人胃癌侧群细胞分选与生物学特性鉴定
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摘要
第一部分人胃癌侧群细胞检测分选与干细胞基因表型分析
[目的]检测和分选胃癌细胞株中的SP细胞,并分析其干细胞相关基因表达情况。
[方法]选择4株不同分化程度的人胃癌细胞系MKN-28、SGC-7901、BGC-823和AGS,以Hoechst33342/碘化丙啶荧光染料双染,维拉帕米拮抗对照,应用流式细胞仪荧光激活分选法检测SP细胞比例并进行分选；RT-PCR比较分选所得的SP细胞和nonSP细胞中药物转运蛋白ABCG2、干细胞膜蛋白表型CD133、CD24、CD44和干细胞信号通路相关调控基因OCT-4、NOTCH、NANOG、BMI-1的表达差异。
[结果]胃癌细胞MKN-28、SGC7901和BGC-823中SP细胞比例分别为0.46%-2.7%、1.89%-2.33%和1.00%-3.55%；胃癌细胞AGS中未能检测出SP细胞。半定量PCR结果显示,SP细胞中ABCG2的表达量明显高于nonSP细胞；实时荧光定量PCR结果进一步显示,侧群细胞中ABCG2约为非侧群细胞中的8倍。干细胞膜蛋白表型CD24和CD44在胃癌SP细胞中的表达强于nonSP细胞；干细胞信号通路相关调控基因OCT-4、NOTCH、NANOG在SP细胞中的表达强于nonSP细胞：CD133、BMI-1基因在SP和nonSP细胞中的表达无差异。
[结论]侧群细胞可在胃癌细胞中被检测和分选,但并非所有的胃癌细胞株中均含有侧群细胞。胃癌侧群细胞高度表达药物转运蛋白ABCG2、干细胞膜蛋白表型CD44、CD24和干细胞调控基因OCT-4、NANOG、NOTCH。
第二部分人胃癌侧群细胞生物学特性鉴定
[目的]系统分析胃癌SP细胞体内外增殖活力、成瘤能力、侵袭力等基本生物学特性。
[方法]通过细胞生长曲线(CCK-8法)、平板克隆形成试验比较胃癌SP与nonSP细胞体外增殖活力；应用细胞侵袭transwell试验比较胃癌SP与nonSP细胞侵袭力差异；应用异种移植Nod/SCID小鼠成瘤实验比较胃癌SP与nonSP细胞体内致瘤能力差异；通过胃癌SP细胞体外培养比例回归和体内成瘤细胞分化现象观察鉴定其不对称分裂和多向分化特性。
[结果]细胞生长曲线实验显示,仅胃癌MKN-28细胞株SP细胞增殖活力明显强于nonSP细胞,而BGC-823和SGC-7901细胞株来源的SP与nonSP细胞总体生长曲线差别未能无统计学意义(P>0.05)。平板克隆实验结果显示,胃癌细胞株MKN-28、BGC-823和SGC-7901中SP细胞克隆形成率均高于nonSP细胞,其中MKN-28 SP细胞克隆形成能力明显高于nonSP细胞(P<0.05)。胃癌nonSP细胞侵袭力明显强于SP细胞(P<0.05)。异种移植瘤实验结果显示,Nod/SCID小鼠体内胃癌SP与nonSP细胞成瘤能力相仿(P>0.05)。胃癌SP细胞体外培养后,其中SP比例由起始的100%下降至1.0%,nonSP细胞中SP比例由起始的0%增加到0.3%；胃癌SP与nonSP细胞在体内成瘤后,均可转化成不同分化程度的胃癌细胞。
[结论]胃癌SP细胞体外增殖活力、体内成瘤和分化能力nonSP细胞相仿,SP细胞富集胃癌干细胞的依据不足。胃癌SP细胞侵袭能力较弱,胃癌细胞侵袭力可能主要与nonSP细胞有关。
第三部分人胃癌侧群细胞化疗药物耐受性的相关分析
[目的]研究胃癌SP与nonSP细胞对化疗药物的耐受性差异,并对其表达肿瘤耐药相关基因情况进行分析。
[方法]通过CCK-8法检测比较胃癌SP与nonSP细胞对于化疗药物5-FU和DDP的耐受性差异；应用肿瘤化疗耐药相关的功能基因芯片,对胃癌SP与nonSP细胞中表达肿瘤耐药相关基因情况进行比较分析
[结果]化疗药物5-FU对胃癌细胞株SGC7901来源的SP的半效抑制浓度IC50为0.3346 mg/ml,明显高于nonSP细胞的0.0142mg/ml (P<0.05);化疗药物DDP对胃癌SP的半效抑制浓度IC50为0.0055 mg/ml,亦明显高于nonSP细胞的0.0032mg/ml (P<0.05)。结果显示胃癌SP细胞对化疗药物5-FU和DDP的耐受性明显强于nonSP细胞。功能基因芯片结果显示,在84个常见的肿瘤化疗耐药相关基因中,1个基因在胃癌SP细胞中表达低于nonSP细胞；15个基因在胃癌SP细胞中表达高于nonSP细胞,其中ABCB1、ABCG2、BAX、MYC、GSTP1、AR等6个基因的表达差异显著(P<0.05)。
[结论]胃癌SP细胞对化疗药物的耐受性明显强于胃癌nonSP细胞,并高度表达一系列肿瘤耐药相关基因,可能在胃癌多药耐药机制中发挥重要作用。
Part I Isolation and stem cell related gene characterization of the side population cells from human gastric cancer cell lines
Objective:To isolate and characterize the side population cells from gastric cancer cell lines with a series of stem cell related gene.
Methods:Side populations of four human gastric cancer cell lines with different differentiation grades, named MKN-28, SGC-7901, BGC-823, and AGS were analyzed and isolated by fluorescence-activated cell sorting after being stained by fluorochrome Hoechst33342 and PI; expression of drug transporters ABCG2, stem cell related cellular membrane phenotype(CD 133, CD24, CD44) and signaling molecules(OCT-4, NOTCH, NANOG, BMI-1) were detected by reverse transcriptase PCR.
Results:Side population were detected in three of the four gastric cancer cell lines, with a proportion of 0.46%-3.55%, without SP cells detected in AGS. The SP cells showed a higher expression of ABCG2, CD24, CD44, OCT-4, NANOG and NOTCH, compared to nonSP cells.
Conclusion:Side population could be detected in the cell lines of gastric cancer, with a higher expression of a series of stem cell related gene compared to nonSP cells.
Part II Identification of the side population cells from human gastric cancer cell lines
Objective:To identify the side population cells from human gastric cell lines.
Methods:Sorted SP and nonSP cells from gastric cancer cell lines were analyzed by cell growth assay(CCK-8), clonogenic assay, and matrigel invasion assay in vitro, furthermore by tumorigenicity assay, differentiation study in vivo.
Results:Only SP cells from cell line MKN-28 showed a higher proliferation activity and clonogenicity compared to the nonSP cells in vitro(P<0.05). Sorted SP and nonSP cells from cell line SGC-7901 and BGC-823 showed similar proliferation activity, clonogenicity in vitro, tumorigenicity in vivo(P>0.05). Matrigel invasion assay showed that the number of nonSP cells which penetrated artificial basement membrane was more than SP cells (P<0.05). Additionally, culturing sorted SP and non-SP cells showed that the populations are interconvertible in vitro, and both conversed to different degree of differentiation cells in vivo.
Conclusion:Sorted SP and nonSP cells from gastric cancer cell lines showed similar proliferation activity, clonogenicity, tumorigenicity and multi-directional differentiation potential, which standed in contrast to the observations that tumor SP cells were enriched in stem cells.
PartⅢChemoresistance study of the side population cells from human gastric cancer cell lines
Objective:To examine chemotherapeutic drug resistance of the side population cells from human gastric cancer cell lines.
Methods:Cell growth assay was performed for sorted SP and nonSP cells from gastric cancer cell line by drug intervention. Gene profile for tumor chemotherapeutic drug resistance was analyzed with a Quantitative Real-Time PCR Arrays.
Results:The half maximal inhibitory concentration (IC50) of 5-FU for SP cells from gastric cancer cell line was significant higher than nonSP cells(0.3346 mg/ml vs 0.0142mg/ml, P<0.05). Similarly, the IC50 value of DDP for SP cells from gastric cancer cell line was significant higher than nonSP cells(0.0055 mg/ml vs 0.0032mg/ml, P<0.05). Quantitative Real-Time PCR Arrays displayed a series of 15 higher expression gene and 1 lower expression gene in SP cells rom gastric cancer cell line compared to nonSP cells, substantially including ABCB1, ABCG2, BAX, MYC, GSTP1 and AR (P<0.05)
Conclusion:Sorted SP cells from gastric cancer cell line showed higher resistance to chemotherapeutic drugs, with a stronger expression of a series of tumor drug resisitance related genes.
