抗人CD133单克隆抗体的制备及CD133抗原在肝癌组织中的表达
摘要
肝细胞肝癌(hepatocellular carcinoma, HCC)是世界范围内死亡率最高的恶性肿瘤之一,也是我国常见的恶性肿瘤之一,恶性程度高,发展迅速,治疗困难,总体疗效不理想。
肿瘤干细胞(Tumor stem cell, TSC;亦称癌干细胞,cancer stem cell, CSC)的概念是在长期的研究中逐步发展形成的。肿瘤干细胞是指癌瘤组织中少量存在的具有自我更新能力、分化潜能的细胞,该群细胞属于成体干细胞的范畴且自我更新失控。研究认为肿瘤干细胞是肿瘤形成的起始细胞,可能是肿瘤发生、发展、转移、复发的根源。目前研究表明,肿瘤干细胞存在于包括白血病、乳腺癌、脑肿瘤、结直肠癌及胰腺癌等恶性肿瘤中。而对肝细胞肝癌的研究显示肝细胞癌的发生发展过程中可能也有肿瘤干细胞的参与。
在不同类型的肿瘤中研究者们发现了不同的肿瘤干细胞表面标记分子。而CD133分子则是其中的重要成员之一。人CD133基因位于4号染色体,基因全长约160Kb,含有27个外显子,开放性读框(ORF)为2598bp,编码865个氨基酸(从),分子量约为120KD,基因的编码产物——CD133抗原为5跨膜糖蛋白。
大量研究表明,通过细胞表面标记CD133分子,可有效地识别和鉴定多种肿瘤的肿瘤干细胞,从而对肿瘤干细胞的特性进行分析。并且CD133与肿瘤的转移、肿瘤的血管生成都有关系。另外研究者报道,可通过检测CD133 mRNA水平预测肿瘤的复发,并且认为CD133可以作为某些肿瘤的预后指标。而对肝癌干细胞的研究表明CD133抗原可能是肝癌干细胞的表面标记物。
鉴此,本研究以普外科常见病肝癌为研究对象,以肿瘤干细胞表面标记分子CD133为切入点,初步探讨CD133在肝癌临床标本的表达及其临床意义。
本研究利用高质量的cDNA基因文库提供的模板,为克隆CD133全长基因提供了可靠的物质基础,采用PCR分段克隆重叠片段,从技术层面解决了此类长基因克隆的瓶颈。
进而,本研究将CD133基因克隆入真核表达载体,转染小鼠成纤维细胞L929细胞,获得了基因工程细胞株L-CD133,这为进一步研究CD133的生物学功能提供了物质基础,同时,基因工程细胞株的构建也使CD133抗原胞外段的天然空间结构充分展示,获得了后续的抗人CD133单抗得研制过程关键的筛选抗原。
鉴于与CD133相互作用的生物因子尚未被发现,利用特异性抗体刺激细胞膜表面分子是目前能用于激发CD133分子生物学功能的有效手段。然而目前国际上已有的抗CD133单抗中,尚无功能性CD133的报道。因此,本部分研究在克隆人CD133全长基因和建立其基因工程细胞株的基础上,进而研制抗人CD133单克隆抗体,具有重要的理论意义和应用价值。为了进一步深入探讨CD133分子在肿瘤干细胞的的表达和临床意义,获得探索诊断和治疗肿瘤的新手段,本研究以单核细胞性白血病细胞株U937细胞株免疫Balb/c小鼠,L-CD133基因工程细胞株为筛选抗原,采用B淋巴瘤杂交瘤技术,成功地建立了稳定分泌抗人CD133单克隆抗体(686)的杂交瘤细胞株,并分离纯化单克隆抗体和进行了单抗特性的初步鉴定。单抗686的识别谱与商品化抗人CD133单抗AC141类似,该抗体还可用于肠癌组织的免疫组织化学分析,在肠癌组织标本上检测到CD133抗原的表达。进而发现,单抗686可有效抑制CD133+肠癌细胞Caco-2的增殖。
继而,本研究用自制鼠抗人CD133单克隆抗体686作为工具,以免疫组织化学为主要方法对CD133抗原在人肝癌组织中的表达情况进行系统的研究,并对其在肝癌组织中的表达同患者的主要临床病理特征之间的关系进行探讨。研究发现：单抗6B6可用于肝癌组织的免疫组织化学分析,可在肝癌组织标本上检测到CD133抗原的表达。且大部分标本阳性细胞比率<1%,一般不超过5%。这说明CD133+肝癌干细胞在整个肝癌组织中所占比例是比较低的。本研究发现CD133抗原的表达同患者的血清AFP水平、肝癌病理分化等级有显著相关性P<0.05。血清AFP水平高、肿瘤分化程度低的病例更多见CD133抗原表达。而CD133抗原表达同患者的年龄、性别、肿瘤的大小没有相关性。
综上,我们获得了一株特异性抗人CD133单克隆抗体,在肿瘤临床诊断和免疫治疗中具有潜在应用价值。
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide, one of the most common malignant tumors in China as well. It is difficult to cure because of its high-grade malignancy and rapid progress.
The theory of tumor stem cell (TSC), or cancer stem cell (CSC) is well established based on numerous data that accumulated in dozens of decades.
