结直肠癌中新的细胞亚群NCCC的分离与生物学功能的研究
|
摘要
目的：在活细胞内，通过准确而有效的方法，将ki67high和ki67low/-两个细胞亚群区别并分选出来，为研究两者功能提供稳定的体系。
方法：构建ki67启动子（-1182～+575）驱动绿色荧光蛋白（GFP）表达的慢病毒系统，包装病毒后感染肿瘤细胞；将阳性克隆注射于裸鼠皮下，4-6周后处死裸鼠收获移植瘤，处理成单细胞悬液后用流式细胞仪分选出GFP+和GFPlow/-的细胞，再鉴定其ki67的表达，检测GFP能否反映ki67内源性表达。
结果:成功构建了ki67启动子驱动GFP表达的慢病毒系统；通过该系统分选的GFP+表达较高的ki67和各种cyclins，GFPlow/-的细胞低或不表达ki67和cyclins。
结论：ki67启动子驱动GFP表达的慢病毒系统能够有效的分选出ki67+和ki67low/-两个细胞亚群。
目的：比较ki67low/-和ki67+两个细胞亚群在成瘤能力，自我更新能力，转移能力，耐化疗能力等肿瘤干细胞相关特性方面的差异。
方法：通过第一部分中的方法，将分选得到的ki67low/-（GFPlow/-）和ki67+（GFP+）进行体外的克隆形成试验（clone formation assay），连续成球试验（serial sphereformation assay）以及体内的有限稀释试验（limited dilution assay）比较ki67low/-和ki67+两个细胞亚群在成瘤能力和自我更新能力；通过脾包膜下注射肿瘤细胞观察肝转移比较二者转移能力；通过腹腔注射5-Fu观察皮下移植瘤的生长，比较二者体内耐化疗的能力。
结果：ki67low/-（GFPlow/-）较ki67+（GFP+）具有更强的成瘤和自我更新能力；其肝转移的能力也更明显；对5-Fu的不敏感。
结论：ki67low/-表现出更显著的肿瘤干细胞相关特性。
目的：证实ki67low/-细胞在临床结直肠癌中的存在，探讨其与肿瘤的病理即病人预后的关系。
方法：收集2005年胃肠外科所有stage III的结直肠癌原位肿瘤标本，免疫组化染色ki67并统计其表达，收集相关临床信息，追访病人生存时间，揭示ki67的表达与肿瘤病理和病人预后的关系。
结果：临床结直肠癌中确实存在ki67表达异质性的细胞；在stage III的结直肠癌中，ki67表达与病人的性别，年龄和肿瘤性质无关，低表达ki67的肿瘤分化越差，发生转移可能性越高，低表达ki67的肿瘤病人5年生存时间更短。
结论：ki67low/-的细胞在临床结直肠癌中存在，低表达ki67的肿瘤病人预后较差
Objectives: In living cells, we will find an accurate and effective system that coulddistinguish the ki67low/-subpopulation from ki67high, which will facilitate the research ofki67low/-subpopulation’s function.
Methods: We will construct a lentivirus vector in which ki67promoter drives GFPexpression, and produce lentivirus for infecting the tumor cells. Then, we pick up thepositive clones and give subcutaneous injection of null mice. After4-6weeks, we will killthe mice and get the xenograft tumors, which then are digested into single cell suspensionby collagenase II. We sorted the GFPlow/-subpopulation from GFPhighby FACS, and thendetected the endogenous ki67expresion by double parameter.
Results: We successfully constructed the lentivirus system that ki67promoter drive theGFP expression. Using the lentivirus system, GFPhighcells have higher expression of ki67and cyclins, while GFPlow/-no or lower expression of ki67and cyclins
Conclusions: the ki67-driving GFP expression lentivirus system could distinguish theki67low/-subpopulation from ki67higheffectively.
Objective: we will compare the properties of cancer stem cell between ki67low/-and ki67highsubpopulation, such as tumorigenicity, self-renew, metastasis and chemoresistance.
Methods: In the part one, we could sort the ki67low/-（GFPlow/-）and ki67high（GFPhigh）, andthen compared its tumorigenicity by clone formation and self-renew by serial sphereformation assay. In addition, we will inject the single cell suspension into the subcapsularregion of spleen, after4weeks, mice were killed and observed. For chemoresistance,five-week-old BALB/C nude mice were injected subcutanously in both flanks with twoindependent sorted cells, and one million cells suspended in50μl PBS were injected ineach flank, meanwhile we also inject the5-Fu into abdominal cavity. After4weeks, wewill kill the mice and observe the number and size of tumors.
Results: the subpopulation of ki67low/（-GFPlow/-）has a more remarkable tumorigeneity andself-renew than ki67high（GFPhigh）. in addition,the subpopulation of ki67low/-（GFPlow/-）iseasier to colonize in liver. Finally, the subpopulation of ki67low/-（GFPlow/-）is difficult to bekilled by chemotherapeutic drugs.
Conclusions: the subpopulation of ki67low/-（GFPlow/-）has a more significant cancer stemcell related features than ki67high（GFPhigh）.
Objective: we will confirm the existence of the subpopulation of ki67low/-in cliniccolorectal cancer, and disclose the relationship among the expression of ki67, tumorpathology and patients survival.
Methods: we collected the clinic samples of stage III in colorectal caners in2005, andinvestigated its clinic information and5-years survival time. Meanwhile, we detected theki67expression by immunohistochemistry (IHC), and found the relationship between ki67expression and tumor pathology and5-years survival time.
Results: In clinic colorectal cancer, there is the subpopulation of ki67low/-in deed. Incolorectal cancer of stage III, the expression of ki67is not related with sex, age andcharacter of tumor (mass or invasive), while the tumors with the lower expression of ki67often exhibited the poor differentiation and easy metastasis. At the same time, the patientswith the lower expression of ki67have a shorter survival time.
Conclusion: the subpopulation of ki67low/-exists in clinic colorectal cancer; the lowerexpression of ki67indicates a poor prognosis.
方法：构建ki67启动子（-1182～+575）驱动绿色荧光蛋白（GFP）表达的慢病毒系统，包装病毒后感染肿瘤细胞；将阳性克隆注射于裸鼠皮下，4-6周后处死裸鼠收获移植瘤，处理成单细胞悬液后用流式细胞仪分选出GFP+和GFPlow/-的细胞，再鉴定其ki67的表达，检测GFP能否反映ki67内源性表达。
结果:成功构建了ki67启动子驱动GFP表达的慢病毒系统；通过该系统分选的GFP+表达较高的ki67和各种cyclins，GFPlow/-的细胞低或不表达ki67和cyclins。
结论：ki67启动子驱动GFP表达的慢病毒系统能够有效的分选出ki67+和ki67low/-两个细胞亚群。
目的：比较ki67low/-和ki67+两个细胞亚群在成瘤能力，自我更新能力，转移能力，耐化疗能力等肿瘤干细胞相关特性方面的差异。
方法：通过第一部分中的方法，将分选得到的ki67low/-（GFPlow/-）和ki67+（GFP+）进行体外的克隆形成试验（clone formation assay），连续成球试验（serial sphereformation assay）以及体内的有限稀释试验（limited dilution assay）比较ki67low/-和ki67+两个细胞亚群在成瘤能力和自我更新能力；通过脾包膜下注射肿瘤细胞观察肝转移比较二者转移能力；通过腹腔注射5-Fu观察皮下移植瘤的生长，比较二者体内耐化疗的能力。
结果：ki67low/-（GFPlow/-）较ki67+（GFP+）具有更强的成瘤和自我更新能力；其肝转移的能力也更明显；对5-Fu的不敏感。
结论：ki67low/-表现出更显著的肿瘤干细胞相关特性。
目的：证实ki67low/-细胞在临床结直肠癌中的存在，探讨其与肿瘤的病理即病人预后的关系。
方法：收集2005年胃肠外科所有stage III的结直肠癌原位肿瘤标本，免疫组化染色ki67并统计其表达，收集相关临床信息，追访病人生存时间，揭示ki67的表达与肿瘤病理和病人预后的关系。
结果：临床结直肠癌中确实存在ki67表达异质性的细胞；在stage III的结直肠癌中，ki67表达与病人的性别，年龄和肿瘤性质无关，低表达ki67的肿瘤分化越差，发生转移可能性越高，低表达ki67的肿瘤病人5年生存时间更短。
结论：ki67low/-的细胞在临床结直肠癌中存在，低表达ki67的肿瘤病人预后较差
Objectives: In living cells, we will find an accurate and effective system that coulddistinguish the ki67low/-subpopulation from ki67high, which will facilitate the research ofki67low/-subpopulation’s function.
Methods: We will construct a lentivirus vector in which ki67promoter drives GFPexpression, and produce lentivirus for infecting the tumor cells. Then, we pick up thepositive clones and give subcutaneous injection of null mice. After4-6weeks, we will killthe mice and get the xenograft tumors, which then are digested into single cell suspensionby collagenase II. We sorted the GFPlow/-subpopulation from GFPhighby FACS, and thendetected the endogenous ki67expresion by double parameter.