[目的]检测和分选胃癌细胞株中的SP细胞,并分析其干细胞相关基因表达情况。
[方法]选择4株不同分化程度的人胃癌细胞系MKN-28、SGC-7901、BGC-823和AGS,以Hoechst33342/碘化丙啶荧光染料双染,维拉帕米拮抗对照,应用流式细胞仪荧光激活分选法检测SP细胞比例并进行分选；RT-PCR比较分选所得的SP细胞和nonSP细胞中药物转运蛋白ABCG2、干细胞膜蛋白表型CD133、CD24、CD44和干细胞信号通路相关调控基因OCT-4、NOTCH、NANOG、BMI-1的表达差异。
[结果]胃癌细胞MKN-28、SGC7901和BGC-823中SP细胞比例分别为0.46%-2.7%、1.89%-2.33%和1.00%-3.55%；胃癌细胞AGS中未能检测出SP细胞。半定量PCR结果显示,SP细胞中ABCG2的表达量明显高于nonSP细胞；实时荧光定量PCR结果进一步显示,侧群细胞中ABCG2约为非侧群细胞中的8倍。干细胞膜蛋白表型CD24和CD44在胃癌SP细胞中的表达强于nonSP细胞；干细胞信号通路相关调控基因OCT-4、NOTCH、NANOG在SP细胞中的表达强于nonSP细胞：CD133、BMI-1基因在SP和nonSP细胞中的表达无差异。
[结论]侧群细胞可在胃癌细胞中被检测和分选,但并非所有的胃癌细胞株中均含有侧群细胞。胃癌侧群细胞高度表达药物转运蛋白ABCG2、干细胞膜蛋白表型CD44、CD24和干细胞调控基因OCT-4、NANOG、NOTCH。
第二部分人胃癌侧群细胞生物学特性鉴定
[目的]系统分析胃癌SP细胞体内外增殖活力、成瘤能力、侵袭力等基本生物学特性。
[方法]通过细胞生长曲线(CCK-8法)、平板克隆形成试验比较胃癌SP与nonSP细胞体外增殖活力；应用细胞侵袭transwell试验比较胃癌SP与nonSP细胞侵袭力差异；应用异种移植Nod/SCID小鼠成瘤实验比较胃癌SP与nonSP细胞体内致瘤能力差异；通过胃癌SP细胞体外培养比例回归和体内成瘤细胞分化现象观察鉴定其不对称分裂和多向分化特性。
[结果]细胞生长曲线实验显示,仅胃癌MKN-28细胞株SP细胞增殖活力明显强于nonSP细胞,而BGC-823和SGC-7901细胞株来源的SP与nonSP细胞总体生长曲线差别未能无统计学意义(P>0.05)。平板克隆实验结果显示,胃癌细胞株MKN-28、BGC-823和SGC-7901中SP细胞克隆形成率均高于nonSP细胞,其中MKN-28 SP细胞克隆形成能力明显高于nonSP细胞(P<0.05)。胃癌nonSP细胞侵袭力明显强于SP细胞(P<0.05)。异种移植瘤实验结果显示,Nod/SCID小鼠体内胃癌SP与nonSP细胞成瘤能力相仿(P>0.05)。胃癌SP细胞体外培养后,其中SP比例由起始的100%下降至1.0%,nonSP细胞中SP比例由起始的0%增加到0.3%；胃癌SP与nonSP细胞在体内成瘤后,均可转化成不同分化程度的胃癌细胞。
[结论]胃癌SP细胞体外增殖活力、体内成瘤和分化能力nonSP细胞相仿,SP细胞富集胃癌干细胞的依据不足。胃癌SP细胞侵袭能力较弱,胃癌细胞侵袭力可能主要与nonSP细胞有关。
第三部分人胃癌侧群细胞化疗药物耐受性的相关分析
[目的]研究胃癌SP与nonSP细胞对化疗药物的耐受性差异,并对其表达肿瘤耐药相关基因情况进行分析。
[方法]通过CCK-8法检测比较胃癌SP与nonSP细胞对于化疗药物5-FU和DDP的耐受性差异；应用肿瘤化疗耐药相关的功能基因芯片,对胃癌SP与nonSP细胞中表达肿瘤耐药相关基因情况进行比较分析
[结果]化疗药物5-FU对胃癌细胞株SGC7901来源的SP的半效抑制浓度IC50为0.3346 mg/ml,明显高于nonSP细胞的0.0142mg/ml (P<0.05);化疗药物DDP对胃癌SP的半效抑制浓度IC50为0.0055 mg/ml,亦明显高于nonSP细胞的0.0032mg/ml (P<0.05)。结果显示胃癌SP细胞对化疗药物5-FU和DDP的耐受性明显强于nonSP细胞。功能基因芯片结果显示,在84个常见的肿瘤化疗耐药相关基因中,1个基因在胃癌SP细胞中表达低于nonSP细胞；15个基因在胃癌SP细胞中表达高于nonSP细胞,其中ABCB1、ABCG2、BAX、MYC、GSTP1、AR等6个基因的表达差异显著(P<0.05)。
[结论]胃癌SP细胞对化疗药物的耐受性明显强于胃癌nonSP细胞,并高度表达一系列肿瘤耐药相关基因,可能在胃癌多药耐药机制中发挥重要作用。
Part I Isolation and stem cell related gene characterization of the side population cells from human gastric cancer cell lines
Objective:To isolate and characterize the side population cells from gastric cancer cell lines with a series of stem cell related gene.
Methods:Side populations of four human gastric cancer cell lines with different differentiation grades, named MKN-28, SGC-7901, BGC-823, and AGS were analyzed and isolated by fluorescence-activated cell sorting after being stained by fluorochrome Hoechst33342 and PI; expression of drug transporters ABCG2, stem cell related cellular membrane phenotype(CD 133, CD24, CD44) and signaling molecules(OCT-4, NOTCH, NANOG, BMI-1) were detected by reverse transcriptase PCR.
Results:Side population were detected in three of the four gastric cancer cell lines, with a proportion of 0.46%-3.55%, without SP cells detected in AGS. The SP cells showed a higher expression of ABCG2, CD24, CD44, OCT-4, NANOG and NOTCH, compared to nonSP cells.
Conclusion:Side population could be detected in the cell lines of gastric cancer, with a higher expression of a series of stem cell related gene compared to nonSP cells.
Part II Identification of the side population cells from human gastric cancer cell lines
Objective:To identify the side population cells from human gastric cell lines.
Methods:Sorted SP and nonSP cells from gastric cancer cell lines were analyzed by cell growth assay(CCK-8), clonogenic assay, and matrigel invasion assay in vitro, furthermore by tumorigenicity assay, differentiation study in vivo.
Results:Only SP cells from cell line MKN-28 showed a higher proliferation activity and clonogenicity compared to the nonSP cells in vitro(P<0.05). Sorted SP and nonSP cells from cell line SGC-7901 and BGC-823 showed similar proliferation activity, clonogenicity in vitro, tumorigenicity in vivo(P>0.05). Matrigel invasion assay showed that the number of nonSP cells which penetrated artificial basement membrane was more than SP cells (P<0.05). Additionally, culturing sorted SP and non-SP cells showed that the populations are interconvertible in vitro, and both conversed to different degree of differentiation cells in vivo.
Conclusion:Sorted SP and nonSP cells from gastric cancer cell lines showed similar proliferation activity, clonogenicity, tumorigenicity and multi-directional differentiation potential, which standed in contrast to the observations that tumor SP cells were enriched in stem cells.
PartⅢChemoresistance study of the side population cells from human gastric cancer cell lines
Objective:To examine chemotherapeutic drug resistance of the side population cells from human gastric cancer cell lines.
Methods:Cell growth assay was performed for sorted SP and nonSP cells from gastric cancer cell line by drug intervention. Gene profile for tumor chemotherapeutic drug resistance was analyzed with a Quantitative Real-Time PCR Arrays.
Results:The half maximal inhibitory concentration (IC50) of 5-FU for SP cells from gastric cancer cell line was significant higher than nonSP cells(0.3346 mg/ml vs 0.0142mg/ml, P<0.05). Similarly, the IC50 value of DDP for SP cells from gastric cancer cell line was significant higher than nonSP cells(0.0055 mg/ml vs 0.0032mg/ml, P<0.05). Quantitative Real-Time PCR Arrays displayed a series of 15 higher expression gene and 1 lower expression gene in SP cells rom gastric cancer cell line compared to nonSP cells, substantially including ABCB1, ABCG2, BAX, MYC, GSTP1 and AR (P<0.05)
Conclusion:Sorted SP cells from gastric cancer cell line showed higher resistance to chemotherapeutic drugs, with a stronger expression of a series of tumor drug resisitance related genes.
引文
1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics,2002. CA Cancer J Clin 2005;55:74-108.