TSC is a small population within tumors, and belongs to adult stem cells with characteristic of self-renewing, differentiation and malignant proliferation. More and more reports demonstrated that CD133+ cell subpopulation from tumor was identified as tumour initiating cells. In a way, the CD133+ cancer stem cells are the origin of chemoresistance, apoptosis resistance, metastasis and recurrence of various kinds of cancers. TSC was found in many types of tumors, including leukemia, breast cancer, brain cancer, colorectal cancer, pancreatic cancer. It is reported that TSC is involved in the pathologic process of hepatocarcinoma as well.
Many kinds of biomarkers of TSC were found on different types of tumors.CD133 is one of the most important biomarkers to identify TSC.CD133 gene is located in chromosome 4. The full length CD133 gene is 160Kb, and it is composed of 27 exons with 1589bp of ORF(open reading frame), edcoding 5-transmembrane glycoprotein with 865 aminoacide residues, and its expected molecule weight is 120KD.
Many reports demonstrated that CD133 is a perfect surface marker to identify TSC from many types of tumor. CD133+ cells are associated with tumor metastasis and tumor microvessels formation. Tumor relapse could be detected by quantitative CD133 expression in mRNA level. CD133 is also the surface biomarker of TSC of hepatocarcinoma.
Hence, our study is focused on the expression of CD133 of hepatocacinoma and its clinical significance.
First, we break through the bottle neck of long gene (>2Kb) cloning by using high quality fetal liver cDNA library as PCR template and cloning 3 overlaped fragments. And then, all the fragments were linked together to get the full length CD 133 gene by PCR.
Then, the full lentgh CD 133 gene was subcloned into eukaryotic expression vector pIRES/EGFP. And the mouse fibroblast cell L929 was infected with the pIRES/EGFP/CD133 expression vector. CD 133 antigen expressed on the L929 cell surface and it is critical for preparation of monoclonal antibody against human CD 133.
However, the counterpart of CD133 is unknown. As our knowledge, the specific monoclonal antibody may ligate and convey the signal to a cell surface receptor. But there is no report of functional monoclonal antibodies against CD133. In this study, Balb/c mice were immunized with CD133+ monocytic cell line U937. Hybridoma was obtained with B-lymphocyte hybridoma technology. Briefly, splenocytes from immunized mice and myeloma cells SP2/0 were fused and screened with CD133 transfectant L-CD133 and its negative control cells L-mock. And then, the monoclonal antibody against human CD133 (6B6) was purified and its characteristic was identified. Similar to commercial antibody AC141, mAb6B6 could recognize CD133 molecules on different type of cell lines by immunostaining and flow cytometric analysis. MAb 6B6 could detect CD133+ cancer cells in colorectal samples by immunohistochemical staining. And then, we stimulated colorectal cell line Caco-2 that expressed CD133 with mAb 6B6 in vitro. Interestingly, we found that the proliferation of Caco-2cells was obviously inhibited in presence of MAb 6B6.
Furthermore, we analyzed CD133 expression on hepatocellular carcinoma samples by immunohistochemical staining and discussed its clinical significance. MAb 6B6 could detect CD133+ cells on hepatocellular carcinoma tissue. The ratios of CD133+ cells were less than 5% and were lower than 1% on most of the samples. It is demonstrated that CD133+ hepatocellular carcinoma TSC is exist but it is a small population. Our data showed that the expression of CD133 is correlated with serum AFP level and pathological differentiation of hepatocellular carcinoma patients.(P<0.05) The higher lever of serum AFP and more poorly differentiation of hepatocellular carcinoma, the higher ratio of CD133+ cells. And there is no correlation of age, sex and tumor volumn with CD133+ TSC ratio.
In conclusion, we have obtained a specific anti-human CD133 MAb with the potential for research and clinical applications in tumor diagnosis and immunotherapy.