Results: We successfully constructed the lentivirus system that ki67promoter drive theGFP expression. Using the lentivirus system, GFPhighcells have higher expression of ki67and cyclins, while GFPlow/-no or lower expression of ki67and cyclins
Conclusions: the ki67-driving GFP expression lentivirus system could distinguish theki67low/-subpopulation from ki67higheffectively.
Objective: we will compare the properties of cancer stem cell between ki67low/-and ki67highsubpopulation, such as tumorigenicity, self-renew, metastasis and chemoresistance.
Methods: In the part one, we could sort the ki67low/-（GFPlow/-）and ki67high（GFPhigh）, andthen compared its tumorigenicity by clone formation and self-renew by serial sphereformation assay. In addition, we will inject the single cell suspension into the subcapsularregion of spleen, after4weeks, mice were killed and observed. For chemoresistance,five-week-old BALB/C nude mice were injected subcutanously in both flanks with twoindependent sorted cells, and one million cells suspended in50μl PBS were injected ineach flank, meanwhile we also inject the5-Fu into abdominal cavity. After4weeks, wewill kill the mice and observe the number and size of tumors.
Results: the subpopulation of ki67low/（-GFPlow/-）has a more remarkable tumorigeneity andself-renew than ki67high（GFPhigh）. in addition,the subpopulation of ki67low/-（GFPlow/-）iseasier to colonize in liver. Finally, the subpopulation of ki67low/-（GFPlow/-）is difficult to bekilled by chemotherapeutic drugs.
Conclusions: the subpopulation of ki67low/-（GFPlow/-）has a more significant cancer stemcell related features than ki67high（GFPhigh）.
Objective: we will confirm the existence of the subpopulation of ki67low/-in cliniccolorectal cancer, and disclose the relationship among the expression of ki67, tumorpathology and patients survival.
Methods: we collected the clinic samples of stage III in colorectal caners in2005, andinvestigated its clinic information and5-years survival time. Meanwhile, we detected theki67expression by immunohistochemistry (IHC), and found the relationship between ki67expression and tumor pathology and5-years survival time.
Results: In clinic colorectal cancer, there is the subpopulation of ki67low/-in deed. Incolorectal cancer of stage III, the expression of ki67is not related with sex, age andcharacter of tumor (mass or invasive), while the tumors with the lower expression of ki67often exhibited the poor differentiation and easy metastasis. At the same time, the patientswith the lower expression of ki67have a shorter survival time.
Conclusion: the subpopulation of ki67low/-exists in clinic colorectal cancer; the lowerexpression of ki67indicates a poor prognosis.
引文
1. Siegel, R., Naishadham, D., and Jemal, A.2013. Cancer statistics,2013. CA CancerJ Clin63:11-30.
2. Desantis, C., Naishadham, D., and Jemal, A.2013. Cancer statistics for AfricanAmericans,2013. CA Cancer J Clin63:151-166.
3. Jemal, A., Bray, F., Center, M.M., Ferlay, J., Ward, E., and Forman, D.2011. GlobalCancer Statistics. Ca-a Cancer Journal for Clinicians61:69-90.
4. Khrizman, P., Niland, J.C., ter Veer, A., Milne, D., Bullard Dunn, K., Carson, W.E.,3rd, Engstrom, P.F., Shibata, S., Skibber, J.M., Weiser, M.R., et al.2013.Postoperative adjuvant chemotherapy use in patients with stage II/III rectal cancertreated with neoadjuvant therapy: a national comprehensive cancer network analysis.J Clin Oncol31:30-38.
5. Valastyan, S., and Weinberg, R.A.2011. Tumor metastasis: molecular insights andevolving paradigms. Cell147:275-292.
6. Hanahan, D., and Weinberg, R.A.2011. Hallmarks of cancer: the next generation.Cell144:646-674.
7. Chaffer, C.L., and Weinberg, R.A.2011. A perspective on cancer cell metastasis.Science331:1559-1564.
8. Salehan, M.R., and Morse, H.R.2013. DNA damage repair and tolerance: a role inchemotherapeutic drug resistance. Br J Biomed Sci70:31-40.
9. Liu, B.L., Liu, X., Zhou, N.C., Qi, M.Y., and Xu, B.2013.[Mechanisms ofOxaliplatin-Induced Apoptosis of Human Multiple Myeloma Cell RPMI8226].Zhongguo Shi Yan Xue Ye Xue Za Zhi21:99-104.
10. Chow, A.K., Ng, L., Sing Li, H., Cheng, C.W., Lam, C.S., Yau, T.C., Cheng, P.N.,Fan, S.T., Poon, R.T., and Pang, R.W.2012. Anti-tumor efficacy of a recombinanthuman arginase in human hepatocellular carcinoma. Curr Cancer Drug Targets12:1233-1243.
11. Weickhardt, A., Wells, K., and Messersmith, W.2011. Oxaliplatin-inducedneuropathy in colorectal cancer. J Oncol2011:201593.
12. Alvarez, P., Marchal, J.A., Boulaiz, H., Carrillo, E., Velez, C., Rodriguez-Serrano,F., Melguizo, C., Prados, J., Madeddu, R., and Aranega, A.2012.5-Fluorouracilderivatives: a patent review. Expert Opin Ther Pat22:107-123.
13. Shah, M.Y., Pan, X., Fix, L.N., Farwell, M.A., and Zhang, B.2011.5-Fluorouracildrug alters the microRNA expression profiles in MCF-7breast cancer cells. J CellPhysiol226:1868-1878.
14. Parker, J.B., and Stivers, J.T.2011. Dynamics of uracil and5-fluorouracil in DNA.Biochemistry50:612-617.
15. Mocellin, S.2012. Editorial: cancer chemoresistance and DNA repair. Curr MedChem19:3857.
16. Castells, M., Thibault, B., Delord, J.P., and Couderc, B.2012. Implication of tumormicroenvironment in chemoresistance: tumor-associated stromal cells protect tumorcells from cell death. Int J Mol Sci13:9545-9571.
17. Gazzaniga, P., Gradilone, A., Naso, G., Cortesi, E., Gianni, W., Frati, L., andAgliano, A.M.2008. Chemoresistance profile of circulating tumor cells: toward aclinical benefit? Int J Cancer123:1730-1732.
18. McAlpine, J.N., Eisenkop, S.M., and Spirtos, N.M.2008. Tumor heterogeneity inovarian cancer as demonstrated by in vitro chemoresistance assays. Gynecol Oncol110:360-364.
19. Kern, D.H.1997. Tumor chemosensitivity and chemoresistance assays. Cancer79:1447-1450.
20. Cree, I.A., Petty, R.D., Kurbacher, C.M., and Untch, M.1996. Tumorchemosensitivity and chemoresistance assays. Cancer78:2031-2032.
21. Veyrac, M.1990.[Colorectal carcinogenesis, tumor progression andchemoresistance]. Gastroenterol Clin Biol14:20D-24D.
22. Suk, K.2012. Proteomic analysis of glioma chemoresistance. CurrNeuropharmacol10:72-79.
23. Guerra, F., Perrone, A.M., Kurelac, I., Santini, D., Ceccarelli, C., Cricca, M.,Zamagni, C., De Iaco, P., and Gasparre, G.2012. Mitochondrial DNA mutation inserous ovarian cancer: implications for mitochondria-coded genes inchemoresistance. J Clin Oncol30:e373-378.
24. Sgambato, A., and Cittadini, A.2010. Inflammation and cancer: a multifaceted link.Eur Rev Med Pharmacol Sci14:263-268.
25. De Raeve, H.R., and Vanderkerken, K.2005. The role of the bone marrowmicroenvironment in multiple myeloma. Histol Histopathol20:1227-1250.
26. Alavi, A.S., Acevedo, L., Min, W., and Cheresh, D.A.2007. Chemoresistance ofendothelial cells induced by basic fibroblast growth factor depends onRaf-1-mediated inhibition of the proapoptotic kinase, ASK1. Cancer Res67:2766-2772.
27. Petriz, J.2013. Flow Cytometry of the Side Population (SP). Curr Protoc CytomChapter9:Unit923.
28. Xia, P., Gou, W.F., Wang, J.J., Niu, Z.F., Chen, S., Takano, Y., and Zheng, H.C.
2013. Distinct Radiosensitivity of Lung Carcinoma Stem-Like Side Population andMain Population Cells. Cancer Biother Radiopharm.
29. Zhang, H.H., Cai, A.Z., Wei, X.M., Ding, L., Li, F.Z., Zheng, A.M., Dai, D.J.,Huang, R.R., Cao, H.J., Zhou, H.Y., et al.2013. Characterization of cancerstem-like cells in the side population cells of human gastric cancer cell lineMKN-45. J Zhejiang Univ Sci B14:216-223.