2.蔡琳,Binh Y, Donald MP.亚太若干地区恶性肿瘤流行趋势分析.肿瘤,2004,24：422-426
3.张思维,陈万青,孔灵芝.中国部分市县1998-2002年恶性肿瘤的发病与死亡.中国肿瘤,2006,15：430-448
4.季加孚.胃癌外科治疗中的若干问题.实用肿瘤杂志,2003,18(5)：341-346.
5.徐光炜.胃癌治疗的现状及问题.外科理论与实践2003；8：3-6.
6. Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature 2009;458:719-724.
7. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001;414:105-111.
8. Houghton J, Morozov A, Smirnova I, Wang TC. Stem cells and cancer. Seminars in Cancer Biology 2007; 17:191-203.
9. Shimkin MB. The written word and cancer--some personal involvements, 1940-1977:autobiographical essay. Cancer Res 1978;38:241-252.
10. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994;367:645-648.
11.Dick JE. Normal and leukemic human stem cells assayed in SCID mice. Seminars in Immunology 1996;8:197-206.
12.Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3:730-737.
13. Blair A, Hogge D E, Ailles L E, et al. Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with longterm proliferative ability in vitro and in vivo. Blood,1997,89(9):3104～3112
14. Blair A, Sutherland H J. Primitive acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo lack surface expression of c-kit (CD117). Exp Hematol,2000,28(6):660～671
15. Feller N, van der Pol M A, Waaijman T, et al. Immunologic purging of autologous peripheral blood stem cell products based on CD34 and CD 133 expression can be effectively and safely applied in half of the acute myeloid leukemia patients. Clin Cancer Res,2005,11(13):4793～4801
16. Peled A, Hardan I, Trakhtenbrot L, et al. Immature leukemic CD34+CXCR4+cells from CML patients have lower integrindependent migration and adhesion in response to the chemokine SDF-1. Stem Cells,2002,20(3):259～266
17.Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003;63:5821-8.
18.Kondo T, Setoguchi T, Taga T. Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci U S A 2004;101:781-786.
19. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumor initiating cells. Nature 2004;432:396-401.
20.Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. N Engl J Med 2005;353:811-22.
21.Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG. 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.
22.Piccirillo SG, Binda E, Fiocco R, Vescovi AL, Shah K. Brain cancer stem cells. J Mol Med 2009;87:1087-1095.
23.Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003;100:3983-8.
24.Dick JE. Breast cancer stem cells revealed. Proc Natl Acad Sci U S A 2003;100:3547-3549.
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(13):5506～5511
26.Marsden CG, Wright MJ, Pochampally R, Rowan BG. Breast tumor-initiating cells isolated from patient core biopsies for study of hormone action. Methods Mol Biol 2009;590:363-375.
27.Taylor M D, Poppleton H, Fuller C, et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell,2005,8(4):323～335
28.Fang D, Nguyen TK, Leishear K, et al. A tumorigenic subpopulaion with stem cell properties in melanomas. Cancer Res 2005;65:9328-37.
29.Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, Zhan Q, et al. Identification of cells initiating human melanomas. Nature 2008;451:345-349.
30. Seigel G M, Campbell L M, Narayan M, et al. Cancer stem cell characteristics in retinoblastoma. Mol Vis,2005,11:729-737
31.Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, et al. Identification of pancreatic cancer stem cells. Cancer Res 2007;67:1030-1037.
32.Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, 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.
33. Li C, Lee CJ, Simeone DM:Identification of Human Pancreatic Cancer Stem Cells. In:Cancer Stem Cells,2009; 161-173.
34.Huang P, Wang CY, Gou SM, Wu HS, Liu T, Xiong JX. Isolation and biological analysis of tumor stem cells from pancreatic adenocarcinoma. World J Gastroenterol 2008;14:3903-3907.
35.Simeone DM. Pancreatic cancer stem cells:implications for the treatment of pancreatic cancer. Clin Cancer Res 2008;14:5646-5648.
36. Fiegel H C, Gluer S, Roth B, et al. Stem-like cells in human hepatoblastoma. J Histochem Cytochem,2004,52(11):1495～1501
37.Houghton J, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H, Cai X, et al. Gastric cancer originating from bone marrow-derived cells. Science.2004;306:1568-1571.
38.Haraguchi N, Inoue H, Tanaka F, Mimori K, Utsunomiya T, Sasaki A, Mori M. Cancer stem cells in human gastrointestinal cancers. Hum Cell 2006; 19:24-29.
39.Haraguchi N, Utsunomiya T, Inoue H, Tanaka F, Mimori K, Barnard GF, Mori M. Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells 2006;24:506-513.
40.O'Brien CA, Pollett A, Gallinger S, et al. A human colon cancer cell capable of initiating tumor growth in immunodeficient mice. Nature 2007;445:106-10.
41.Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification of expansion of human colon-cancer-initiating cells. Nature 2007;445:111-5.
42.Richardson G D, Robson C N, Lang S H, et al. CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci,2004,117(Pt 16):3539～3545.
43.Collins A T, Berry P A, Hyde C, et al. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res,2005,65(23):10946～10951.
44.Xin L, Lawson DA, Witte ON. The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proc Natl Acad Sci U S A 2005;102:6942-6947.
45.Patrawala L, Calhoun-Davis T, Schneider-Broussard R, Tang DG. Hierarchical organization of prostate cancer cells in xenograft tumors:the CD44+alpha2betal+cell population is enriched in tumor-initiating cells. Cancer Res 2007;67:6796-6805.
46. Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, et al. Ovarian cancer sider population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Proc Natl Acad Sci USA 2006; 103:11154-9.
47. Gao Q, Geng L, Kvalheim G, Gaudernack G, Suo Z. Identification of cancer stem-like side population cells in ovarian cancer cell line OVCAR-3. Ultrastruct Pathol2009;33:175-181.
48. Mitsutake N, Iwao A, Nagai K, Namba H, Ohtsuru A, Saenko V, Yamashita S. Characterization of side population in thyroid cancer cell lines:cancer stem-like cells are enriched partly but not exclusively. Endocrinology 2007; 148:1797-1803.
49. Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, Crowley D, et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 2005;121:823-835.
50. Ho MM, Ng AV, Lam S, ed al. Side population in human lung cancer cell lines and tumor is enriched with stem-like cancer cells. Cancer Res 2007;67:4827-33.
51.Chiba T, Kita K, Zheng YW, Yokosuka O, Saisho H, Iwama A, Nakauchi H, et al. Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology 2006;44:240-251.
52.Forbes SJ, Alison MR. Side population (SP) cells:taking center stage in regeneration and liver cancer? Hepatology 2006;44:23-26.
53.Shi GM, Xu Y, Fan J, Zhou J, Yang XR, Qiu SJ, Liao Y, et al. Identification of side population cells in human hepatocellular carcinoma cell lines with stepwise metastatic potentials. J Cancer Res Clin Oncol 2008; 134:1155-1163.
54. Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CHM, Jones DL, Visvader J, et al. Cancer Stem Cells--Perspectives on Current Status and Future Directions:AACR Workshop on Cancer Stem Cells. Cancer Res 2006;66:9339-9344.
55. Lobo NA, Shimono Y, Qian D, Clarke MF. The Biology of Cancer Stem Cells. Annual Review of Cell and Developmental Biology 2007;23:675-699.
56. Balkwill F, Mantovani A. Inflammation and cancer:back to Virchow? The Lancet 2001;357:539-545.
57. Anderson DJ, Gage FH, Weissman IL. Can stem cells cross lineage boundaries? Nat Med 2001;7:393-395.
58. Takaishi S, Okumura T, Wang TC. Gastric Cancer Stem Cells. J Clin Oncol 2008;26:2876-2882.
59.李锦军,顾健人.癌干细胞研究进展.生命科学2006；18：333-339.
60. Goodell MA, Brose K, Paradis G, et al. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 1996;183:1797-1806.
61. Larderet G, Fortunel NO, Vaigot P, et al. Human side population keratinocytes exhibit long-term proliferative potential and a specific gene expression profile and can form a pluristratified epidermis. Stem Cells 2006;24:965-74.
62.Summer R, Kotton DN, Sun X, et al. Side population cells and Bcrp1 expression in lung. Am J Physiol Lung Cell Mol Physiol 2003;285:97-104.
63.Shimano K, Satake M, Okaya A, et al. Hepatic oval cells have the side population phenotype defined by expression of ATP-binding cassette transporter ABCG2/BCRP1. Am J Pathol 2003; 163:3-9.
64.Martin CM, Meeson AP, Robertson SM, et al. Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart. Dev Biol 2004;265:262-75.
65.Kim M, Morshead CM. Distinct population of forebrain neural stem progenitor cells can be isolated using side population analysis. J Neurosci 2003;23:10703-9.
66.Behbod F, Xian W, Shaw CA, et al. Transcriptional profiling of mammary gland side population cells. Stem Cells 2006;24:1065-74.