肿瘤干细胞(Tumor stem cell, TSC;亦称癌干细胞,cancer stem cell, CSC)的概念是在长期的研究中逐步发展形成的。肿瘤干细胞是指癌瘤组织中少量存在的具有自我更新能力、分化潜能的细胞,该群细胞属于成体干细胞的范畴且自我更新失控。研究认为肿瘤干细胞是肿瘤形成的起始细胞,可能是肿瘤发生、发展、转移、复发的根源。目前研究表明,肿瘤干细胞存在于包括白血病、乳腺癌、脑肿瘤、结直肠癌及胰腺癌等恶性肿瘤中。而对肝细胞肝癌的研究显示肝细胞癌的发生发展过程中可能也有肿瘤干细胞的参与。
在不同类型的肿瘤中研究者们发现了不同的肿瘤干细胞表面标记分子。而CD133分子则是其中的重要成员之一。人CD133基因位于4号染色体,基因全长约160Kb,含有27个外显子,开放性读框(ORF)为2598bp,编码865个氨基酸(从),分子量约为120KD,基因的编码产物——CD133抗原为5跨膜糖蛋白。
大量研究表明,通过细胞表面标记CD133分子,可有效地识别和鉴定多种肿瘤的肿瘤干细胞,从而对肿瘤干细胞的特性进行分析。并且CD133与肿瘤的转移、肿瘤的血管生成都有关系。另外研究者报道,可通过检测CD133 mRNA水平预测肿瘤的复发,并且认为CD133可以作为某些肿瘤的预后指标。而对肝癌干细胞的研究表明CD133抗原可能是肝癌干细胞的表面标记物。
鉴此,本研究以普外科常见病肝癌为研究对象,以肿瘤干细胞表面标记分子CD133为切入点,初步探讨CD133在肝癌临床标本的表达及其临床意义。
本研究利用高质量的cDNA基因文库提供的模板,为克隆CD133全长基因提供了可靠的物质基础,采用PCR分段克隆重叠片段,从技术层面解决了此类长基因克隆的瓶颈。
进而,本研究将CD133基因克隆入真核表达载体,转染小鼠成纤维细胞L929细胞,获得了基因工程细胞株L-CD133,这为进一步研究CD133的生物学功能提供了物质基础,同时,基因工程细胞株的构建也使CD133抗原胞外段的天然空间结构充分展示,获得了后续的抗人CD133单抗得研制过程关键的筛选抗原。
鉴于与CD133相互作用的生物因子尚未被发现,利用特异性抗体刺激细胞膜表面分子是目前能用于激发CD133分子生物学功能的有效手段。然而目前国际上已有的抗CD133单抗中,尚无功能性CD133的报道。因此,本部分研究在克隆人CD133全长基因和建立其基因工程细胞株的基础上,进而研制抗人CD133单克隆抗体,具有重要的理论意义和应用价值。为了进一步深入探讨CD133分子在肿瘤干细胞的的表达和临床意义,获得探索诊断和治疗肿瘤的新手段,本研究以单核细胞性白血病细胞株U937细胞株免疫Balb/c小鼠,L-CD133基因工程细胞株为筛选抗原,采用B淋巴瘤杂交瘤技术,成功地建立了稳定分泌抗人CD133单克隆抗体(686)的杂交瘤细胞株,并分离纯化单克隆抗体和进行了单抗特性的初步鉴定。单抗686的识别谱与商品化抗人CD133单抗AC141类似,该抗体还可用于肠癌组织的免疫组织化学分析,在肠癌组织标本上检测到CD133抗原的表达。进而发现,单抗686可有效抑制CD133+肠癌细胞Caco-2的增殖。
继而,本研究用自制鼠抗人CD133单克隆抗体686作为工具,以免疫组织化学为主要方法对CD133抗原在人肝癌组织中的表达情况进行系统的研究,并对其在肝癌组织中的表达同患者的主要临床病理特征之间的关系进行探讨。研究发现：单抗6B6可用于肝癌组织的免疫组织化学分析,可在肝癌组织标本上检测到CD133抗原的表达。且大部分标本阳性细胞比率<1%,一般不超过5%。这说明CD133+肝癌干细胞在整个肝癌组织中所占比例是比较低的。本研究发现CD133抗原的表达同患者的血清AFP水平、肝癌病理分化等级有显著相关性P<0.05。血清AFP水平高、肿瘤分化程度低的病例更多见CD133抗原表达。而CD133抗原表达同患者的年龄、性别、肿瘤的大小没有相关性。
综上,我们获得了一株特异性抗人CD133单克隆抗体,在肿瘤临床诊断和免疫治疗中具有潜在应用价值。
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide, one of the most common malignant tumors in China as well. It is difficult to cure because of its high-grade malignancy and rapid progress.
The theory of tumor stem cell (TSC), or cancer stem cell (CSC) is well established based on numerous data that accumulated in dozens of decades.
TSC is a small population within tumors, and belongs to adult stem cells with characteristic of self-renewing, differentiation and malignant proliferation. More and more reports demonstrated that CD133+ cell subpopulation from tumor was identified as tumour initiating cells. In a way, the CD133+ cancer stem cells are the origin of chemoresistance, apoptosis resistance, metastasis and recurrence of various kinds of cancers. TSC was found in many types of tumors, including leukemia, breast cancer, brain cancer, colorectal cancer, pancreatic cancer. It is reported that TSC is involved in the pathologic process of hepatocarcinoma as well.
Many kinds of biomarkers of TSC were found on different types of tumors.CD133 is one of the most important biomarkers to identify TSC.CD133 gene is located in chromosome 4. The full length CD133 gene is 160Kb, and it is composed of 27 exons with 1589bp of ORF(open reading frame), edcoding 5-transmembrane glycoprotein with 865 aminoacide residues, and its expected molecule weight is 120KD.
Many reports demonstrated that CD133 is a perfect surface marker to identify TSC from many types of tumor. CD133+ cells are associated with tumor metastasis and tumor microvessels formation. Tumor relapse could be detected by quantitative CD133 expression in mRNA level. CD133 is also the surface biomarker of TSC of hepatocarcinoma.
Hence, our study is focused on the expression of CD133 of hepatocacinoma and its clinical significance.
First, we break through the bottle neck of long gene (>2Kb) cloning by using high quality fetal liver cDNA library as PCR template and cloning 3 overlaped fragments. And then, all the fragments were linked together to get the full length CD 133 gene by PCR.
Then, the full lentgh CD 133 gene was subcloned into eukaryotic expression vector pIRES/EGFP. And the mouse fibroblast cell L929 was infected with the pIRES/EGFP/CD133 expression vector. CD 133 antigen expressed on the L929 cell surface and it is critical for preparation of monoclonal antibody against human CD 133.