30. Golebiewska, A., Bougnaud, S., Stieber, D., Brons, N.H., Vallar, L., Hertel, F.,Klink, B., Schrock, E., Bjerkvig, R., and Niclou, S.P.2013. Side population inhuman glioblastoma is non-tumorigenic and characterizes brain endothelial cells.Brain136:1462-1475.
31. Ergen, A.V., Jeong, M., Lin, K.K., Challen, G.A., and Goodell, M.A.2013. Isolationand characterization of mouse side population cells. Methods Mol Biol946:151-162.
32. Chen, Y., Zhao, J., Luo, Y., Wang, Y., Wei, N., and Jiang, Y.2012. Isolation andidentification of cancer stem-like cells from side population of human prostatecancer cells. J Huazhong Univ Sci Technolog Med Sci32:697-703.
33. Wang, J., Wei, X., Ling, J., Huang, Y., Gong, Q., and Huo, Y.2012. Identificationand characterization of side population cells from adult human dental pulp afterischemic culture. J Endod38:1489-1497.
34. Yu, Y., and Zhu, Z.2013. Cell dormancy and tumor refractory. Anticancer AgentsMed Chem13:199-202.
35. Nishikawa, S., Ishii, H., Haraguchi, N., Kano, Y., Fukusumi, T., Ohta, K., Ozaki, M.,Sakai, D., Satoh, T., Nagano, H., et al.2012. Genotoxic therapy stimulateserror-prone DNA repair in dormant hepatocellular cancer stem cells. Exp Ther Med3:959-962.
36. Nishikawa, S., Dewi, D.L., Ishii, H., Konno, M., Haraguchi, N., Kano, Y.,Fukusumi, T., Ohta, K., Noguchi, Y., Ozaki, M., et al.2012. Transcriptomic study ofdormant gastrointestinal cancer stem cells. Int J Oncol41:979-984.
37. Donnenberg, A.D., Hicks, J.B., Wigler, M., and Donnenberg, V.S.2013. The cancerstem cell: cell type or cell state? Cytometry A83:5-7.
38. Valent, P., Bonnet, D., De Maria, R., Lapidot, T., Copland, M., Melo, J.V.,Chomienne, C., Ishikawa, F., Schuringa, J.J., Stassi, G., et al.2012. Cancer stem celldefinitions and terminology: the devil is in the details. Nat Rev Cancer12:767-775.
39. Gilbertson, R.J., and Graham, T.A.2012. Cancer: Resolving the stem-cell debate.Nature488:462-463.
40. Gilbertson, R.J., and Graham, T.A.2012. Cancer: Resolving the stem-cell debate.Nature.
41. Shigdar, S., Lin, J., Li, Y., Yang, C.J., Wei, M., Zhus, Y., Liu, H., and Duan, W.2012.Cancer stem cell targeting: the next generation of cancer therapy and molecularimaging. Ther Deliv3:227-244.
42. Tang, D.G.2012. Understanding cancer stem cell heterogeneity and plasticity. CellRes22:457-472.
43. Zheng, S., Xin, L., Liang, A., and Fu, Y.2012. Cancer stem cell hypothesis: a briefsummary and two proposals. Cytotechnology.
44. Yu, C., Yao, Z., Jiang, Y., and Keller, E.T.2012. Prostate cancer stem cell biology.Minerva Urol Nefrol64:19-33.
45. Sayed, S.I., Dwivedi, R.C., Katna, R., Garg, A., Pathak, K.A., Nutting, C.M.,Rhys-Evans, P., Harrington, K.J., and Kazi, R.2011. Implications of understandingcancer stem cell (CSC) biology in head and neck squamous cell cancer. Oral Oncol47:237-243.
46. Rahman, M., Deleyrolle, L., Vedam-Mai, V., Azari, H., Abd-El-Barr, M., andReynolds, B.A.2011. The cancer stem cell hypothesis: failures and pitfalls.Neurosurgery68:531-545; discussion545.
47. Merlos-Suarez, A., Barriga, F.M., Jung, P., Iglesias, M., Cespedes, M.V., Rossell, D.,Sevillano, M., Hernando-Momblona, X., da Silva-Diz, V., Munoz, P., et al.2011.The intestinal stem cell signature identifies colorectal cancer stem cells and predictsdisease relapse. Cell Stem Cell8:511-524.
48. Nie, D.2010. Cancer stem cell and niche. Front Biosci (Schol Ed)2:184-193.
49. Bomken, S., Fiser, K., Heidenreich, O., and Vormoor, J.2010. Understanding thecancer stem cell. Br J Cancer103:439-445.
50. Tang, C., Ang, B.T., and Pervaiz, S.2007. Cancer stem cell: target for anti-cancertherapy. FASEB J21:3777-3785.
51. Pelechano, V., Wei, W., and Steinmetz, L.M.2013. Extensive transcriptionalheterogeneity revealed by isoform profiling. Nature497:127-131.
52. Hu, J., Locasale, J.W., Bielas, J.H., O'Sullivan, J., Sheahan, K., Cantley, L.C.,Heiden, M.G., and Vitkup, D.2013. Heterogeneity of tumor-induced geneexpression changes in the human metabolic network. Nat Biotechnol.
53. Holzel, M., Bovier, A., and Tuting, T.2013. Plasticity of tumour and immune cells:a source of heterogeneity and a cause for therapy resistance? Nat Rev Cancer13:365-376.
54. Alderton, G.K.2013. Tumour heterogeneity: The rise of the minority. Nat RevCancer13:225.
55. Wang, Z.A., Mitrofanova, A., Bergren, S.K., Abate-Shen, C., Cardiff, R.D.,Califano, A., and Shen, M.M.2013. Lineage analysis of basal epithelial cellsreveals their unexpected plasticity and supports a cell-of-origin model for prostatecancer heterogeneity. Nat Cell Biol15:274-283.
56. Valent, P., Bonnet, D., Wohrer, S., Andreeff, M., Copland, M., Chomienne, C., andEaves, C.2013. Heterogeneity of neoplastic stem cells: theoretical, functional, andclinical implications. Cancer Res73:1037-1045.
57. Zhang, J., Grubor, V., Love, C.L., Banerjee, A., Richards, K.L., Mieczkowski, P.A.,Dunphy, C., Choi, W., Au, W.Y., Srivastava, G., et al.2013. Genetic heterogeneityof diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A110:1398-1403.
58. Raza, A., and Galili, N.2012. The genetic basis of phenotypic heterogeneity inmyelodysplastic syndromes. Nat Rev Cancer12:849-859.
59. MacArthur, B.D., Sevilla, A., Lenz, M., Muller, F.J., Schuldt, B.M., Schuppert, A.A.,Ridden, S.J., Stumpf, P.S., Fidalgo, M., Ma'ayan, A., et al.2012. Nanog-dependentfeedback loops regulate murine embryonic stem cell heterogeneity. Nat Cell Biol14:1139-1147.
60. Dooley, J., Erickson, M., and Farr, A.G.2009. Lessons from thymic epithelialheterogeneity: FoxN1and tissue-restricted gene expression by extrathymic,endodermally derived epithelium. J Immunol183:5042-5049.
61. Shackleton, M., Quintana, E., Fearon, E.R., and Morrison, S.J.2009. Heterogeneityin cancer: cancer stem cells versus clonal evolution. Cell138:822-829.
62. Magee, J.A., Piskounova, E., and Morrison, S.J.2012. Cancer stem cells: impact,heterogeneity, and uncertainty. Cancer Cell21:283-296.
63. Salerno, M., Avnet, S., Bonuccelli, G., Eramo, A., De Maria, R., Gambarotti, M.,Gamberi, G., and Baldini, N.2013. Sphere-forming cell subsets with cancer stemcell properties in human musculoskeletal sarcomas. Int J Oncol.
64. Ma, L., Zhang, G., Miao, X.B., Deng, X.B., Wu, Y., Liu, Y., Jin, Z.R., Li, X.Q., Liu,Q.Z., Sun, D.X., et al.2013. Cancer stem-like cell properties are regulated byEGFR/AKT/beta-catenin signaling and preferentially inhibited by gefitinib innasopharyngeal carcinoma. FEBS J280:2027-2041.
65. Nishi, M., Sakai, Y., Akutsu, H., Nagashima, Y., Quinn, G., Masui, S., Kimura, H.,Perrem, K., Umezawa, A., Yamamoto, N., et al.2013. Induction of cells with cancerstem cell properties from nontumorigenic human mammary epithelial cells bydefined reprogramming factors. Oncogene.
66. Yamazaki, H., Naito, M., Ghani, F.I., Dang, N.H., Iwata, S., and Morimoto, C.2012.Characterization of cancer stem cell properties of CD24and CD26-positive humanmalignant mesothelioma cells. Biochem Biophys Res Commun419:529-536.
67. Zucchi, I., Sanzone, S., Astigiano, S., Pelucchi, P., Scotti, M., Valsecchi, V., Barbieri,O., Bertoli, G., Albertini, A., Reinbold, R.A., et al.2007. The properties of amammary gland cancer stem cell. Proc Natl Acad Sci U S A104:10476-10481.