67.Meeson AP, Hawke TJ, Graham S, et al. Cellular and molecular regulation of skeletal muscle side population cells. Stem Cells 2004;22:1305-20.
68. Triel C, Vestergaard ME, Bolund L,et al.Side population cells in human and mouse epiderm is lack stem cell characteristics.Exp Cell Res 2004;295:79-90.
69. Burkert J, Otto WR, Wright NA. Side populations of gastrointestinal cancers are not enriched in stem cells. J Pathol 2008;214:564-573.
70. Zhou S, Schuetz JD, Bunting KD, Colapietro A-M, Sampath J, Morris JJ, Lagutina I, 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. Nat Med 2001;7:1028-1034.
71.Sales-Pardo I, Avendano A, Martinez-Munoz V, Garcia-Escarp M, Celis R, Whittle P, Barquinero J, et al. Flow cytometry of the Side Population:tips & tricks. Cell Oncol 2006;28:37-53.
72. Montanaro F, Liadaki K, Schienda J, Flint A, Gussoni E, Kunkel LM. Demystifying SP cell purification:viability, yield, and phenotype are defined by isolation parameters. Experimental Cell Research 2004;298:144-154.
73.Fried J, Doblin J, Takamoto S, et al. Effects of Hoechst 33342 on survival and growth of two tumor cell lines and on hematopoietically normal bone marrow cells [J]. Cytometry,1982,3 (1):42-47.
74. Van Zant G, Fry C G. Hoechst 33342 staining of mouse bone marrow: effects on colonyforming cells. Cytometry,1983,4 (1):40-46.
75. Adamski D, Mayol J F, Platet N, et al. Effects of Hoechst 33342 on C2C12 and PC12 cell differentiation. FEBS Lett,2007,581(16):3076-3080.
76.Zheng X, Shen G, Yang X, et al. Most C6 Cells Are Cancer Stem Cells: Evidence from Clonal and Population Analyses.Cancer Res,2007,67(8):3691-3697.
77. Clement V, Marino D, Cudalbu C, Hamou M-F, Mlynarik V, de Tribolet N, Dietrich P-Y, et al. Marker-independent identification of glioma-initiating cells. Nat Meth;7:224-228.
78.Wu C, Alman BA. Side population cells in human cancers. Cancer Lett 2008;268:1-9.
79.Moserle L, Ghisi M, Amadori A, Indraccolo S. Side population and cancer stem cells:therapeutic implications. Cancer Lett 2010;288:1-9.
80. Hirschmann-Jax C, Foster AE, Wulf GG, et al. A distinct "side population" of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci,2004,101(39):14228-14233.
81.O/'Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007;445:106-110.
82.Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R. Identification and expansion of human colon-cancer-initiating cells. Nature 2007;445:111-115.
83.Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, Milde T, St. Clair R, et al. CD133 expression is not restricted to stem cells, and both CD133+and CD133-metastatic colon cancer cells initiate tumors. The Journal of Clinical Investigation 2008;118:2111-2120.
84.Challen GA, Little MH. A Side Order of Stem Cells:The SP Phenotype. Stem Cells 2006;24:3-12.
85.Ponta H, Sherman L, Herrlich PA. CD44:From adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 2003;4:33-45.
86.付英杰.人CD44的结构与功能.基础医学与临床2006：26：657-661.
87. Takaishi S, Okumura T, Tu S, Wang SSW, Shibata W, Vigneshwaran R, Gordon SAK, et al. Identification of Gastric Cancer Stem Cells Using the Cell Surface Marker CD44. Stem Cells 2009;27:1006-1020.
88.周一叶,曾凡一.维持胚胎干细胞多能性和自我更新的转录因子Oct-4/Nanog以及相关的调控网络.遗传2008：30：529-536.
89.Jin GP, Chang ZY, Scholer HR, Pei D. Stem cell pluripotency and transcription factor Oct4. Cell Res 2002;12:321-329.
90.Bray SJ. Notch signalling:a simple pathway becomes complex. Nat Rev Mol Cell Biol 2006;7:678-689.
91. Gussoni E, Soneoka Y, Strickland CD, Buzney EA, Khan MK, Flint AF, Kunkel LM, et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 1999;401:390-394.
92. Fukuda K, Saikawa Y, Ohashi M, Kumagai K, Kitajima M, Okano H, Matsuzaki Y, et al. Tumor initiating potential of side population cells in human gastric cancer. Int J Oncol 2009;34:1201-1207.
93. Al-Hajj M, Clarke MF. Self-renewal and solid tumor stem cells. Oncogene;23:7274-7282.
94.Christgen M, Ballmaier M, Bruchhardt H, von Wasielewski R, Kreipe H, Lehmann U. Identification of a distinct side population of cancer cells in the Cal-51 human breast carcinoma cell line. Molecular and Cellular Biochemistry 2007;306:201-212.
95. Stavrovskaya AA. Cellular mechanisms of multidrug resistance of tumor cells. Biochemistry (Mosc) 2000;65:95-106.
96.Chua C, Zaiden N, Chong K-H, See S-J, Wong M-C, Ang B-T, Tang C. Characterization of a side population of astrocytoma cells in response to temozolomide. Journal of Neurosurgery 2008;109:856-866.
97.Eyler CE, Rich JN. Survival of the Fittest:Cancer Stem Cells in Therapeutic Resistance and Angiogenesis. J Clin Oncol 2008;26:2839-2845.
98.Krishnamurthy P, Ross DD, Nakanishi T, Bailey-Dell K, Zhou S, Mercer KE, Sarkadi B, et al. The Stem Cell Marker Bcrp/ABCG2 Enhances Hypoxic Cell Survival through Interactions with Heme. Journal of Biological Chemistry 2004;279:24218-24225.
99.Lu M, Xia L, Luo D, Waxman S, Jing Y. Dual effects of glutathione-S-transferase on As2O3 action in prostate cancer cells:enhancement of growth inhibition and inhibition of apoptosis. Oncogene 2004;23:3945-3952.
100.Hemann MT, Bric A, Teruya-Feldstein J, Herbst A, Nilsson JA, Cordon-Cardo C, Cleveland JL, et al. Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants. Nature 2005;436:807-811.
101. Shachaf CM, Felsher DW. Tumor Dormancy and MYC Inactivation: Pushing Cancer to the Brink of Normalcy. Cancer Res 2005;65:4471-4474.
102. el-Deiry WS.Role of oncogenes in resistance and killing by cancer therapeutic agents. Curr Opin Oncol 1997;9(1):79-87.
103. Wong DJ, Liu H, Ridky TW, Cassarino D, Segal E, Chang HY. Module Map of Stem Cell Genes Guides Creation of Epithelial Cancer Stem Cells. Cell Stem Cell 2008;2:333-344.
104. Liang Y, Zhong Z, Huang Y, Deng W, Cao J, Tsao G, Liu Q, et al. Stem-like Cancer Cells Are Inducible by Increasing Genomic Instability in Cancer Cells. Journal of Biological Chemistry;285:4931-4940.
1. Houghton J, Morozov A, Smirnova I, Wang TC. Stem cells and cancer. Seminars in Cancer Biology 2007;17:191-203.
2. Shimkin MB. The written word and cancer--some personal involvements, 1940-1977:autobiographical essay. Cancer Res 1978;38:241-252.
3. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001;414:105-111.
4. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994;367:645-648.
5. Dick JE. Normal and leukemic human stem cells assayed in SCID mice. Seminars in Immunology 1996;8:197-206.
6. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3:730-737.
7. Blair A, Hogge D E, Ailles L E, et al. Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with longterm proliferative ability in vitro and in vivo. Blood,1997,89(9):3104～3112
8. Blair A, Sutherland H J. Primitive acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo lack surface expression of c-kit (CD117). Exp Hematol,2000,28(6):660～671
9. Feller N, van der Pol M A, Waaijman T, et al. Immunologic purging of autologous peripheral blood stem cell products based on CD34 and CD 133 expression can be effectively and safely applied in half of the acute myeloid leukemia patients. Clin Cancer Res,2005,11(13): 4793～4801
10. Peled A, Hardan I, Trakhtenbrot L, et al. Immature leukemic CD34+CXCR4+cells from CML patients have lower integrindependent migration and adhesion in response to the chemokine SDF-1. Stem Cells, 2002,20(3):259～266
11. Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003;63:5821-8.
12. Kondo T, Setoguchi T, Taga T. Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci U S A 2004;101:781-786.
13. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumor initiating cells. Nature 2004;432:396-401.
14. Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. N Engl J Med 2005;353:811-22.
15. Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG. 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.
16. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA2003;100:3983-8.
17. Dick JE. Breast cancer stem cells revealed. Proc Natl Acad Sci U S A 2003;100:3547-3549.
18. 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(13):5506～5511
19. Taylor M D, Poppleton H, Fuller C, et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell,2005,8(4):323～335
20. Fang D, Nguyen TK, Leishear K, et al. A tumorigenic subpopulaion with stem cell properties in melanomas. Cancer Res 2005;65:9328-37.
21. Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, Zhan Q, et al. Identification of cells initiating human melanomas. Nature 2008;451:345-349.
22. Seigel G M, Campbell L M, Narayan M, et al. Cancer stem cell characteristics in retinoblastoma. Mol Vis,2005,11:729～737
23. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, et al. Identification of pancreatic cancer stem cells. Cancer Res 2007;67:1030-1037.
24. Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, 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.
25. Huang P, Wang CY, Gou SM, Wu HS, Liu T, Xiong JX. Isolation and biological analysis of tumor stem cells from pancreatic adenocarcinoma. World J Gastroenterol 2008; 14:3903-3907.
26. Simeone DM. Pancreatic cancer stem cells:implications for the treatment of pancreatic cancer. Clin Cancer Res 2008;14:5646-5648.
27. Fiegel H C, Gluer S, Roth B, et al. Stem-like cells in human hepatoblastoma. J Histochem Cytochem,2004,52(11):1495～1501
28. Houghton J, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H, Cai X, et al. Gastric cancer originating from bone marrow-derived cells. Science.2004;306:1568-1571.
29. Haraguchi N, Inoue H, Tanaka F, Mimori K, Utsunomiya T, Sasaki A, Mori M. Cancer stem cells in human gastrointestinal cancers. Hum Cell 2006; 19:24-29.
30. Haraguchi N, Utsunomiya T, Inoue H, Tanaka F, Mimori K, Barnard GF, Mori M. Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells 2006;24:506-513.
31.0'Brien CA, Pollett A, Gallinger S, et al. A human colon cancer cell capable of initiating tumor growth in immunodeficient mice. Nature 2007;445:106-10.
32. Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification of expansion of human colon-cancer-initiating cells. Nature 2007;445:111-5.
33. Richardson G D, Robson C N, Lang S H, et al. CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci,2004,117(Pt 16): 3539～3545.
34. Collins A T, Berry P A, Hyde C, et al. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res,2005,65(23): 10946～10951.
35. Xin L, Lawson DA, Witte ON. The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proc Natl Acad Sci U S A 2005; 102:6942-6947.
36. Patrawala L, Calhoun-Davis T, Schneider-Broussard R, Tang DG. Hierarchical organization of prostate cancer cells in xenograft tumors: the CD44+alpha2betal+cell population is enriched in tumor-initiating cells. Cancer Res 2007;67:6796-6805.
37. Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, et al. Ovarian cancer sider population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Proc Natl Acad Sci USA 2006;103:11154-9.
38. Mitsutake N, Iwao A, Nagai K, Namba H, Ohtsuru A, Saenko V, Yamashita S. Characterization of side population in thyroid cancer cell lines:cancer stem-like cells are enriched partly but not exclusively. Endocrinology 2007; 148:1797-1803.
39. Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, Crowley D, et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 2005;121:823-835.
40. Ho MM, Ng AV, Lam S, ed al. Side population in human lung cancer cell lines and tumor is enriched with stem-like cancer cells. Cancer Res 2007;67:4827-33.
41. Chiba T, Kita K, Zheng YW, Yokosuka O, Saisho H, Iwama A, Nakauchi H, et al. Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology 2006;44:240-251.
42. Forbes SJ, Alison MR. Side population (SP) cells:taking center stage in regeneration and liver cancer? Hepatology 2006;44:23-26.
43. Shi GM, Xu Y, Fan J, Zhou J, Yang XR, Qiu SJ, Liao Y, et al. Identification of side population cells in human hepatocellular carcinoma cell lines with stepwise metastatic potentials. J Cancer Res Clin Oncol 2008;134:1155-1163.
44. Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CHM, Jones DL, Visvader J, et al. Cancer Stem Cells-Perspectives on Current Status and Future Directions:AACR Workshop on Cancer Stem Cells. Cancer Res 2006;66:9339-9344.
45. Goodell MA, Brose K, Paradis G, et al. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 1996; 183:1797-1806.
46. Larderet G, Fortunel NO, Vaigot P, et al. Human side population keratinocytes exhibit long-term proliferative potential and a specific gene expression profile and can form a pluristratified epidermis. Stem Cells 2006;24:965-74.
47. Summer R, Kotton DN, Sun X, et al. Side population cells and Bcrpl expression in lung. Am J Physiol Lung Cell Mol Physiol 2003;285:97-104.
48. Shimano K, Satake M, Okaya A, et al. Hepatic oval cells have the side population phenotype defined by expression of ATP-binding cassette transporter ABCG2/BCRP1. Am J Pathol 2003;163:3-9.
49. Martin CM, Meeson AP, Robertson SM, et al. Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart. Dev Biol 2004;265:262-75.
50. Kim M, Morshead CM. Distinct population of forebrain neural stem progenitor cells can be isolated using side population analysis. J Neurosci 2003;23:10703-9.
51. Behbod F, Xian W, Shaw CA, et al. Transcriptional profiling of mammary gland side population cells. Stem Cells 2006;24:1065-74.
52. Meeson AP, Hawke TJ, Graham S, et al. Cellular and molecular regulation of skeletal muscle side population cells. Stem Cells 2004;22:1305-20.
53. Zhou S, Schuetz JD, Bunting KD, Colapietro A-M, Sampath J, Morris JJ, Lagutina I, et al. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 2001;7:1028-1034.
54. Challen GA, Little MH. A Side Order of Stem Cells:The SP Phenotype. Stem Cells 2006;24:3-12.
55. Majka, S.M., 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.
56. Jackson, K.A., et al., Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells [J]. J Clin Invest,2001.107(11): 1395-1402.
57. Wulf, G.G., et al., Cells of the hepatic side population contribute to liver regeneration and can be replenished with bone marrow stem cells[J]. Haematologica,2003.88(4):368-378.
58. Asakura, A. and M.A. Rudnicki, Side population cells from diverse adult tissues are capable of in vitro hematopoietic differentiation[J]. Exp Hematol,2002.30(11):1339-1345.
59. Hirschmann-Jax C, Foster AE, Wulf GG, et al. A distinct "side population" of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci,2004,101(39):14228-14233.
60. J. Zhou, J. Wulfkuhle, H. Zhang, et al. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci. 2007;104(41):16158-16163.
61. Horsley V, Aliprantis AO, Polak L, et al. NFATc1 Balances Quiescence and Proliferation of Skin Stem Cells. Cell.2008;132(2):299-310.
62. Wu C, Alman BA. Side population cells in human cancers. Cancer Lett 2008;268:1-9.
63. Wang J, Guo LP, Chen LZ, Zeng YX, Lu SH. Identification of cancer stem cell-like side population cells in human nasopharyngeal carcinoma cell line. Cancer Res 2007;67:3716-3724.
64. Burkert J, Otto WR, Wright NA. Side populations of gastrointestinal cancers are not enriched in stem cells. J Pathol 2008;214:564-573.
65. Eyler CE, Rich JN. Survival of the Fittest:Cancer Stem Cells in Therapeutic Resistance and Angiogenesis. J Clin Oncol 2008;26:2839-2845.
66. Fried J, Doblin J, Takamoto S, et al. Effects of Hoechst 33342 on survival and growth of two tumor cell lines and on hematopoietically normal bone marrow cells [J]. Cytometry,1982,3 (1):42-47.
67. Van Zant G, Fry C G. Hoechst 33342 staining of mouse bone marrow: effects on colonyforming cells. Cytometry,1983,4 (1):40-46.
68. Adamski D, Mayol J F, Platet N, et al. Effects of Hoechst 33342 on C2C12 and PC 12 cell differentiation. FEBS Lett,2007 581(16):3076-3080.
69. Zheng X, Shen G, Yang X, et al. Most C6 Cells Are Cancer Stem Cells: Evidence from Clonal and Population Analyses.Cancer Res,2007, 67(8):3691-3697.
70. Sales-Pardo I, Avendano A, Martinez-Munoz V, Garcia-Escarp M, Celis R, Whittle P, Barquinero J, et al. Flow cytometry of the Side Population: tips & tricks. Cell Oncol 2006;28:37-53.
71. Montanaro F, Liadaki K, Schienda J, Flint A, Gussoni E, Kunkel LM. Demystifying SP cell purification:viability, yield, and phenotype are defined by isolation parameters. Experimental Cell Research 2004;298:144-154.
72. Morita Y, Ema H, Yamazaki S, Nakauchi H. Non-side-population hematopoietic stem cells in mouse bone marrow.Blood. 2006;108(8):2850-2856.
73. Platet N, Mayol JF, Berger F, et al. Fluctuation of the SP/non-SP phenotype in the C6 glioma cell line. FEBS Lett. 2007;581(7):1435-1440.