However, the counterpart of CD133 is unknown. As our knowledge, the specific monoclonal antibody may ligate and convey the signal to a cell surface receptor. But there is no report of functional monoclonal antibodies against CD133. In this study, Balb/c mice were immunized with CD133+ monocytic cell line U937. Hybridoma was obtained with B-lymphocyte hybridoma technology. Briefly, splenocytes from immunized mice and myeloma cells SP2/0 were fused and screened with CD133 transfectant L-CD133 and its negative control cells L-mock. And then, the monoclonal antibody against human CD133 (6B6) was purified and its characteristic was identified. Similar to commercial antibody AC141, mAb6B6 could recognize CD133 molecules on different type of cell lines by immunostaining and flow cytometric analysis. MAb 6B6 could detect CD133+ cancer cells in colorectal samples by immunohistochemical staining. And then, we stimulated colorectal cell line Caco-2 that expressed CD133 with mAb 6B6 in vitro. Interestingly, we found that the proliferation of Caco-2cells was obviously inhibited in presence of MAb 6B6.
Furthermore, we analyzed CD133 expression on hepatocellular carcinoma samples by immunohistochemical staining and discussed its clinical significance. MAb 6B6 could detect CD133+ cells on hepatocellular carcinoma tissue. The ratios of CD133+ cells were less than 5% and were lower than 1% on most of the samples. It is demonstrated that CD133+ hepatocellular carcinoma TSC is exist but it is a small population. Our data showed that the expression of CD133 is correlated with serum AFP level and pathological differentiation of hepatocellular carcinoma patients.(P<0.05) The higher lever of serum AFP and more poorly differentiation of hepatocellular carcinoma, the higher ratio of CD133+ cells. And there is no correlation of age, sex and tumor volumn with CD133+ TSC ratio.
In conclusion, we have obtained a specific anti-human CD133 MAb with the potential for research and clinical applications in tumor diagnosis and immunotherapy.
引文
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[53]Mehra N, Penning M, Maas J, et al. Progenitor Marker CD 133 mRNA Is Elevated in Peripheral Blood of Cancer Patients with Bone Metastases. Clin. Cancer Res.,2006,12: 4859-4866.
[54]Rappa G, Fodstad O, and Lorico A. The Stem Cell-Associated Antigen CD133 (Prominin-1) Is a Molecular Therapeutic Target for Metastatic Melanoma. Stem Cells, 2008,26:3008-3017.
[55]Suetsugu A, Nagaki M, Aoki H, et al. Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells. Biochem Biophys Res Commun., 2006,35 1(4):820-824.
[56]Ma S Chan KW Hu L et al. Identification and characterization of tumorigenic liver
cancer stem/progenitor cells.Gastroenterology,2007,132(7):2542-2556.
[57]Song W, Li H,Tao K, et al. Expression and clinical significance of the stem cell marker CD 133 in hepatocellular carcinoma J. Int J Clin Pract.2008,62(8):1212-1218.
[58]Salnikov AV, Kusumawidjaja, GRausch V,et al. Cancer stem cell marker expression in hepatocellular carcinoma and liver metastases is not sufficient as single prognostic parameter. Cancer Lett,2009,275 (2):185-193.
[59]Yin S, Li J, Hu C,et al. CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity.Int J Cancer,2007,120(7):1444-1450.
[2]Weigmann A, Corbeil D, Hellwig A, et al. Prominin, a novel microvilli_specific polytopic membrane protein of the apical surface of epithelial cells, is targeted to plasmalemmal protrusions of non_epithelial cells. Proc Natl Acad Sci USA,1997, 94(23):12425-12430.
[3]Yu Y, Flint A, Dvorin EL, et al. AC133-2,a novel isoform of human AC133 stem cell antigen. J Biol Chem,2002,277(23):207112-20716.
[4]Fargears CA, Corbeil D and Huttner WB. AC133 Antigen, CD133, Prominin-1, Prominin-2, Etc:Prominin Family Genes in Need of A Rational Nomemclature. Stem Cell,2003,21(4):506-508.
[5]Corbeil D, Roper K, Weigmann A, et al. AC133 Hematopoietic Stem Cell Antigen: Human Homologue of Mouse Kidney Prominin or Distinct Member of a Novel Protein Family? Blood,1998,91:2625-2626.
[6]Corbeil D, Roper K, Hellwig A, et al. The Human AC 133 Hematopoietic Stem Cell Antigen Is also Expressed in Epithelial Cells and Targeted to Plasma Membrane Protrusions. J Biol Chem,2000,275(8):5512-5520.
[7]Richardson GD, Robson CN, Lang SH, et al. CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci,2004,117:3539-3545.
[8]Torrente Y, Belicchi M, Sampaolesi M, et al. Human circulating AC133+ stem cells restore dystrophin expression and ameliorate function in dystrophic skeletal muscle. J Clin Invest.2004,114(2):182-195.
[9]Maw MA, Corbeil D, Koch J, et al. A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. Hum Mol Genet,2000,9(1):27-34.
[10]Bhatia MA. AC133 expression in human stem cells. Leukemia,2001,15(11): 1685-1688.
[11]Wynter EA, Buck D, Hart C, et al. CD34+AC133+ Cells Isolated from Cord Blood are Highly Enriched in Long-Term Culture-Initiating Cells, NOD/SCID-Repopulating Cells and Dendritic Cell Progenitors. Stem Cells,1998,16:387-396.
[12]Pfenninger CV, Roschupkina T, Hertwig F, et al. CD133 Is Not Present on Neurogenic Astrocytes in the Adult Subventricular Zone, but on Embryonic Neural Stem Cells, Ependymal Cells, and Glioblastoma Cells. Cancer Res,2007,67(12):5727-5736.
[13]Rountree CB, Barsky L, Ge S, et al. A CD133-Expressing Murine Liver Oval Cell Population with Bilineage Potential. Stem Cells,2007,25:2419-2429.