68. Ponti, D., Costa, A., Zaffaroni, N., Pratesi, G., Petrangolini, G., Coradini, D., Pilotti,S., Pierotti, M.A., and Daidone, M.G.2005. Isolation and in vitro propagation oftumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res65:5506-5511.
69. Adhikari, A.S., Agarwal, N., and Iwakuma, T.2011. Metastatic potential oftumor-initiating cells in solid tumors. Front Biosci16:1927-1938.
70. Hiraga, T., Ito, S., and Nakamura, H.2013. Cancer Stem-like Cell Marker CD44Promotes Bone Metastases by Enhancing Tumorigenicity, Cell Motility andHyaluronan Production. Cancer Res.
71. Schneider, M., Huber, J., Hadaschik, B., Siegers, G.M., Fiebig, H.H., and Schuler, J.
2012. Characterization of colon cancer cells: a functional approach characterizingCD133as a potential stem cell marker. BMC Cancer12:96.
72. Takaishi, S., Okumura, T., Tu, S., Wang, S.S., Shibata, W., Vigneshwaran, R.,Gordon, S.A., Shimada, Y., and Wang, T.C.2009. Identification of gastric cancerstem cells using the cell surface marker CD44. Stem Cells27:1006-1020.
73. Gopisetty, G., Xu, J., Sampath, D., Colman, H., and Puduvalli, V.K.2012.Epigenetic regulation of CD133/PROM1expression in glioma stem cells bySp1/myc and promoter methylation. Oncogene.
74. Zhang, L., Sun, H., Zhao, F., Lu, P., Ge, C., Li, H., Hou, H., Yan, M., Chen, T.,Jiang, G., et al.2012. BMP4administration induces differentiation of CD133+hepatic cancer stem cells, blocking their contributions to hepatocellular carcinoma.Cancer Res72:4276-4285.
75. Taylor, R.A., Toivanen, R., Frydenberg, M., Pedersen, J., Harewood, L., AustralianProstate Cancer, B., Collins, A.T., Maitland, N.J., and Risbridger, G.P.2012. Humanepithelial basal cells are cells of origin of prostate cancer, independent of CD133status. Stem Cells30:1087-1096.
76. Tang, K.H., Ma, S., Lee, T.K., Chan, Y.P., Kwan, P.S., Tong, C.M., Ng, I.O., Man,K., To, K.F., Lai, P.B., et al.2012. CD133(+) liver tumor-initiating cells promotetumor angiogenesis, growth, and self-renewal throughneurotensin/interleukin-8/CXCL1signaling. Hepatology55:807-820.
77. Shmelkov, S.V., Butler, J.M., Hooper, A.T., Hormigo, A., Kushner, J., Milde, T., StClair, R., Baljevic, M., White, I., Jin, D.K., et al.2008. CD133expression is notrestricted to stem cells, and both CD133+and CD133-metastatic colon cancer cellsinitiate tumors. J Clin Invest118:2111-2120.
78. LaBarge, M.A., and Bissell, M.J.2008. Is CD133a marker of metastatic coloncancer stem cells? J Clin Invest118:2021-2024.
79. Fedorchenko, O., Stiefelhagen, M., Peer Zada, A.A., Barthel, R., Mayer, P., Eckei,L., Breuer, A., Crispatzu, G., Rosen, N., Landwehr, T., et al.2013. CD44regulatesthe apoptotic response and promotes disease development in chronic lymphocyticleukemia. Blood.
80. Du, L., Rao, G., Wang, H., Li, B., Tian, W., Cui, J., He, L., Laffin, B., Tian, X., Hao,C., et al.2013. CD44-Positive Cancer Stem Cells Expressing Cellular Prion ProteinContribute to Metastatic Capacity in Colorectal Cancer. Cancer Res73:2682-2694.
81. Nagano, O., Okazaki, S., and Saya, H.2013. Redox regulation in stem-like cancercells by CD44variant isoforms. Oncogene.
82. Zhao, P., Damerow, M.S., Stern, P., Liu, A.H., Sweet-Cordero, A., Siziopikou, K.,Neilson, J.R., Sharp, P.A., and Cheng, C.2012. CD44promotes Kras-dependentlung adenocarcinoma. Oncogene.
83. Dallas, M.R., Liu, G., Chen, W.C., Thomas, S.N., Wirtz, D., Huso, D.L., andKonstantopoulos, K.2012. Divergent roles of CD44and carcinoembryonic antigenin colon cancer metastasis. FASEB J26:2648-2656.
84. Szabo, A.Z., Fong, S., Yue, L., Zhang, K., Strachan, L.R., Scalapino, K., Mancianti,M.L., and Ghadially, R.2012. The CD44+ALDH+population of humankeratinocytes is enriched for epidermal stem cells with long-term repopulatingability. Stem Cells31:786-799.
85. Fleischman, A.G.2012. ALDH marks leukemia stem cell. Blood119:3376-3377.
86. Visus, C., Wang, Y., Lozano-Leon, A., Ferris, R.L., Silver, S., Szczepanski, M.J.,Brand, R.E., Ferrone, C.R., Whiteside, T.L., Ferrone, S., et al.2011. TargetingALDH(bright) human carcinoma-initiating cells with ALDH1A1-specific CD8(+) Tcells. Clin Cancer Res17:6174-6184.
87. Oelze, M., Knorr, M., Schell, R., Kamuf, J., Pautz, A., Art, J., Wenzel, P., Munzel,T., Kleinert, H., and Daiber, A.2011. Regulation of human mitochondrial aldehydedehydrogenase (ALDH-2) activity by electrophiles in vitro. J Biol Chem286:8893-8900.
88. Pierre-Louis, O., Clay, D., Brunet de la Grange, P., Blazsek, I., Desterke, C.,Guerton, B., Blondeau, C., Malfuson, J.V., Prat, M., Bennaceur-Griscelli, A., et al.
2009. Dual SP/ALDH functionalities refine the human hematopoieticLin-CD34+CD38-stem/progenitor cell compartment. Stem Cells27:2552-2562.
89. Moreb, J.S., Baker, H.V., Chang, L.J., Amaya, M., Lopez, M.C., Ostmark, B., andChou, W.2008. ALDH isozymes downregulation affects cell growth, cell motilityand gene expression in lung cancer cells. Mol Cancer7:87.
90. Visvader, J.E., and Lindeman, G.J.2012. Cancer stem cells: current status andevolving complexities. Cell Stem Cell10:717-728.
91. Visvader, J.E.2011. Cells of origin in cancer. Nature469:314-322.
92. Saito, Y., Uchida, N., Tanaka, S., Suzuki, N., Tomizawa-Murasawa, M., Sone, A.,Najima, Y., Takagi, S., Aoki, Y., Wake, A., et al.2010. Induction of cell cycle entry
eliminates human leukemia stem cells in a mouse model of AML. Nat Biotechnol
28:275-280.
1. Fuchs E, Horsley V. Ferreting out stem cells from their niches.Nature Cell Biol2011;13:513-518.
2. Medema JP, Vermulen L. Microenvironmental regulation of stem cells in intestinalhomeostasis and cancer. Nature2011;474:318-326.
3. Simons BD, Clevers H. Strategies for homeostatic stem cell self-renewal in adulttissues. Cell2011;145:851-862.
4. Li L, Clevers H. Coexistence of quiescent and active adult stem cells in mammals.Science2010;327:542-545.
5. Cotsarelis G, Cheng SZ, Dong G, Sun TT, Lavker RM. Existence of slow-cyclinglimbal epithelial basal cells that can be preferentially stimulated to proliferate:Implications on epithelial stem cells. Cell1989;57:201-209.
6. Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area ofpilosebaceous unit: implications for follicular stem cells, hair cycle, and skincarcinogenesis. Cell1990;61:1329-1337.
7. Golebiewska A, Brons NH, Bjerkvig R, Niclou SP. Critical appraisal of the sidepopulation assay in stem cell and cancer stem cell research. Cell Stem Cell2011;8:136-147.
8. Storms RW, Trujillo AP, Springer JB, et al. Isolation of primitive humanhematopoietic progenitors on the basis of aldehyde dehydrogenase activity. Proc NatlAcad Sci USA1999;96:9118-9123.
9. Passegué E, Jamieson CH, Ailles LE, Weissman IL. Normal and leukemichematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cellcharacteristics? Proc Natl Acad Sci USA2003;100(Suppl1):11842-11849.
10. Notta F, Doulatov S, Laurenti E, Poeppl A, Jurisica I, Dick JE. Isolation of singlehuman hematopoietic stem cells capable of long-term multilineage engraftment.Science2011;333:218-221.
11. Majeti R, Park CY, Weissman IL. Identification of a hierarchy of multipotenthematopoietic progenitors in human cord blood. Cell Stem Cell2007;1:635-645.
12. Osawa M, Hanada K, Hamada H, Nakauchi H. Long-term lymphohematopoieticreconstitution by a single CD34-low/negative hematopoietic stem cell. Science1996;273:242-245.