2.蔡琳,Binh Y, Donald MP.亚太若干地区恶性肿瘤流行趋势分析.肿瘤,2004,24：422-426
3.张思维,陈万青,孔灵芝.中国部分市县1998-2002年恶性肿瘤的发病与死亡.中国肿瘤,2006,15：430-448
4.季加孚.胃癌外科治疗中的若干问题.实用肿瘤杂志,2003,18(5)：341-346.
5.徐光炜.胃癌治疗的现状及问题.外科理论与实践2003；8：3-6.
6. Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature 2009;458:719-724.
7. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001;414:105-111.
8. Houghton J, Morozov A, Smirnova I, Wang TC. Stem cells and cancer. Seminars in Cancer Biology 2007; 17:191-203.
9. Shimkin MB. The written word and cancer--some personal involvements, 1940-1977:autobiographical essay. Cancer Res 1978;38:241-252.
10. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994;367:645-648.
11.Dick JE. Normal and leukemic human stem cells assayed in SCID mice. Seminars in Immunology 1996;8:197-206.
12.Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3:730-737.
13. Blair A, Hogge D E, Ailles L E, et al. Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with longterm proliferative ability in vitro and in vivo. Blood,1997,89(9):3104～3112
14. Blair A, Sutherland H J. Primitive acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo lack surface expression of c-kit (CD117). Exp Hematol,2000,28(6):660～671
15. Feller N, van der Pol M A, Waaijman T, et al. Immunologic purging of autologous peripheral blood stem cell products based on CD34 and CD 133 expression can be effectively and safely applied in half of the acute myeloid leukemia patients. Clin Cancer Res,2005,11(13):4793～4801
16. Peled A, Hardan I, Trakhtenbrot L, et al. Immature leukemic CD34+CXCR4+cells from CML patients have lower integrindependent migration and adhesion in response to the chemokine SDF-1. Stem Cells,2002,20(3):259～266
17.Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003;63:5821-8.
18.Kondo T, Setoguchi T, Taga T. Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci U S A 2004;101:781-786.
19. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumor initiating cells. Nature 2004;432:396-401.
20.Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. N Engl J Med 2005;353:811-22.
21.Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG. 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.
22.Piccirillo SG, Binda E, Fiocco R, Vescovi AL, Shah K. Brain cancer stem cells. J Mol Med 2009;87:1087-1095.
23.Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003;100:3983-8.
24.Dick JE. Breast cancer stem cells revealed. Proc Natl Acad Sci U S A 2003;100:3547-3549.
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(13):5506～5511
26.Marsden CG, Wright MJ, Pochampally R, Rowan BG. Breast tumor-initiating cells isolated from patient core biopsies for study of hormone action. Methods Mol Biol 2009;590:363-375.
27.Taylor M D, Poppleton H, Fuller C, et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell,2005,8(4):323～335
28.Fang D, Nguyen TK, Leishear K, et al. A tumorigenic subpopulaion with stem cell properties in melanomas. Cancer Res 2005;65:9328-37.
29.Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, Zhan Q, et al. Identification of cells initiating human melanomas. Nature 2008;451:345-349.
30. Seigel G M, Campbell L M, Narayan M, et al. Cancer stem cell characteristics in retinoblastoma. Mol Vis,2005,11:729-737
31.Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, et al. Identification of pancreatic cancer stem cells. Cancer Res 2007;67:1030-1037.
32.Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, 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.
33. Li C, Lee CJ, Simeone DM:Identification of Human Pancreatic Cancer Stem Cells. In:Cancer Stem Cells,2009; 161-173.
34.Huang P, Wang CY, Gou SM, Wu HS, Liu T, Xiong JX. Isolation and biological analysis of tumor stem cells from pancreatic adenocarcinoma. World J Gastroenterol 2008;14:3903-3907.
35.Simeone DM. Pancreatic cancer stem cells:implications for the treatment of pancreatic cancer. Clin Cancer Res 2008;14:5646-5648.
36. Fiegel H C, Gluer S, Roth B, et al. Stem-like cells in human hepatoblastoma. J Histochem Cytochem,2004,52(11):1495～1501
37.Houghton J, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H, Cai X, et al. Gastric cancer originating from bone marrow-derived cells. Science.2004;306:1568-1571.
38.Haraguchi N, Inoue H, Tanaka F, Mimori K, Utsunomiya T, Sasaki A, Mori M. Cancer stem cells in human gastrointestinal cancers. Hum Cell 2006; 19:24-29.
39.Haraguchi N, Utsunomiya T, Inoue H, Tanaka F, Mimori K, Barnard GF, Mori M. Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells 2006;24:506-513.
40.O'Brien CA, Pollett A, Gallinger S, et al. A human colon cancer cell capable of initiating tumor growth in immunodeficient mice. Nature 2007;445:106-10.
41.Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification of expansion of human colon-cancer-initiating cells. Nature 2007;445:111-5.
42.Richardson G D, Robson C N, Lang S H, et al. CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci,2004,117(Pt 16):3539～3545.
43.Collins A T, Berry P A, Hyde C, et al. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res,2005,65(23):10946～10951.
44.Xin L, Lawson DA, Witte ON. The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proc Natl Acad Sci U S A 2005;102:6942-6947.
45.Patrawala L, Calhoun-Davis T, Schneider-Broussard R, Tang DG. Hierarchical organization of prostate cancer cells in xenograft tumors:the CD44+alpha2betal+cell population is enriched in tumor-initiating cells. Cancer Res 2007;67:6796-6805.
46. Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, et al. Ovarian cancer sider population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Proc Natl Acad Sci USA 2006; 103:11154-9.
47. Gao Q, Geng L, Kvalheim G, Gaudernack G, Suo Z. Identification of cancer stem-like side population cells in ovarian cancer cell line OVCAR-3. Ultrastruct Pathol2009;33:175-181.
48. Mitsutake N, Iwao A, Nagai K, Namba H, Ohtsuru A, Saenko V, Yamashita S. Characterization of side population in thyroid cancer cell lines:cancer stem-like cells are enriched partly but not exclusively. Endocrinology 2007; 148:1797-1803.
49. Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, Crowley D, et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 2005;121:823-835.
50. Ho MM, Ng AV, Lam S, ed al. Side population in human lung cancer cell lines and tumor is enriched with stem-like cancer cells. Cancer Res 2007;67:4827-33.
51.Chiba T, Kita K, Zheng YW, Yokosuka O, Saisho H, Iwama A, Nakauchi H, et al. Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology 2006;44:240-251.
52.Forbes SJ, Alison MR. Side population (SP) cells:taking center stage in regeneration and liver cancer? Hepatology 2006;44:23-26.
53.Shi GM, Xu Y, Fan J, Zhou J, Yang XR, Qiu SJ, Liao Y, et al. Identification of side population cells in human hepatocellular carcinoma cell lines with stepwise metastatic potentials. J Cancer Res Clin Oncol 2008; 134:1155-1163.
54. Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CHM, Jones DL, Visvader J, et al. Cancer Stem Cells--Perspectives on Current Status and Future Directions:AACR Workshop on Cancer Stem Cells. Cancer Res 2006;66:9339-9344.
55. Lobo NA, Shimono Y, Qian D, Clarke MF. The Biology of Cancer Stem Cells. Annual Review of Cell and Developmental Biology 2007;23:675-699.
56. Balkwill F, Mantovani A. Inflammation and cancer:back to Virchow? The Lancet 2001;357:539-545.
57. Anderson DJ, Gage FH, Weissman IL. Can stem cells cross lineage boundaries? Nat Med 2001;7:393-395.
58. Takaishi S, Okumura T, Wang TC. Gastric Cancer Stem Cells. J Clin Oncol 2008;26:2876-2882.
59.李锦军,顾健人.癌干细胞研究进展.生命科学2006；18：333-339.
60. Goodell MA, Brose K, Paradis G, et al. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 1996;183:1797-1806.
61. Larderet G, Fortunel NO, Vaigot P, et al. Human side population keratinocytes exhibit long-term proliferative potential and a specific gene expression profile and can form a pluristratified epidermis. Stem Cells 2006;24:965-74.
62.Summer R, Kotton DN, Sun X, et al. Side population cells and Bcrp1 expression in lung. Am J Physiol Lung Cell Mol Physiol 2003;285:97-104.
63.Shimano K, Satake M, Okaya A, et al. Hepatic oval cells have the side population phenotype defined by expression of ATP-binding cassette transporter ABCG2/BCRP1. Am J Pathol 2003; 163:3-9.
64.Martin CM, Meeson AP, Robertson SM, et al. Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart. Dev Biol 2004;265:262-75.
65.Kim M, Morshead CM. Distinct population of forebrain neural stem progenitor cells can be isolated using side population analysis. J Neurosci 2003;23:10703-9.
66.Behbod F, Xian W, Shaw CA, et al. Transcriptional profiling of mammary gland side population cells. Stem Cells 2006;24:1065-74.