[14]Vander Griend DJ, Karthaus WL, Dalrymple S, et al. The Role of CD133 in Normal Human Prostate Stem Cells and Malignant Cancer-Initiating Cells. Cancer Res.,2008, 68:9703-9711.
[15]Shi M, Ishikawa M, Nakasa T, et al. Acceleration of Skeletal Muscle Regeneration in a Rat Skeletal Muscle Injury Model by Local Injection of Human Peripheral Blood-Derived CD133-Positive Cells. Stem Cells,2009,27:949-960.
[16]Alakel N, Jing D, Muller K, et al. Direct contact with mesenchymal stromal cells affects migratory behavior and gene expression profile of CD133+ hematopoietic stem cells during ex vivo expansion. Experimental hematology,2009,37(4):504-513.
[17]Tondreau T, Meuleman N, Delforge A, et al. Mesenchymal Stem Cells Derived from CD133-Positive Cells in Mobilized Peripheral Blood and Cord Blood:Proliferation, Oct4 Expression, and Plasticity. Stem Cells,2005; 23:1105-1112.
[18]Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med 2006; 355:1253-1261.
[19]Reya T, Morrison SJ, Clafke M F, et al. Stem cells, cancer, and cancer stem cells. Nature,2001,414:105-111.
[20]Lapidot T, Sirarad C, Vormoor J, et al. Acellinitiating human acute myeloid leukemia after transplantation into SCID mice. Nature,1994,367:645-648.
[21]Passegue E, Jamieson C, Ailles LE, et al. Normal and leukemic hematopoiesis:Are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc Natl Acad Sci U S A.2003,100:11842-11849.
[22]Singh SK, Clarke ID, Hide T, et al. Cancer stem cells in nervous system tumors. Oncogene,2004,23:7267-7273.
[23]Kim CF, Jackson EL, Woolfenden AE, et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell,2005,121:823-835.
[24]Haraguchi N, Utsunomiya T, Inoue H, et al. Characterization of a Side Population of Cancer Cells from Human Gastrointestinal System. Stem Cells,2006,24(3): 506-513.
[25]Patrawala L, Calhoun T, Schneider-Broussard R, et al. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastasis progenitor cells. Oncogene,2006,25:1696-1708.
[26]Prince ME, Sivanandan R, Kaczorowski A, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc. Natl. Acad. Sci. U.S.A.,2007,104:973-978.
[27]Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification an dexpansion of human colon cancer initiating cells. Nature,2007,445:111-115.
[28]Li C, Heidt DC, Dalerba T, et al. Identification of pancreatic cancer stem cells. Cancer Res.,2007,67:1030-1037.
[29]O'brien CA, Pollett A, Gallinger S, et al. A human colon cancer cell capable of initiating tumour growth in immunodeficiency mice. Nature,2007,445:106-110.
[30]李锦军顾健人.癌干细胞研究进展.生命科学.2006,18(4)：333-339.
[31]Singh SK, Calrke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res.,2003,63:5821-5828.
[32]Ma S, Chan KW, Hu L, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology,2007,132:2542-2556.
[33]Dalerba P, Dylla SJ, Park Park IK, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA.,2007,104:10158-10163.
[34]Collins AT, Berry PA, Hyde C, et al. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res.,2005,65:10946-10951.
[35]Harper LJ, Piper K, Common J, et al. Stem cell patterns in cell lines derived from head and neck squamous cell carcinoma. J Oral Pathol Med.,2007,36:594-603.
[36]Ponti D, Costa A, Zaffaroni N, et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res.,2005,65: 5506-5511.
[37]Patrawala L, Calhoun T, Schneider-Broussard R, et al. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic. Cancer Res.,2005,65:6207-6219.
[38]Tirino V, Camerlingo R, Malanga D, et al. The role of CD 133 in the identification and characterisation of tumour-initiating cells in non-small-cell lung cancer. Eur. J. Cardiothorac. Surg.,2009,36:446-453.
[39]Rutella S, Bonanno G, Procoli A, et al. Cells with Characteristics of Cancer Stem/Progenitor Cells Express the CD133 Antigen in Human Endometrial Tumors. Clin. Cancer Res.,2009,15:4299-4311.
[40]Hermann PC, Huber SL, Herrler T, et al. Distinct Populations of Cancer Stem Cells Determine Tumor Growth and Metastatic Activity in Human Pancreatic Cancer. Cell Stem Cell,2007,1:313-323.
[41]Mehra N, Penning M, Maas J, et al. Progenitor Marker CD133 mRNA Is Elevated in Peripheral Blood of Cancer Patients with Bone Metastases. Clin. Cancer Res.,2006, 12:4859-4866.
[42]Rappa G, Fodstad O, and Lorico A. The Stem Cell-Associated Antigen CD133 (Prominin-1) Is a Molecular Therapeutic Target for Metastatic Melanoma. Stem Cells,2008,26:3008-3017.
[43]Kusumbe AP, Mali AM, and Bapat SA. CD133-Expressing Stem Cells Associated with Ovarian Metastases Establish an Endothelial Hierarchy and Contribute to Tumor Vasculature. Stem Cells,2009,27:498-508.
[44]Zeppernick F, Ahmadi R, Campos B, et al. Stem Cell Marker CD133 Affects Clinical Outcome in Glioma Patients. Clin. Cancer Res.,2008,14:123-129.