13. Kiel MJ, Yilmaz OH, Iwashita T, Yilmaz OH, Terhorst C, Morrison SJ. SLAM familyreceptors distinguish hematopoietic stem and progenitor cells and reveal endothelialniches for stem cells. Cell2005;121:1109-1121.
14. Xin L, Lawson DA, Witte ON. The Sca-1cell surface marker enriches for aprostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. ProcNatl Acad Sci USA2005;102:6942-6947.
15. Burger PE, Xiong X, Coetzee S, et al. Sca-1expression identifies stem cells in theproximal region of prostatic ducts with high capacity to reconstitute prostatic tissue.Proc Natl Acad Sci USA2005;102:7180-7185.
16. Lawson DA, Xin L, Lukacs RU, Cheng D, Witte ON. Isolation and functionalcharacterization of murine prostate stem cells. Proc Natl Acad Sci USA2007;104:181-186.
17. Leong KG, Wang BE, Johnson L, Gao WQ. Generation of a prostate from a singleadult stem cell. Nature2008;456:804-808.
18. Hong SH, Rampalli S, Lee JB, et al. Cell fate potential of human pluripotent stem cellsis encoded by histone modifications. Cell Stem Cell2011;9:24-36.
19. Bergmann O, Bhardwaj RD, Bernard S, et al. Evidence for cardiomyocyte renewal inhumans. Science2009;324:98-102.
20. Spalding KL, Arner E, Westermark PO, et al. Dynamics of fat cell turnover in humans.Nature2008;453:783-787.
21. Arner P, Bernard S, Salehpour M, et al. Dynamics of human adipose lipid turnover inhealth and metabolic disease. Nature2011;478:110-113.
22. Katoh M, Shaw C, Xu Q, et al. An orderly retreat: Dedifferentiation is a regulatedprocess. Proc Natl Acad Sci USA2004;101:7005-7010.
23. Brawley C, Matunis E. Regeneration of male germline stem cells by spermatogonialdedifferentiation in vivo. Science2004;304:1331-1334.
24. Dor Y, Brown J, Martinez OI, Melton DA. Adult pancreatic beta-cells are formed byself-duplication rather than stem-cell differentiation. Nature2004;429:41-46.
25. Cobaleda C, Jochum W, Busslinger M. Conversion of mature B cells into T cells bydedifferentiation to uncommitted progenitors. Nature2007;449:473-477.
26. Heyworth C, Pearson S, May G, Enver T. Transcription factor-mediated lineageswitching reveals plasticity in primarycommitted progenitor cells. EMBO J2002;21:3770-3781.
27. Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming ofadult pancreatic exocrine cells to betacells.Nature2008;455:627-632.
28. Zhou Q, Melton DA. Extreme makeover: converting one cell into another. Cell StemCell2008;3:382-388.
29. Chambers SM, Studer L. Cell fate plug and play: Direct reprogramming and inducedpluripotency. Cell2011;145:827-830.
30. Pang ZP, Yang N, Vierbuchen T, et al. Induction of human neuronal cells by definedtranscription factors. Nature2011;476:220-223.
31. Caiazzo M, Dell’Anno MT, Dvorestskova E, et al. Direct generation of functionaldopaminergic neurons from mouse and human fibroblasts. Nature2011;476:224-227.
32. Yoo AS, Sun AX, Li L, et al. MicroRNA-mediated conversion of human fibroblasts toneurons. Nature2011;476:228-231.
33. Huang P, He, Z, Ji S, et al. Induction of functional hepatocytelike cells from mousefibroblasts by defined factors. Nature2011;475:386-389.
34. Sekiya S, Suzuki A. Direct conversion of mouse fibroblasts to hepatocyte-like cells bydefined factors. Nature2011;475:390-393.
35. Collombat P, Xu X, Ravassard P, et al. The ectopic expression of Pax4in the mousepancreas converts progenitor cells into α and subsequently β cells. Cell2009;138:449-462.
36. Kondo T, Raff M. Oligodendrocyte precursor cells reprogrammed to becomemultipotential CNS stem cells. Science2000;289:1754-1757.
37. Yamanaka S. Elite and stochastic models for induced pluripotent stem cell generation.Nature2009;460:49-52.
38. Shackleton M, Quintana E, Fearon ER, Morrison SJ. Heterogeneity in cancer: cancerstem cells versus clonal evolution. Cell2009;138:822-829.
39. Anderson K, Lutz C, van Delft FW, et al. Genetic variegation of clonal architecture andpropagating cells in leukaemia. Nature2011;469:356-361.
40. Notta F, Mullighan CG, Wang JC, et al. Evolution of human BCR-ABL1lymphoblastic leukaemia-initiating cells. Nature2011;469:362-367.
41. Visvader JE. Cells of origin in cancer. Nature2011;469:314-322.
42. Lim E, Vaillant F, Wu D, et al. Aberrant luminal progenitors as the candidate targetpopulation for basal tumor development in BRCA1mutation carriers. Nat Med2009;15:907-913.
43. Molyneux G, Geyer FC, Magnay FA, et al. BRCA1basal-like breast cancers originatefrom luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell2010;7:403-417.
44. Proia TA, Keller PJ, Gupta PB, et al. Genetic predisposition directs breast cancerphenotype by dictating progenitor cell fate. Cell Stem Cell2011;8:149-163.
45. Liu C, Sage JC, Miller MR, et al. Mosaic analysis with double markers reveals tumorcell of origin in glioma. Cell2011;146:209-221.
46. Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ. Efficienttumour formation by single human melanoma cells. Nature2008;456:593-598.
47. Ishizawa K, Rasheed ZA, Karisch R, et al. Tumor-initiating cells are rare in manyhuman tumors. Cell Stem Cell2010;7:279-282.
48. Alison MR, Guppy NJ, Lim SML, Nicholson LJ. Finding cancer stem cells: Arealdehyde dehydrogenases fit for purpose? J Pathol2010;222:335-344.
49. Pastrana E, Silva-Vargas V, Doetsch F. Eyes wide open: a critical review ofsphere-formation as an assay for stem cells. Cell Stem Cell2011;8:486-498.
50. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospectiveidentification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA2003;100:3983-3938.
51. Hirschmann-Jax C, Foster AE, Wulf GG, et al. A distinct "side population" of cellswith high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA2004;101:14228-14233.
52. Engelmann K, Shen H, Finn OJ. MCF7side population cells with characteristics ofcancer stem/progenitor cells express the tumor antigen MUC1. Cancer Res2008;68:2419-2426.
53. Ginestier C, Hur MH, Charafe-Jauffret E, et al. ALDH1is a marker of normal andmalignant human mammary stem cells and a predictor of poor clinical outcome. CellStem Cell2007;1:555-567.
54. Charafe-Jauffret E, Ginestier C, Iovino F, et al. Breast cancer cell lines containfunctional cancer stem cells with metastatic capacity and a distinct molecular signature.Cancer Res2009;69:1302-1313.
55. Pece S, Tosoni D, Confalonieri S, et al. Biological and molecular heterogeneity ofbreast cancers correlates with their cancer stem cell content. Cell2010;140:62-73.
56. Hwang-Verslues WW, Kuo WH, Chang PH, et al. Multiple lineages of human breastcancer stem/progenitor cells identified by profiling with stem cell markers. PLoS One2009;4:e8377.
57. Park SY, Lee HE, Li H, Shipitsin M, Gelman R, Polyak K. Heterogeneity for stemcell-related markers according to tumor subtype and histologic stage in breast cancer.Clin Cancer Res2010;16:876-887.
58. Deng S, Yang X, Lassus H, et al. Distinct expression levels and patterns of stem cellmarker, aldehyde dehydrogenase isoform1(ALDH1), in human epithelial cancers.PLoS One2010;5:e10277.
59. Meyer MJ, Fleming JM, Lin AF, Hussnain SA, Ginsburg E, Vonderhaar BK.CD44posCD49fhiCD133/2hi defines xenograftinitiating cells in estrogenreceptor-negative breast cancer. Cancer Res2010;70:4624-4633.
60. Cicalese A, Bonizzi G, Pasi CE, et al. The tumor suppressor p53regulates polarity ofself-renewing divisions in mammary stem cells. Cell2009;138:1083-1095.
61. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiatingcells. Nature2004;432:396-401.
62. Beier D, Hau P, Proescholdt M, et al. CD133(+) and CD133(-) glioblastoma-derivedcancer stem cells show differential growth characteristics and molecular profiles.Cancer Res2007;67:4010-4015.
63. Bleau AM, Hambardzumyan D, Ozawa T, et al. PTEN/PI3K/Akt pathway regulates theside population phenotype and ABCG2activity in glioma tumor stem-like cells. CellStem Cell2009;4:226-235.
64. Son MJ, Woolard K, Nam DH, Lee J, Fine HA. SSEA-1is an enrichment marker fortumor-initiating cells in human glioblastoma. Cell Stem Cell2009;4:440-452.
