natl Acad Sci U S A,2009,106(38):16281-16286.
[176]Ho M M, Ng A V, Lam S, et al. Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells[J]. Cancer Res,2007,67(10):4827-4833.
[177]Tirino V, Desiderio V, D'Aquino R, et al. Detection and characterization of CD133+ cancer stem cells in human solid tumours[J]. PLoS One,2008,3(10):e3469.
[178]Tomuleasa C, Soritau O, Rus-Ciuca D, et al. Isolation and characterization of hepatic cancer cells with stem-like properties from hepatocellular carcinoma[J]. J Gastrointestin Liver Dis,2010,19(1):61-67.
[179]Zhu Z, Hao X, Yan M, et al. Cancer stem/progenitor cells are highly enriched in CD133+CD44+ population in hepatocellular carcinoma[J]. Int J Cancer,2010,126(9):2067-2078.
[180]Zen Y, Fujii T, Yoshikawa S, et al. Histological and culture studies with respect to ABCG2 expression support the existence of a cancer cell hierarchy in human hepatocellular carcinoma[J]. Am J Pathol.2007,170(5):1750-1762.
[181]Dalerba P, Dylla S J, Park I K, et al. Phenotypic characterization of human colorectal cancer stem cells[J]. Proc Natl Acad Sci U S A,2007,104(24):10158-10163.
[182]Kondo T. Stem cell-like cancer cells in cancer cell lines[J]. Cancer Biomark,2007,3(4-5):245-250.
[183]Setoguchi T, Taga T, Kondo T. Cancer stem cells persist in many cancer cell lines[J]. Cell Cycle,2004,3(4):414-415.
[184]Collins A T, Berry P A, Hyde C, et al. Prospective identification of tumorigenic prostate cancer stem cells[J]. Cancer Res,2005,65(23):10946-10951.
[185]Yu J, Vodyanik M A, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells[J]. Science,2007,318(5858):1917-1920.
[186]Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors[J]. Cell,2007,131(5):861-872.
[187]Hugo H, Ackland M L, Blick T, et al. Epithelial--mesenchymal and mesenchymal--epithelial transitions in carcinoma progression[J]. J Cell Physiol,2007,213(2):374-383.
[188]Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression:an alliance against the epithelial phenotype?[J]. Nat Rev Cancer,2007,7(6):415-428.
[189]Gupta P B, Mani S, Yang J, et al. The evolving portrait of cancer metastasis[J]. Cold Spring Harb Symp Quant Biol,2005,70:291-297.
[190]Yang J, Mani S A, Weinberg R A. Exploring a new twist on tumor metastasis [J]. Cancer Res,2006,66(9):4549-4552.
[191]Hendrix M J, Seftor R E, Seftor E A, et al. Transendothelial function of human metastatic melanoma cells:role of the microenvironment in cell-fate determination[J]. Cancer Res,2002,62(3):665-668.
[192]Hess A R, Margaryan N V, Seftor E A, et al. Deciphering the signaling events that promote melanoma tumor cell vasculogenic mimicry and their link to embryonic vasculogenesis:role of the Eph receptors[J]. Dev Dyn,2007,236(12):3283-3296.
[193]Read T A, Fogarty M P, Markant S L, et al. Identification of CD 15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma[J]. Cancer Cell,2009,15(2):135-147.
[194]Son M J, Woolard K, Nam D H, et al. SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma[J]. Cell Stem Cell,2009,4(5):440-452.
[195]Ward R J, Lee L, Graham K, et al. Multipotent CD15+ cancer stem cells in patched-1-deficient mouse medulloblastoma[J]. Cancer Res,2009,69(11):4682-4690.
[196]Du L, Wang H, He L, et al. CD44 is of functional importance for colorectal cancer stem cells[J]. Clin Cancer Res,2008,14(21):6751-6760.
[197]Chu P, Clanton D J, Snipas T S, et al. Characterization of a subpopulation of colon cancer cells with stem cell-like properties[J]. Int J Cancer,2009,124(6):1312-1321.
[198]Li C, Heidt D G, Dalerba P, et al. Identification of pancreatic cancer stem cells[J]. Cancer Res,2007,67(3):1030-1037.
[199]Zhou S, Schuetz J D, Bunting K D, et al. The ABC transporter Bcrpl/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype[J]. Nat Med,2001,7(9):1028-1034.
[200]Hirschmann-Jax C, Foster A E, Wulf G G, et al. A distinct "side population" of cells with high drug efflux capacity in human tumor cells[J]. Proc Natl Acad Sci U S A,2004,101(39):14228-14233.
[201]Komuro H, Saihara R, Shinya M, et al. Identification of side population cells (stem-like cell population) in pediatric solid tumor cell lines[J]. J Pediatr Surg,2007,42(12):2040-2045.
[202]Wang Y H, Li F, Luo B, et al. A side population of cells from a human pancreatic carcinoma cell line harbors cancer stem cell characteristics^]. Neoplasma,2009,56(5):371-378.