67.Meeson AP, Hawke TJ, Graham S, et al. Cellular and molecular regulation of skeletal muscle side population cells. Stem Cells 2004;22:1305-20.
68. Triel C, Vestergaard ME, Bolund L,et al.Side population cells in human and mouse epiderm is lack stem cell characteristics.Exp Cell Res 2004;295:79-90.
69. Burkert J, Otto WR, Wright NA. Side populations of gastrointestinal cancers are not enriched in stem cells. J Pathol 2008;214:564-573.
70. Zhou S, Schuetz JD, Bunting KD, Colapietro A-M, Sampath J, Morris JJ, Lagutina I, 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. Nat Med 2001;7:1028-1034.
71.Sales-Pardo I, Avendano A, Martinez-Munoz V, Garcia-Escarp M, Celis R, Whittle P, Barquinero J, et al. Flow cytometry of the Side Population:tips & tricks. Cell Oncol 2006;28:37-53.
72. Montanaro F, Liadaki K, Schienda J, Flint A, Gussoni E, Kunkel LM. Demystifying SP cell purification:viability, yield, and phenotype are defined by isolation parameters. Experimental Cell Research 2004;298:144-154.
73.Fried J, Doblin J, Takamoto S, et al. Effects of Hoechst 33342 on survival and growth of two tumor cell lines and on hematopoietically normal bone marrow cells [J]. Cytometry,1982,3 (1):42-47.
74. Van Zant G, Fry C G. Hoechst 33342 staining of mouse bone marrow: effects on colonyforming cells. Cytometry,1983,4 (1):40-46.
75. Adamski D, Mayol J F, Platet N, et al. Effects of Hoechst 33342 on C2C12 and PC12 cell differentiation. FEBS Lett,2007,581(16):3076-3080.
76.Zheng X, Shen G, Yang X, et al. Most C6 Cells Are Cancer Stem Cells: Evidence from Clonal and Population Analyses.Cancer Res,2007,67(8):3691-3697.
77. Clement V, Marino D, Cudalbu C, Hamou M-F, Mlynarik V, de Tribolet N, Dietrich P-Y, et al. Marker-independent identification of glioma-initiating cells. Nat Meth;7:224-228.
78.Wu C, Alman BA. Side population cells in human cancers. Cancer Lett 2008;268:1-9.
79.Moserle L, Ghisi M, Amadori A, Indraccolo S. Side population and cancer stem cells:therapeutic implications. Cancer Lett 2010;288:1-9.
80. Hirschmann-Jax C, Foster AE, Wulf GG, et al. A distinct "side population" of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci,2004,101(39):14228-14233.
81.O/'Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007;445:106-110.
82.Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R. Identification and expansion of human colon-cancer-initiating cells. Nature 2007;445:111-115.
83.Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, Milde T, St. Clair R, et al. CD133 expression is not restricted to stem cells, and both CD133+and CD133-metastatic colon cancer cells initiate tumors. The Journal of Clinical Investigation 2008;118:2111-2120.
84.Challen GA, Little MH. A Side Order of Stem Cells:The SP Phenotype. Stem Cells 2006;24:3-12.
85.Ponta H, Sherman L, Herrlich PA. CD44:From adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 2003;4:33-45.
86.付英杰.人CD44的结构与功能.基础医学与临床2006：26：657-661.
87. Takaishi S, Okumura T, Tu S, Wang SSW, Shibata W, Vigneshwaran R, Gordon SAK, et al. Identification of Gastric Cancer Stem Cells Using the Cell Surface Marker CD44. Stem Cells 2009;27:1006-1020.
88.周一叶,曾凡一.维持胚胎干细胞多能性和自我更新的转录因子Oct-4/Nanog以及相关的调控网络.遗传2008：30：529-536.
89.Jin GP, Chang ZY, Scholer HR, Pei D. Stem cell pluripotency and transcription factor Oct4. Cell Res 2002;12:321-329.
90.Bray SJ. Notch signalling:a simple pathway becomes complex. Nat Rev Mol Cell Biol 2006;7:678-689.
91. Gussoni E, Soneoka Y, Strickland CD, Buzney EA, Khan MK, Flint AF, Kunkel LM, et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 1999;401:390-394.
92. Fukuda K, Saikawa Y, Ohashi M, Kumagai K, Kitajima M, Okano H, Matsuzaki Y, et al. Tumor initiating potential of side population cells in human gastric cancer. Int J Oncol 2009;34:1201-1207.
93. Al-Hajj M, Clarke MF. Self-renewal and solid tumor stem cells. Oncogene;23:7274-7282.
94.Christgen M, Ballmaier M, Bruchhardt H, von Wasielewski R, Kreipe H, Lehmann U. Identification of a distinct side population of cancer cells in the Cal-51 human breast carcinoma cell line. Molecular and Cellular Biochemistry 2007;306:201-212.
95. Stavrovskaya AA. Cellular mechanisms of multidrug resistance of tumor cells. Biochemistry (Mosc) 2000;65:95-106.
96.Chua C, Zaiden N, Chong K-H, See S-J, Wong M-C, Ang B-T, Tang C. Characterization of a side population of astrocytoma cells in response to temozolomide. Journal of Neurosurgery 2008;109:856-866.
97.Eyler CE, Rich JN. Survival of the Fittest:Cancer Stem Cells in Therapeutic Resistance and Angiogenesis. J Clin Oncol 2008;26:2839-2845.
98.Krishnamurthy P, Ross DD, Nakanishi T, Bailey-Dell K, Zhou S, Mercer KE, Sarkadi B, et al. The Stem Cell Marker Bcrp/ABCG2 Enhances Hypoxic Cell Survival through Interactions with Heme. Journal of Biological Chemistry 2004;279:24218-24225.
99.Lu M, Xia L, Luo D, Waxman S, Jing Y. Dual effects of glutathione-S-transferase on As2O3 action in prostate cancer cells:enhancement of growth inhibition and inhibition of apoptosis. Oncogene 2004;23:3945-3952.
100.Hemann MT, Bric A, Teruya-Feldstein J, Herbst A, Nilsson JA, Cordon-Cardo C, Cleveland JL, et al. Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants. Nature 2005;436:807-811.
101. Shachaf CM, Felsher DW. Tumor Dormancy and MYC Inactivation: Pushing Cancer to the Brink of Normalcy. Cancer Res 2005;65:4471-4474.
102. el-Deiry WS.Role of oncogenes in resistance and killing by cancer therapeutic agents. Curr Opin Oncol 1997;9(1):79-87.
103. Wong DJ, Liu H, Ridky TW, Cassarino D, Segal E, Chang HY. Module Map of Stem Cell Genes Guides Creation of Epithelial Cancer Stem Cells. Cell Stem Cell 2008;2:333-344.
104. Liang Y, Zhong Z, Huang Y, Deng W, Cao J, Tsao G, Liu Q, et al. Stem-like Cancer Cells Are Inducible by Increasing Genomic Instability in Cancer Cells. Journal of Biological Chemistry;285:4931-4940.
1. Houghton J, Morozov A, Smirnova I, Wang TC. Stem cells and cancer. Seminars in Cancer Biology 2007;17:191-203.
2. Shimkin MB. The written word and cancer--some personal involvements, 1940-1977:autobiographical essay. Cancer Res 1978;38:241-252.
3. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001;414:105-111.
4. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994;367:645-648.
5. Dick JE. Normal and leukemic human stem cells assayed in SCID mice. Seminars in Immunology 1996;8:197-206.
6. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3:730-737.
7. Blair A, Hogge D E, Ailles L E, et al. Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with longterm proliferative ability in vitro and in vivo. Blood,1997,89(9):3104～3112
8. Blair A, Sutherland H J. Primitive acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo lack surface expression of c-kit (CD117). Exp Hematol,2000,28(6):660～671
9. Feller N, van der Pol M A, Waaijman T, et al. Immunologic purging of autologous peripheral blood stem cell products based on CD34 and CD 133 expression can be effectively and safely applied in half of the acute myeloid leukemia patients. Clin Cancer Res,2005,11(13): 4793～4801
10. Peled A, Hardan I, Trakhtenbrot L, et al. Immature leukemic CD34+CXCR4+cells from CML patients have lower integrindependent migration and adhesion in response to the chemokine SDF-1. Stem Cells, 2002,20(3):259～266
11. Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003;63:5821-8.
12. Kondo T, Setoguchi T, Taga T. Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci U S A 2004;101:781-786.
13. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumor initiating cells. Nature 2004;432:396-401.
14. Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. N Engl J Med 2005;353:811-22.
15. Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG. 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.
16. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA2003;100:3983-8.