65. Piccirillo SG, Combi R, Cajola L, et al. Distinct pools of cancer stem-like cells coexistwithin human glioblastomas and display different tumorigenicity and independentgenomic evolution. Oncogene2009;28:1807-1811.
66. Chen R, Nishimura MC, Bumbaca SM, et al. A hierarchy of self-renewingtumor-initiating cell types in glioblastoma. Cancer Cell2010;17:362-375.
67. Mazzoleni S, Politi LS, Pala M, et al. Epidermal growth factor receptor expressionidentifies functionally and molecularly distinct tumor-initiating cells in humanglioblastoma multiforme and is required for gliomagenesis. Cancer Res2010;70:7500-7513.
68. Inda MM, Bonavia R, Mukasa A, et al. Tumor heterogeneity is an active processmaintained by a mutant EGFR-induced cytokine circuit in glioblastoma. Genes Dev2010;24:1731-1745.
69. Anido J, Sáez-Borderías A, Gonzàlez-Juncà A, et al. TGF-β receptor inhibitors targetthe CD44(high)/Id1(high) gliomainitiating cell population in human glioblastoma.Cancer Cell2010;18:655-668.
70. Lottaz C, Beier D, Meyer K, et al. Transcriptional profiles of CD133+and CD133-glioblastoma-derived cancer stem cell lines suggest different cells of origin. CancerRes2010;70:2030-2040.
71. Yan X, Ma L, Yi D, et al. A CD133-related gene expression signature identifies anaggressive glioblastoma subtype with excessive mutations. Proc Natl Acad Sci USA2011;108:1591-1596.
72. Eyler CE, Wu Q, Yan K, et al. Glioma stem cell proliferation and tumor growth arepromoted by nitric oxide synthase-2. Cell2011;146:53-66.
73. Broadley KW, Hunn MK, Farrand KJ, et al. Side population is not necessary orsufficient for a cancer stem cell phenotype in glioblastoma multiforme. Stem Cells2011;29:452-461.
74. Bonavia R, Inda MM, Cavenee WK, Furnari FB. Heterogeneity maintenance inglioblastoma: a social network. Cancer Res2011;71:4055-4060.
75. O'Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable ofinitiating tumour growth in immunodeficient mice. Nature2007;445:106-110.
76. Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expansion of humancolon-cancer-initiating cells. Nature2007;445:111-115.
77. Todaro M, Alea MP, Di Stefano AB, et al. Colon cancer stem cells dictate tumorgrowth and resist cell death by production of interleukin-4. Cell Stem Cell2007;1:389-402.
78. Dalerba P, Dylla SJ, Park IK, et al. Phenotypic characterization of human colorectalcancer stem cells. Proc Natl Acad Sci USA2007;04:10158-10163.
79. Du L, Wang H, He L, et al. CD44is of functional importance for colorectal cancerstem cells. Clin Cancer Res2008;14:6751-6760.
80. Odoux C, Fohrer H, Hoppo T, et al. A stochastic model for cancer stem cell origin inmetastatic colon cancer. Cancer Res2008;68:6932-6941.
81. Shmelkov SV, Butler JM, Hooper AT, et al. CD133expression is not restricted to stemcells, and both CD133+and CD133-metastatic colon cancer cells initiate tumors. JClinInvest2008;118:2111-2120.
82. Vermeulen L, Todaro M, de Sousa Mello F, et al. Aldehyde dehydrogenase1is amarker for normal and malignant human colonic stem cells (SC) and tracks SCoverpopulation during colon tumorigenesis. Cancer Res2009;69:3382-3389.
83. Kemper K, Sprick MR, de Bree M, et al. The AC133epitope, but not the CD133protein, is lost upon cancer stem cell differentiation. Cancer Res2010;70:719-729.
84. Inoda S, Hirohashi Y, Torigoe T, et al. Cytotoxic T lymphocytes efficiently recognizehuman colon cancer stem-like cells. Am J Pathol2011;178:1805-1813.
85. Wilson BJ, Schatton T, Zhan Q, et al. ABCB5identifies a therapy-refractory tumor cellpopulation in colorectal cancer patients. Cancer Res2011;71:5307-5316.
86. Medema JP, Vermeulen L. Microenvironmental regulation of stem cells in intestinalhomeostasis and cancer. Nature2011;474:318-326.
87. Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J-J, Claypool K, Tang DG. Sidepopulation (SP) is enriched in tumorigenic, stem-like cancer cells whereas ABCG2+and ABCG2–cancer cells are similarly tumorigenic. Cancer Res2005;65:6207-6219.
88. Huss WJ, Gray DR, Greenberg NM, Mohler JL, Smith GJ. Breast cancer resistanceprotein-mediated efflux of androgen in putative benign and malignant prostate stemcells. Cancer Res2005;65:6640–6650.
89. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification oftumorigenic prostate cancer stem cells. Cancer Res2005;65:10946-10951.
90. Patrawala L, Calhoun T, Schneider-Broussard R, et al. Highly purified CD44+prostatecancer cells from xenograft human tumors are enriched in tumorigenic and metastaticprogenitor cells. Oncogene2006;25:1696-1708.
91. Patrawala L, Calhoun-Davis T, Schneider-Broussard R, Tang DG. Hierarchicalorganization of prostate cancer cells in xenograft tumors: The CD44+α2β1+cellpopulation is enriched in tumor-initiating cells. Cancer Res2007;67:6796-6805.
92. Miki J, Furusato B, Li H, et al. Identification of putative stem cell markers, CD133andCXCR4, in hTERT-immortalized primary nonmalignant and malignant tumor-derivedhuman prostate epithelial cell lines and in prostate cancer specimens. Cancer Res2007;67:3153-3161.
93. Gu G, Yuan J, Wills M, Kasper S. Prostate cancer cells with stem cell characteristicsreconstitute the original human tumor in vivo. Cancer Res2007;67:4807-4815.
94. Li HW, Chen X, Calhoun-Davis T, Claypool K, Tang DG. PC3Human prostatecarcinoma cell holoclones contain selfrenewing tumor-initiating cells. Cancer Res2008;68:1820-1825.
95. Jeter C, Badeaux M, Choy G, et al. Functional evidence that the self-renewal geneNANOG regulates human tumor development. Stem Cells2009;27:993-1005.
96. Dubrovska A, Kim S, Salamone RJ, et al. The role of PTEN/Akt/PI3K signaling in themaintenance and viability of prostate cancer stem-like cell populations. Proc Natl AcadSci USA2009;106:268-273.
97. Li T, Su Y, Mei Y, et al. ALDH1A1is a marker for malignant prostate stem cells andpredictor of prostate cancer patients’outcome. Lab Invest2010;90:234-244.
98. van den Hoogen C, van der Horst G, Cheung H, et al. High aldehyde dehydrogenaseactivity identifies tumor-initiating and metastasis-initiating cells in human prostatecancer. Cancer Res2010;70:5163-5173.
99. Rajasekhar VK, Studer L, Gerald W, Socci ND, Scher HI. Tumour-initiating stem-likecells in human prostate cancer exhibit increased NF-κB signalling. Nat Commun2011;2:162.
100. Liu C, Kelnar K, Liu B, et al. The microRNA miR-34a inhibits prostate cancer stemcells and metastasis by directly repressing CD44. Nature Med2011;17:211-215.
101. Ho MM, Ng AV, Lam S, Hung JY. Side population in human lung cancer cell linesand tumors is enriched with stem-like cancer cells. Cancer Res2007;67:4827-4833.
102. Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M. Identification and expansion of thetumorigenic lung cancer stem cell population. Cell Death Differ2008;15:504-414.
103. Jiang T, Collins BJ, Jin N, Watkins DN, Brock MV. Achaetescute complex homologue1regulates tumor-initiating capacity in human small cell lung cancer. Cancer Res2009;69:845-854.
104. Bertolini G, Roz L, Perego P, Tortoreto M, Fontanella E. Highly tumorigenic lungcancer CD133+cells display stemlike features and are spared by cisplatin treatment.Proc Natl Acad Sci USA2009;106:16281-16286.
105. Levina V, Marrangoni A, Wang T, et al. Elimination of human lung cancer stem cellsthrough targeting of the stem cell factor-c-kit autocrine signaling loop. Cancer Res2010;70:338-346.
106. Eramo A, Haas TL, De Maria R. Lung cancer stem cells: tools and targets to fight lungcancer. Oncogene2010;29:4625-4635.
107. Sullivan JP, Spinola M, Dodge M, et al. Aldehyde dehydrogenase activity selects forlung adenocarcinoma stem cells dependent on notch signaling. Cancer Res2010;70:9937-9948.
108. Chiou SH, Wang ML, Chou YT, et al. Coexpression of Oct4and Nanog enhancesmalignancy in lung adenocarcinoma by inducing cancer stem cell-like properties andepithelial-mesenchymal transdifferentiation. Cancer Res2010;70:10433-10444.