[45]Lin EH, Hassan M, Li Y, et al. Elevated stem cell marker CD133 mRNA in peripheral blood predicts colon cancer recurrence. (ASCO Meeting Abstracts) J Clin. Onco. 2007; 25:10504.
[46]Inoue Y, Tanaka K, Saigusa S, et al. Evaultion of CD133, VEGF, or EGFR as predictive markers of distant recurrence after preoperative chemoradiotherapy in rectal cancer. (ASCO Meeting Abstracts). J Clin. Onco.2009; 27:4050.
[47]Rappa G, Fodstad O, and Lorico A. The Stem Cell-Associated Antigen CD133 (Prominin-1) Is a Molecular Therapeutic Target for Metastatic Melanoma. Stem Cells,2008,26,3008-3017.
[48]Sell S, Leffert HL. Liver Cancer Stem Cells. J Clin. Onco.2008,26(17):2800-2805.
[49]Suetsugu A, Nagaki M, Aoki H, et al. Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells. Biochem Biophys Res Commun., 2006,35 1(4):820-824.
[1]Miraglia S, Godfrey W, Yin AH, et al. A novel five transmembrane hematopoietic stem cell antigen:isolation, characterization, and molecular cloning. Blood,1997, 90(12):5013-5021.
[2]Weigmann A, Corbeil D, Hellwig A, et al. Prominin, a novel microvilli_specific polytopic membrane protein of the apical surface of epithelial cells, is targeted to plasmalemmal protrusions of non_epithelial cells. Proc Natl Acad Sci USA,1997, 94(23):12425-12430.
[3]Yu Y, Flint A, Dvorin EL, et al. AC133-2,a novel isoform of human AC133 stem cell antigen. J Biol Chem,2002,277(23):207112-20716.
[4]Fargears CA, Corbeil D and Huttner WB. AC133 Antigen, CD133, Prominin-1, Prominin-2, Etc:Prominin Family Genes in Need of A Rational Nomemclature. Stem Cell,2003,21(4):506-508.
[5]Corbeil D, Roper K, Weigmann A, et al. AC133 Hematopoietic Stem Cell Antigen: Human Homologue of Mouse Kidney Prominin or Distinct Member of a Novel Protein Family? Blood,1998,91:2625-2626.
[6]Corbeil D, Roper K, Hell wig A, et al. The Human AC 133 Hematopoietic Stem Cell Antigen Is also Expressed in Epithelial Cells and Targeted to Plasma Membrane Protrusions. J Biol Chem,2000,275(8):5512-5520.
[7]Maw MA, Corbeil D, Koch J, et al. A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. Hum Mol Genet,2000,9(1):27-34.
[8]Bhatia MA. AC133 expression in human stem cells. Leukemia,2001,15(11): 1685-1688.
[9]Pfenninger CV, Roschupkina T, Hertwig F, et al. CD133 Is Not Present on Neurogenic Astrocytes in the Adult Subventricular Zone, but on Embryonic Neural Stem Cells, Ependymal Cells, and Glioblastoma Cells. Cancer Res,2007, 67(12):5727-5736.
[10]Rountree CB, Barsky L, Ge S, et al. A CD133-Expressing Murine Liver Oval Cell Population with Bilineage Potential. Stem Cells,2007,25:2419-2429.
[11]Vander Griend DJ, Karthaus WL, Dalrymple S, et al. The Role of CD 133 in Normal Human Prostate Stem Cells and Malignant Cancer-Initiating Cells. Cancer Res.,2008, 68:9703-9711.
[12]Alakel N, Jing D, Muller K, et al. Direct contact with mesenchymal stromal cells affects migratory behavior and gene expression profile of CD133+ hematopoietic stem cells during ex vivo expansion. Experimental hematology,2009,37(4):504-513.
[13]Reya T, Morrison SJ, Clafke M F, et al. Stem cells, cancer, and cancer stem cells. Nature,2001,414:105-111.
[14]Lapidot T, Sirarad C, Vormoor J, et al. Acellinitiating human acute myeloid leukemia after transplantation into SCID mice. Nature,1994,367:645-648.
[15]Passegue E, Jamieson C, Ailles LE, et al. Normal and leukemic hematopoiesis:Are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc Natl Acad Sci U S A.2003,100:11842-11849.
[16]Singh SK, Clarke ID, Hide T, et al. Cancer stem cells in nervous system tumors. Oncogene,2004,23:7267-7273.
[17]Kim CF, Jackson EL, Woolfenden AE, et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell,2005,121:823-835.
[19]Patrawala L, Calhoun T, Schneider-Broussard R, et al. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastasis progenitor cells. Oncogene,2006,25:1696-1708.
[20]Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification an dexpansion of human colon cancer initiating cells. Nature,2007,445:111-115.
[21]Li C, Heidt DC, Dalerba T, et al. Identification of pancreatic cancer stem cells. Cancer Res.,2007,67:1030-1037.
[22]Singh SK, Calrke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res.,2003,63:5821-5828.
[23]Ma S, Chan KW, Hu L, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology,2007,132:2542-2556.
[24]Collins AT, Berry PA, Hyde C, et al. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res.,2005,65:10946-10951.
[25]Ponti D, Costa A, Zaffaroni N, et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res.,2005,65: 5506-5511.
[26]Rutella S, Bonanno G, Procoli A, et al. Cells with Characteristics of Cancer Stem/Progenitor Cells Express the CD133 Antigen in Human Endometrial Tumors. Clin. Cancer Res.,2009,15:4299-4311.