[203]Yao J, Cai H H, Wei J S, et al. Side population in the pancreatic cancer cell lines SW1990 and CFPAC-1 is enriched with cancer stem-like cells[J]. Oncol Rep,2010,23(5):1375-1382.
[204]Ginestier C, Hur M H, Charafe-Jauffret E, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome[J]. Cell Stem Cell,2007,1(5):555-567.
[205]Huang E H, Hynes M J, Zhang T, et al. Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis[J]. Cancer Res,2009,69(8):3382-3389.
[206]Kelly P N, Dakic A, Adams J M, et al. Tumor growth need not be driven by rare cancer stem cells[J]. Science,2007,317(5836):337.
[207]Hill R P. Identifying cancer stem cells in solid tumors:case not proven[J]. Cancer Res,2006,66(4):1891-1895,1890.
[208]Kuperwasser C, Chavarria T, Wu M, et al. Reconstruction of functionally normal and malignant human breast tissues in mice[J]. Proc Natl Acad Sci U S A,2004,101(14):4966-4971.
[209]Scadden D T. The stem cell niche in health and leukemic disease[J]. Best Pract Res Clin Haematol,2007,20(1):19-27.
[210]Gilbertson R J, Rich J N. Making a tumour's bed:glioblastoma stem cells and the vascular niche[J]. Nat Rev Cancer,2007,7(10):733-736.
[211]Baguley B C. Tumor stem cell niches:a new functional framework for the action of anticancer drugs[J]. Recent Pat Anticancer Drug Discov,2006,1(1):121-127.
[212]Yang Z J, Wechsler-Reya R J. Hit 'em where they live:targeting the cancer stem cell niche[J]. Cancer Cell,2007,11(1):3-5.
[213]Hoelzinger D B, Demuth T, Berens M E. Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment[J]. J Natl Cancer Inst,2007,99(21):1583-1593.
[214]Fodde R, Brabletz T. Wnt/beta-catenin signaling in cancer sternness and malignant behavior[J]. Curr Opin Cell Biol,2007,19(2):150-158.
[215]Dontu G, Wicha M S. Survival of mammary stem cells in suspension culture: implications for stem cell biology and neoplasia[J]. J Mammary Gland Biol Neoplasia,2005,10(1):75-86.
[216]Liu S, Dontu G, Wicha M S. Mammary stem cells, self-renewal pathways, and carcinogenesis[J]. Breast Cancer Res,2005,7(3):86-95.
[217]Hosen N, Park C Y, Tatsumi N, et al. CD96 is a leukemic stem cell-specific marker in human acute myeloid leukemia[J]. Proc Natl Acad Sci U S A,2007,104(26):11008-11013.
[218]Katoh M. Networking of WNT, FGF, Notch, BMP, and Hedgehog signaling pathways during carcinogenesis[J]. Stem Cell Rev,2007,3(1):30-38.
[219]Tung D C, Chao K S. Targeting hedgehog in cancer stem cells:how a paradigm shift can improve treatment response[J]. Future Oncol,2007,3(5):569-574.
[220]Cho R W, Wang X, Diehn M, et al. Isolation and molecular characterization of cancer stem cells in MMTV-Wnt-1 murine breast tumors[J]. Stem Cells,2008,26(2):364-371.
[221]Korkaya H, Wicha M S. Selective targeting of cancer stem cells:a new concept in cancer therapeutics [J]. BioDrugs,2007,21(5):299-310.
[222]Dontu G, Jackson K W, Mcnicholas E, et al. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells[J]. Breast Cancer Res,2004,6(6):R605-R615.
[223]Bailey J M, Singh P K, Hollingsworth M A. Cancer metastasis facilitated by developmental pathways:Sonic hedgehog, Notch, and bone morphogenic proteins[J]. J Cell Biochem,2007,102(4):829-839.
[224]Rizzo P, Osipo C, Foreman K, et al. Rational targeting of Notch signaling in cancer[J].Oncogene,2008,27(38):5124-5131.
[225]Shih A H, Holland E C. Notch signaling enhances nestin expression in gliomas[J]. Neoplasia,2006,8(12):1072-1082.
[226]Phillips H S, Kharbanda S, Chen R, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis[J]. Cancer Cell,2006,9(3):157-173.
[227]Fan X, Matsui W, Khaki L, et al. Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors[J]. Cancer Res,2006,66(15):7445-7452.
[228]Reedijk M, Odorcic S, Chang L, et al. High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival[J]. Cancer Res,2005,65(18):8530-8537.
[229]Dickson B C, Mulligan A M, Zhang H, et al. High-level JAG1 mRNA and protein predict poor outcome in breast cancer[J]. Mod Pathol,2007,20(6):685-693.
[230]Farnie G, Clarke R B, Spence K, et al. Novel cell culture technique for primary ductal carcinoma in situ:role of Notch and epidermal growth factor receptor signaling pathways[J]. J Natl Cancer Inst,2007,99(8):616-627.