109. Leung EL, Fiscus RR, Tung JW, et al. Non-small cell lung cancer cells expressingCD44are enriched for stem cell-like properties. PLoS One2010;5:e14062.
110. Curtis SJ, Sinkevicius KW, Li D, et al. Primary tumor genotype is an importantdeterminant in identification of lung cancer propagating cells. Cell Stem Cell2010;7:127-133.
111. Damelin M, Geles KG, Follettie MT, et al. Delineation of a cellular hierarchy in lungcancer reveals an oncofetal antigen expressed on tumor-initiating cells. Cancer Res2011;71:4236-4246.
112. Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemiaafter transplantation into SCID mice. Nature1994;367:645-648.
113. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy thatoriginates from a primitive hematopoietic cell. Nat Med1997;3:730-737.
114. Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy ofleukemic stem cell classes that differ in self-renewal capacity. Nat Immunol2004;5:738-743.
115. Sarry JE, Murphy K, Perry R, et al. Human acute myelogenous leukemia stemcells are rare and heterogeneous when assayed in NOD/SCID/IL2Rγc-deficient mice. JClin Invest2011;121:384-395.
116. Shipitsin M, Campbell LL, Argani P, et al. Molecular definition of breast tumorheterogeneity. Cancer Cell2007;11:259-273.
117. Park SY, G nen M, Kim HJ, Michor F, Polyak K. Cellular and genetic diversity in theprogression of in situ human breast carcinomas to an invasive phenotype. J Clin Invest2010;120:636-644.
118. Lotem J, Sachs L. Epigenetics and the plasticity of differentiation in normal and cancerstem cells. Oncogene2006;25:7663-7672.
119. Hendrix MJ, Seftor EA, Hess AR, Seftor RE. Molecular plasticity of human melanomacells. Oncogene2003;22:3070-3075.
120. Casal C, Torres-Collado AX, Plaza-Calonge Mdel C, et al. ADAMTS1contributes tothe acquisition of an endotheliallike phenotype in plastic tumor cells. Cancer Res2010;70:4676-4686.
121. Wang R, Chadalavada K, Wilshire J, et al. Glioblastoma stem-like cells give rise totumour endothelium. Nature2010;468:829-833.
122. Ricci-Vitiani L, Pallini R, Biffoni M, et al. Tumour vascularization via endothelialdifferentiation of glioblastoma stemlike cells. Nature2010;468:824-828.
123. Sharma SV, Lee DY, Li B, et al. A chromatin-mediated reversible drug-tolerant state incancer cell subpopulations. Cell2010;141:69-80.
124. Yan H, Chen X, Zhang Q, et al. Drug-tolerant cancer cells show reducedtumor-initiating capacity: Depletion of CD44+cells and evidence for epigeneticmechanisms. PLoS One2011;6:e24397.
125. Chaffer CL, Brueckmann I, Scheel C, et al. Normal and neoplastic nonstem cells canspontaneously convert to a stem-like state. Proc Natl Acad Sci USA2011;108:7950-7955.
126. Gupta PB, Fillmore CM, Jiang G, et al. Stochastic state transitions give rise tophenotypic equilibrium in populations of cancer cells. Cell2011;146:633-644.
127. Das B, Tsuchida R, Malkin D, et al. Hypoxia enhances tumor stemness by increasingthe invasive and tumorigenic side population fraction. Stem Cells2008;26:1818-1830.
128. Mathieu J, Zhang Z, Zhou W, et al. HIF induces human embryonic stem cell markersin cancer cells. Cancer Res2011;71:4640-4652.
129. Koh MY, Lemos R Jr, Liu X, Powis G. The hypoxia-associated factor switches cellsfrom HIF-1α-to HIF-2α-dependent signaling promoting stem cell characteristics,aggressive tumor growth and invasion. Cancer Res2011;71:4015-4027.
130. Mani SA, Guo W, Liao MJ, et al. The epithelial-mesenchymal transition generatescells with properties of stem cells. Cell2008;133:704-715.
131. Santisteban M, Reiman JM, Asiedu MK, et al. Immuneinduced epithelial tomesenchymal transition in vivo generates breast cancer stem cells. Cancer Res2009;69:2887-2895.
132. Iliopoulos D, Hirsch HA, Struhl K. An epigenetic switch involving NF-kappaB, Lin28,Let-7MicroRNA, and IL6links inflammation to cell transformation. Cell2009;139:693-706.
133. Iliopoulos D, Lindahl-Allen M, Polytarchou C, Hirsch HA, Tsichlis PN, Struhl K. Lossof miR-200inhibition of Suz12leads to polycomb-mediated repression required for theformation and maintenance of cancer stem cells. Mol Cell2010;39:761-772.
134. Asiedu MK, Ingle JN, Behrens MD, Radisky DC, Knutson KL. TGFβ/TNFα-mediatedepithelial-mesenchymal transition generates breast cancer stem cells with a claudin-lowphenotype. Cancer Res2011;71:4707-4719.
135. Iliopoulos D, Hirsch HA, Wang G, Struhl K. Inducible formation of breast cancer stemcells and their dynamic equilibrium with non-stem cancer cells via IL6secretion. ProcNatl Acad Sci USA2011;108:1397-1402.
136. Jeter CR, Liu B, Liu X, et al. NANOG promotes cancer stemcell characteristics andprostate cancer resistance to androgen deprivation. Oncogene2011;30:3833-3845.
137. Arzumanyan A, Friedman T, Ng IO, Clayton MM, Lian Z, Feitelson MA. Does thehepatitis B antigen HBx promote the appearance of liver cancer stem cells? Cancer Res2011;71:3701-3708.
138. Su YJ, Lai HM, Chang YW, Chen GY, Lee JL. Direct reprogramming of stem cellproperties in colon cancer cells by CD44. EMBO J2011;30:3186-3199.
139. Scaffidi P, Misteli T. In vitro generation of human cells with cancer stem cellproperties. Nat Cell Biol2011;13:1051-1061.
140. Hwang WL, Yang MH, Tsai ML, et al. SNAIL regulates interleukin-8expression, stemcell-like activity, and tumorigenicity of human colorectal carcinoma cells.Gastroenterology2011;141:279-291.
141. Paranjape AN, Mandal T, Mukherjee G, Kumar MV, Sengupta K, Rangarajan A.Introduction of SV40ER and hTERT into mammospheres generates breast cancer cellswith stem cell properties. Oncogene2011Aug29. doi:10.1038/onc.2011.378
142. Bissell MJ, Labarge MA. Context, tissue plasticity, and cancer: are tumor stem cellsalso regulated by the microenvironment? Cancer Cell2005;7:17-23.
143. Liu S, Ginestier C, Ou SJ, et al. Breast cancer stem cells are regulated by mesenchymalstem cells through cytokine networks. Cancer Res2011;71:614-624.
144. Li X, Lewis MT, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cellsto chemotherapy. J Natl Cancer Inst2008;100:672-679.
145. Reim F, Dombrowski Y, Ritter C, et al. Immunoselection of breast and ovarian cancercells with trastuzumab and natural killer cells: selective escape ofCD44high/CD24low/HER2low breast cancer stem cells. Cancer Res2009;69:8058-8066.
146. Liu H, Patel MR, Prescher JA, et al. Cancer stem cells from human breast tumors areinvolved in spontaneous metastases in orthotopic mouse models. Proc Natl Acad SciUSA2010;107:18115-18120.
147. Yu F, Yao H, Zhu P, et al. let-7regulates self renewal and tumorigenicity of breastcancer cells. Cell2007;131:1109-1123.
148. Emmink BL, Van Houdt WJ, Vries RG, et al. Differentiated human colorectal cancercells protect tumor-initiating cells from irinotecan. Gastroenterology2011;141:269-278.
149. Dubrovska A, Elliott J, Salamone RJ, et al. Combination therapy targeting bothtumor-initiating and differentiated cell populations in prostate carcinoma. Clin CancerRes2010;16:5692-5702.
150. Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancerstem cells, and acts together with chemotherapy to block tumor growth and prolongremission. Cancer Res2009;69:7507-7511.
151. Shats I, Gatza ML, Chang JT, et al. Using a stem cell-based signature to guidetherapeutic selection in cancer. Cancer Res2011;71:1772-1780.
152. Eppert K, Takenaka K, Lechman ER, et al. Stem cell gene expression programsinfluence clinical outcome in human leukemia. Nat Med2011;17:1086-1093.
2. Desantis, C., Naishadham, D., and Jemal, A.2013. Cancer statistics for AfricanAmericans,2013. CA Cancer J Clin63:151-166.
3. Jemal, A., Bray, F., Center, M.M., Ferlay, J., Ward, E., and Forman, D.2011. GlobalCancer Statistics. Ca-a Cancer Journal for Clinicians61:69-90.
4. Khrizman, P., Niland, J.C., ter Veer, A., Milne, D., Bullard Dunn, K., Carson, W.E.,3rd, Engstrom, P.F., Shibata, S., Skibber, J.M., Weiser, M.R., et al.2013.Postoperative adjuvant chemotherapy use in patients with stage II/III rectal cancertreated with neoadjuvant therapy: a national comprehensive cancer network analysis.J Clin Oncol31:30-38.