[27]Mehra N, Penning M, Maas J, et al. Progenitor Marker CD 133 mRNA Is Elevated in Peripheral Blood of Cancer Patients with Bone Metastases. Clin. Cancer Res.,2006, 12:4859-4866.
[28]Rappa G, Fodstad O, and Lorico A. The Stem Cell-Associated Antigen CD133 (Prominin-1) Is a Molecular Therapeutic Target for Metastatic Melanoma. Stem Cells, 2008,26:3008-3017.
[29]Kusumbe AP, Mali AM, and Bapat SA. CD133-Expressing Stem Cells Associated with Ovarian Metastases Establish an Endothelial Hierarchy and Contribute to Tumor Vasculature. Stem Cells,2009,27:498-508.
[30]Sell S, Leffert HL. Liver Cancer Stem Cells. J Clin. Onco.2008,26(17):2800-2805.
[1]Miraglia S, Godfrey W, Yin AH, et al. A novel five transmembrane hematopoietic stem cell antigen:isolation, characterization, and molecular cloning. Blood,1997, 90(12):5013-5021.
[2]Weigmann A, Corbeil D, Hellwig A, et al. Prominin, a novel microvilli_specific polytopic membrane protein of the apical surface of epithelial cells, is targeted to plasmalemmal protrusions of non_epithelial cells. Proc Natl Acad Sci USA,1997, 94(23):12425-12430.
[3]Yu Y, Flint A, Dvorin EL, et al. AC133-2,a novel isoform of human AC 133 stem cell antigen. J Biol Chem,2002,277(23):207112-20716.
[4]Corbeil D, Roper K, Hellwig A, et al. The Human AC133 Hematopoietic Stem Cell Antigen Is also Expressed in Epithelial Cells and Targeted to Plasma Membrane Protrusions. J Biol Chem,2000,275(8):5512-5520.
[5]Richardson GD, Robson CN, Lang SH, et al. CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci,2004,117:3539-3545.
[6]Torrente Y, Belicchi M, Sampaolesi M, et al. Human circulating AC133+ stem cells restore dystrophin expression and ameliorate function in dystrophic skeletal muscle. J Clin Invest.2004,114(2):182-195.
[7]Maw MA, Corbeil D, Koch J, et al. A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. Hum Mol Genet,2000,9(1):27-34.
[8]Bhatia MA. AC133 expression in human stem cells. Leukemia,2001,15(11): 1685-1688.
[9]Wynter EA, Buck D, Hart C, et al. CD34+AC133+ Cells Isolated from Cord Blood are Highly Enriched in Long-Term Culture-Initiating Cells, NOD/SCID-Repopulating Cells and Dendritic Cell Progenitors. Stem Cells,1998,16:387-396.
[10]Prince ME, Sivanandan R, Kaczorowski A, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc. Natl. Acad. Sci. U.S.A.,2007,104:973-978.
[11]Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification an dexpansion of human colon cancer initiating cells. Nature,2007,445:111-115.
[12]Li C, Heidt DC, Dalerba T, et al. Identification of pancreatic cancer stem cells. Cancer Res.,2007,67:1030-1037.
[13]O'brien CA, Pollett A, Gallinger S, et al. A human colon cancer cell capable of initiating tumour growth in immunodeficiency mice. Nature,2007,445:106-110.
[14]李锦军 顾健人.癌干细胞研究进展.生命科学.2006,18(4)：333-339.
[15]Singh SK, Calrke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res.,2003,63:5821-5828.
[16]Ma S, Chan KW, Hu L, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology,2007,132:2542-2556.
[17]Dalerba P, Dylla SJ, Park Park IK, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA.,2007,104:10158-10163.
[18]Collins AT, Berry PA, Hyde C, et al. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res.,2005,65:10946-10951.
[35]Harper LJ, Piper K, Common J, et al. Stem cell patterns in cell lines derived from head and neck squamous cell carcinoma. J Oral Pathol Med.,2007,36:594-603.
[19]Ponti D, Costa A, Zaffaroni N, et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res.,2005,65: 5506-5511.
[20]Patrawala L, Calhoun T, Schneider-Broussard R, et al. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic. Cancer Res.,2005,65:6207-6219.
[21]Tirino V, Camerlingo R, Malanga D, et al. The role of CD133 in the identification and characterisation of tumour-initiating cells in non-small-cell lung cancer. Eur. J. Cardiothorac. Surg.,2009,36:446-453.
[22]Rutella S, Bonanno G, Procoli A, et al. Cells with Characteristics of Cancer Stem/Progenitor Cells Express the CD 133 Antigen in Human Endometrial Tumors.
Clin. Cancer Res.,2009,15:4299-4311.
[23]Rappa G, Fodstad O, and Lorico A. The Stem Cell-Associated Antigen CD133 (Prominin-1) Is a Molecular Therapeutic Target for Metastatic Melanoma. Stem Cells, 2008,26:3008-3017.
[24]Kusumbe AP, Mali AM, and Bapat SA. CD133-Expressing Stem Cells Associated with Ovarian Metastases Establish an Endothelial Hierarchy and Contribute to Tumor Vasculature. Stem Cells,2009,27:498-508.
[25]Zeppernick F, Ahmadi R, Campos B, et al. Stem Cell Marker CD133 Affects Clinical Outcome in Glioma Patients. Clin. Cancer Res.,2008,14:123-129.