17. Dick JE. Breast cancer stem cells revealed. Proc Natl Acad Sci U S A 2003;100:3547-3549.
18. 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(13):5506～5511
19. Taylor M D, Poppleton H, Fuller C, et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell,2005,8(4):323～335
20. Fang D, Nguyen TK, Leishear K, et al. A tumorigenic subpopulaion with stem cell properties in melanomas. Cancer Res 2005;65:9328-37.
21. Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, Zhan Q, et al. Identification of cells initiating human melanomas. Nature 2008;451:345-349.
22. Seigel G M, Campbell L M, Narayan M, et al. Cancer stem cell characteristics in retinoblastoma. Mol Vis,2005,11:729～737
23. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, et al. Identification of pancreatic cancer stem cells. Cancer Res 2007;67:1030-1037.
24. Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, 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.
25. Huang P, Wang CY, Gou SM, Wu HS, Liu T, Xiong JX. Isolation and biological analysis of tumor stem cells from pancreatic adenocarcinoma. World J Gastroenterol 2008; 14:3903-3907.
26. Simeone DM. Pancreatic cancer stem cells:implications for the treatment of pancreatic cancer. Clin Cancer Res 2008;14:5646-5648.
27. Fiegel H C, Gluer S, Roth B, et al. Stem-like cells in human hepatoblastoma. J Histochem Cytochem,2004,52(11):1495～1501
28. Houghton J, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H, Cai X, et al. Gastric cancer originating from bone marrow-derived cells. Science.2004;306:1568-1571.
29. Haraguchi N, Inoue H, Tanaka F, Mimori K, Utsunomiya T, Sasaki A, Mori M. Cancer stem cells in human gastrointestinal cancers. Hum Cell 2006; 19:24-29.
30. Haraguchi N, Utsunomiya T, Inoue H, Tanaka F, Mimori K, Barnard GF, Mori M. Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells 2006;24:506-513.
31.0'Brien CA, Pollett A, Gallinger S, et al. A human colon cancer cell capable of initiating tumor growth in immunodeficient mice. Nature 2007;445:106-10.
32. Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification of expansion of human colon-cancer-initiating cells. Nature 2007;445:111-5.
33. Richardson G D, Robson C N, Lang S H, et al. CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci,2004,117(Pt 16): 3539～3545.
34. Collins A T, Berry P A, Hyde C, et al. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res,2005,65(23): 10946～10951.
35. Xin L, Lawson DA, Witte ON. The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proc Natl Acad Sci U S A 2005; 102:6942-6947.
36. Patrawala L, Calhoun-Davis T, Schneider-Broussard R, Tang DG. Hierarchical organization of prostate cancer cells in xenograft tumors: the CD44+alpha2betal+cell population is enriched in tumor-initiating cells. Cancer Res 2007;67:6796-6805.
37. Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, et al. Ovarian cancer sider population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Proc Natl Acad Sci USA 2006;103:11154-9.
38. Mitsutake N, Iwao A, Nagai K, Namba H, Ohtsuru A, Saenko V, Yamashita S. Characterization of side population in thyroid cancer cell lines:cancer stem-like cells are enriched partly but not exclusively. Endocrinology 2007; 148:1797-1803.
39. Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, Crowley D, et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 2005;121:823-835.
40. Ho MM, Ng AV, Lam S, ed al. Side population in human lung cancer cell lines and tumor is enriched with stem-like cancer cells. Cancer Res 2007;67:4827-33.
41. Chiba T, Kita K, Zheng YW, Yokosuka O, Saisho H, Iwama A, Nakauchi H, et al. Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology 2006;44:240-251.
42. Forbes SJ, Alison MR. Side population (SP) cells:taking center stage in regeneration and liver cancer? Hepatology 2006;44:23-26.
43. Shi GM, Xu Y, Fan J, Zhou J, Yang XR, Qiu SJ, Liao Y, et al. Identification of side population cells in human hepatocellular carcinoma cell lines with stepwise metastatic potentials. J Cancer Res Clin Oncol 2008;134:1155-1163.
44. Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CHM, Jones DL, Visvader J, et al. Cancer Stem Cells-Perspectives on Current Status and Future Directions:AACR Workshop on Cancer Stem Cells. Cancer Res 2006;66:9339-9344.
45. Goodell MA, Brose K, Paradis G, et al. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 1996; 183:1797-1806.
46. Larderet G, Fortunel NO, Vaigot P, et al. Human side population keratinocytes exhibit long-term proliferative potential and a specific gene expression profile and can form a pluristratified epidermis. Stem Cells 2006;24:965-74.
47. Summer R, Kotton DN, Sun X, et al. Side population cells and Bcrpl expression in lung. Am J Physiol Lung Cell Mol Physiol 2003;285:97-104.
48. Shimano K, Satake M, Okaya A, et al. Hepatic oval cells have the side population phenotype defined by expression of ATP-binding cassette transporter ABCG2/BCRP1. Am J Pathol 2003;163:3-9.
49. Martin CM, Meeson AP, Robertson SM, et al. Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart. Dev Biol 2004;265:262-75.
50. Kim M, Morshead CM. Distinct population of forebrain neural stem progenitor cells can be isolated using side population analysis. J Neurosci 2003;23:10703-9.
51. Behbod F, Xian W, Shaw CA, et al. Transcriptional profiling of mammary gland side population cells. Stem Cells 2006;24:1065-74.
52. Meeson AP, Hawke TJ, Graham S, et al. Cellular and molecular regulation of skeletal muscle side population cells. Stem Cells 2004;22:1305-20.
53. Zhou S, Schuetz JD, Bunting KD, Colapietro A-M, Sampath J, Morris JJ, Lagutina I, et al. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 2001;7:1028-1034.
54. Challen GA, Little MH. A Side Order of Stem Cells:The SP Phenotype. Stem Cells 2006;24:3-12.
55. Majka, S.M., 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.
56. Jackson, K.A., et al., Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells [J]. J Clin Invest,2001.107(11): 1395-1402.
57. Wulf, G.G., et al., Cells of the hepatic side population contribute to liver regeneration and can be replenished with bone marrow stem cells[J]. Haematologica,2003.88(4):368-378.
58. Asakura, A. and M.A. Rudnicki, Side population cells from diverse adult tissues are capable of in vitro hematopoietic differentiation[J]. Exp Hematol,2002.30(11):1339-1345.
59. Hirschmann-Jax C, Foster AE, Wulf GG, et al. A distinct "side population" of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci,2004,101(39):14228-14233.
60. J. Zhou, J. Wulfkuhle, H. Zhang, et al. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci. 2007;104(41):16158-16163.
61. Horsley V, Aliprantis AO, Polak L, et al. NFATc1 Balances Quiescence and Proliferation of Skin Stem Cells. Cell.2008;132(2):299-310.
62. Wu C, Alman BA. Side population cells in human cancers. Cancer Lett 2008;268:1-9.
63. Wang J, Guo LP, Chen LZ, Zeng YX, Lu SH. Identification of cancer stem cell-like side population cells in human nasopharyngeal carcinoma cell line. Cancer Res 2007;67:3716-3724.
64. Burkert J, Otto WR, Wright NA. Side populations of gastrointestinal cancers are not enriched in stem cells. J Pathol 2008;214:564-573.
65. Eyler CE, Rich JN. Survival of the Fittest:Cancer Stem Cells in Therapeutic Resistance and Angiogenesis. J Clin Oncol 2008;26:2839-2845.
66. Fried J, Doblin J, Takamoto S, et al. Effects of Hoechst 33342 on survival and growth of two tumor cell lines and on hematopoietically normal bone marrow cells [J]. Cytometry,1982,3 (1):42-47.
67. Van Zant G, Fry C G. Hoechst 33342 staining of mouse bone marrow: effects on colonyforming cells. Cytometry,1983,4 (1):40-46.
68. Adamski D, Mayol J F, Platet N, et al. Effects of Hoechst 33342 on C2C12 and PC 12 cell differentiation. FEBS Lett,2007 581(16):3076-3080.
69. Zheng X, Shen G, Yang X, et al. Most C6 Cells Are Cancer Stem Cells: Evidence from Clonal and Population Analyses.Cancer Res,2007, 67(8):3691-3697.
70. Sales-Pardo I, Avendano A, Martinez-Munoz V, Garcia-Escarp M, Celis R, Whittle P, Barquinero J, et al. Flow cytometry of the Side Population: tips & tricks. Cell Oncol 2006;28:37-53.
71. Montanaro F, Liadaki K, Schienda J, Flint A, Gussoni E, Kunkel LM. Demystifying SP cell purification:viability, yield, and phenotype are defined by isolation parameters. Experimental Cell Research 2004;298:144-154.
72. Morita Y, Ema H, Yamazaki S, Nakauchi H. Non-side-population hematopoietic stem cells in mouse bone marrow.Blood. 2006;108(8):2850-2856.
73. Platet N, Mayol JF, Berger F, et al. Fluctuation of the SP/non-SP phenotype in the C6 glioma cell line. FEBS Lett. 2007;581(7):1435-1440.