[26]Rappa G, Fodstad O, and Lorico A. The Stem Cell-Associated Antigen CD133 (Prominin-1) Is a Molecular Therapeutic Target for Metastatic Melanoma. Stem Cells, 2008,26,3008-3017.
[27]Sell S, Leffert HL. Liver Cancer Stem Cells. J Clin. Onco.2008,26(17):2800-2805.
1 Wu XZ, Chen D. Origin of hepatocellular carcinoma:role of stem cells [J]. J Gastroenterol Hepatol,2006; 21(7):1093
2 Sharma AD, Cantz T, Manns MP,etal. The role of stem cells in physiology, pathophysiology, and therapy of the liver [J]. Stem Cell Rev,2006; 2(1) : 51
3 Weissman IL. Translating stem and progenitor cell biology to the clinic:barriers and opportunities [J]. Science,2000; 287(5457):1442
4 Suzuki A, Zheng YW, Fukao K,et al. Hepatic stem/progenitor cells with high proliferative potential in liver organ formation [J]. Transplant Proc,2001; 33(1-2):585
5 Ramiya VK, Maraist M, Arfors KE,etal. Reversal of insulin-dependent diabetes using islets generatedinvitrofrom pancreatic stem cells [J]. Nat Med,2000; 6(3):278
6 钟晓刚,何生,殷舞,等.成体肝干细胞向肝癌细胞趋向性迁移的体外实验[J].中华肝脏病杂志,2005；13(9)：644
7 Hadnagy A,Gaboury L,Beaulieu R,et al.SP analysis may be used to identify cancer stem cell populations.Exp Cell Res 2006;312(19):3701-3710.
8 Ma S, Lee TK,Zheng B-J,et al.CD133+HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway.Oncogene 2008;27(12): 1749-1758.
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[12]Prince ME, Sivanandan R, Kaczorowski A, et al. Identification of a subpopulation of
cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc. Natl. Acad. Sci. U.S.A.,2007,104:973-978.
[13]Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification an dexpansion of human colon cancer initiating cells. Nature,2007,445:111-115.
[14]Li C, Heidt DC, Dalerba T, et al. Identification of pancreatic cancer stem cells. Cancer Res.,2007,67:1030-1037.
[15]O'brien CA, Pollett A, Gallinger S, et al. A human colon cancer cell capable of initiating tumour growth in immunodeficiency mice. Nature,2007,445:106-110.
[16]Singh SK, Calrke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res.,2003,63:5821-5828.
[17]Ma S, Chan KW, Hu L, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology,2007,132:2542-2556.
[18]Rutella S, Bonanno G, Procoli A, et al. Cells with Characteristics of Cancer Stem/Progenitor Cells Express the CD133 Antigen in Human Endometrial Tumors. Clin. Cancer Res.,2009,15:4299-4311.
[19]Suetsugu A, Nagaki M, Aoki H, et al. Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells. Biochem Biophys Res Commun., 2006,35 1(4):820-824.
[20]Yin S, Li J, Hu C,et al. CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity.Int J Cancer,2007,120(7):1444-1450.
[21]Ma S Chan KW Hu L et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells.Gastroenterology,2007,132(7):2542-2556.
[22]Hermann PC, Huber SL, Herrler T, et al. Distinct Populations of Cancer Stem Cells Determine Tumor Growth and Metastatic Activity in Human Pancreatic Cancer. Cell Stem Cell,2007,1:313-323.
[23]Mehra N, Penning M, Maas J, et al. Progenitor Marker CD133 mRNA Is Elevated in Peripheral Blood of Cancer Patients with Bone Metastases. Clin. Cancer Res.,2006,12: 4859-4866.
[24]Rappa G, Fodstad 0, and Lorico A. The Stem Cell-Associated Antigen CD133 (Prominin-1) Is a Molecular Therapeutic Target for Metastatic Melanoma. Stem Cells, 2008,26:3008-3017.
[1]Wu XZ, Chen D. Origin of hepatocellular carcinoma:role of stem cells. J Gastroenterol Hepatol,2006; 21(7):1093
[2]Sharma AD, Cantz T, Manns MP,etal. The role of stem cells in physiology, pathophysiology, and therapy of the liver. Stem Cell Rev,2006; 2(1): 51
[3]Weissman IL. Translating stem and progenitor cell biology to the clinic:barriers and opportunities. Science,2000; 287(5457) : 1442
[4]Suzuki A, Zheng YW, Fukao K,et al. Hepatic stem/progenitor cells with high proliferative potential in liver organ formation. Transplant Proc,2001; 33(1-2):585
[5]Ramiya VK, Maraist M, Arfors KE,etal. Reversal of insulin-dependent diabetes using islets generatedinvitrofrom pancreatic stem cells [J]. Nat Med,2000; 6(3):278
[6]Sell S. Heterogeneity and plasticity of hepatocyte lineage cells. Hepatology,2001; 33(3):738
[7]Paku S, Schnur J, Nagy P, et al. Origin and structural evolution ofthe early proliferating oval cells in rat liver. Am J Pathol,2001,158(4):1313-1323.
[8]Thorgeirsson SS. Hepatic stem cells in liver regeneration. FASEB J,1996; 10(11):1249
[9]Lowes KN, Brennan BA, Yeoh GC,etal. Oval cell numbers in human chronic liver diseases are directly related to disease severity. Am J Pathol,1999; 154(2):537
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