5. Valastyan, S., and Weinberg, R.A.2011. Tumor metastasis: molecular insights andevolving paradigms. Cell147:275-292.
6. Hanahan, D., and Weinberg, R.A.2011. Hallmarks of cancer: the next generation.Cell144:646-674.
7. Chaffer, C.L., and Weinberg, R.A.2011. A perspective on cancer cell metastasis.Science331:1559-1564.
8. Salehan, M.R., and Morse, H.R.2013. DNA damage repair and tolerance: a role inchemotherapeutic drug resistance. Br J Biomed Sci70:31-40.
9. Liu, B.L., Liu, X., Zhou, N.C., Qi, M.Y., and Xu, B.2013.[Mechanisms ofOxaliplatin-Induced Apoptosis of Human Multiple Myeloma Cell RPMI8226].Zhongguo Shi Yan Xue Ye Xue Za Zhi21:99-104.
10. Chow, A.K., Ng, L., Sing Li, H., Cheng, C.W., Lam, C.S., Yau, T.C., Cheng, P.N.,Fan, S.T., Poon, R.T., and Pang, R.W.2012. Anti-tumor efficacy of a recombinanthuman arginase in human hepatocellular carcinoma. Curr Cancer Drug Targets12:1233-1243.
11. Weickhardt, A., Wells, K., and Messersmith, W.2011. Oxaliplatin-inducedneuropathy in colorectal cancer. J Oncol2011:201593.
12. Alvarez, P., Marchal, J.A., Boulaiz, H., Carrillo, E., Velez, C., Rodriguez-Serrano,F., Melguizo, C., Prados, J., Madeddu, R., and Aranega, A.2012.5-Fluorouracilderivatives: a patent review. Expert Opin Ther Pat22:107-123.
13. Shah, M.Y., Pan, X., Fix, L.N., Farwell, M.A., and Zhang, B.2011.5-Fluorouracildrug alters the microRNA expression profiles in MCF-7breast cancer cells. J CellPhysiol226:1868-1878.
14. Parker, J.B., and Stivers, J.T.2011. Dynamics of uracil and5-fluorouracil in DNA.Biochemistry50:612-617.
15. Mocellin, S.2012. Editorial: cancer chemoresistance and DNA repair. Curr MedChem19:3857.
16. Castells, M., Thibault, B., Delord, J.P., and Couderc, B.2012. Implication of tumormicroenvironment in chemoresistance: tumor-associated stromal cells protect tumorcells from cell death. Int J Mol Sci13:9545-9571.
17. Gazzaniga, P., Gradilone, A., Naso, G., Cortesi, E., Gianni, W., Frati, L., andAgliano, A.M.2008. Chemoresistance profile of circulating tumor cells: toward aclinical benefit? Int J Cancer123:1730-1732.
18. McAlpine, J.N., Eisenkop, S.M., and Spirtos, N.M.2008. Tumor heterogeneity inovarian cancer as demonstrated by in vitro chemoresistance assays. Gynecol Oncol110:360-364.
19. Kern, D.H.1997. Tumor chemosensitivity and chemoresistance assays. Cancer79:1447-1450.
20. Cree, I.A., Petty, R.D., Kurbacher, C.M., and Untch, M.1996. Tumorchemosensitivity and chemoresistance assays. Cancer78:2031-2032.
21. Veyrac, M.1990.[Colorectal carcinogenesis, tumor progression andchemoresistance]. Gastroenterol Clin Biol14:20D-24D.
22. Suk, K.2012. Proteomic analysis of glioma chemoresistance. CurrNeuropharmacol10:72-79.
23. Guerra, F., Perrone, A.M., Kurelac, I., Santini, D., Ceccarelli, C., Cricca, M.,Zamagni, C., De Iaco, P., and Gasparre, G.2012. Mitochondrial DNA mutation inserous ovarian cancer: implications for mitochondria-coded genes inchemoresistance. J Clin Oncol30:e373-378.
24. Sgambato, A., and Cittadini, A.2010. Inflammation and cancer: a multifaceted link.Eur Rev Med Pharmacol Sci14:263-268.
25. De Raeve, H.R., and Vanderkerken, K.2005. The role of the bone marrowmicroenvironment in multiple myeloma. Histol Histopathol20:1227-1250.
26. Alavi, A.S., Acevedo, L., Min, W., and Cheresh, D.A.2007. Chemoresistance ofendothelial cells induced by basic fibroblast growth factor depends onRaf-1-mediated inhibition of the proapoptotic kinase, ASK1. Cancer Res67:2766-2772.
27. Petriz, J.2013. Flow Cytometry of the Side Population (SP). Curr Protoc CytomChapter9:Unit923.
28. Xia, P., Gou, W.F., Wang, J.J., Niu, Z.F., Chen, S., Takano, Y., and Zheng, H.C.
2013. Distinct Radiosensitivity of Lung Carcinoma Stem-Like Side Population andMain Population Cells. Cancer Biother Radiopharm.
29. Zhang, H.H., Cai, A.Z., Wei, X.M., Ding, L., Li, F.Z., Zheng, A.M., Dai, D.J.,Huang, R.R., Cao, H.J., Zhou, H.Y., et al.2013. Characterization of cancerstem-like cells in the side population cells of human gastric cancer cell lineMKN-45. J Zhejiang Univ Sci B14:216-223.
30. Golebiewska, A., Bougnaud, S., Stieber, D., Brons, N.H., Vallar, L., Hertel, F.,Klink, B., Schrock, E., Bjerkvig, R., and Niclou, S.P.2013. Side population inhuman glioblastoma is non-tumorigenic and characterizes brain endothelial cells.Brain136:1462-1475.
31. Ergen, A.V., Jeong, M., Lin, K.K., Challen, G.A., and Goodell, M.A.2013. Isolationand characterization of mouse side population cells. Methods Mol Biol946:151-162.
32. Chen, Y., Zhao, J., Luo, Y., Wang, Y., Wei, N., and Jiang, Y.2012. Isolation andidentification of cancer stem-like cells from side population of human prostatecancer cells. J Huazhong Univ Sci Technolog Med Sci32:697-703.
33. Wang, J., Wei, X., Ling, J., Huang, Y., Gong, Q., and Huo, Y.2012. Identificationand characterization of side population cells from adult human dental pulp afterischemic culture. J Endod38:1489-1497.
34. Yu, Y., and Zhu, Z.2013. Cell dormancy and tumor refractory. Anticancer AgentsMed Chem13:199-202.
35. Nishikawa, S., Ishii, H., Haraguchi, N., Kano, Y., Fukusumi, T., Ohta, K., Ozaki, M.,Sakai, D., Satoh, T., Nagano, H., et al.2012. Genotoxic therapy stimulateserror-prone DNA repair in dormant hepatocellular cancer stem cells. Exp Ther Med3:959-962.
36. Nishikawa, S., Dewi, D.L., Ishii, H., Konno, M., Haraguchi, N., Kano, Y.,Fukusumi, T., Ohta, K., Noguchi, Y., Ozaki, M., et al.2012. Transcriptomic study ofdormant gastrointestinal cancer stem cells. Int J Oncol41:979-984.
37. Donnenberg, A.D., Hicks, J.B., Wigler, M., and Donnenberg, V.S.2013. The cancerstem cell: cell type or cell state? Cytometry A83:5-7.
38. Valent, P., Bonnet, D., De Maria, R., Lapidot, T., Copland, M., Melo, J.V.,Chomienne, C., Ishikawa, F., Schuringa, J.J., Stassi, G., et al.2012. Cancer stem celldefinitions and terminology: the devil is in the details. Nat Rev Cancer12:767-775.
39. Gilbertson, R.J., and Graham, T.A.2012. Cancer: Resolving the stem-cell debate.Nature488:462-463.
40. Gilbertson, R.J., and Graham, T.A.2012. Cancer: Resolving the stem-cell debate.Nature.
41. Shigdar, S., Lin, J., Li, Y., Yang, C.J., Wei, M., Zhus, Y., Liu, H., and Duan, W.2012.Cancer stem cell targeting: the next generation of cancer therapy and molecularimaging. Ther Deliv3:227-244.
42. Tang, D.G.2012. Understanding cancer stem cell heterogeneity and plasticity. CellRes22:457-472.
43. Zheng, S., Xin, L., Liang, A., and Fu, Y.2012. Cancer stem cell hypothesis: a briefsummary and two proposals. Cytotechnology.
44. Yu, C., Yao, Z., Jiang, Y., and Keller, E.T.2012. Prostate cancer stem cell biology.Minerva Urol Nefrol64:19-33.
45. Sayed, S.I., Dwivedi, R.C., Katna, R., Garg, A., Pathak, K.A., Nutting, C.M.,Rhys-Evans, P., Harrington, K.J., and Kazi, R.2011. Implications of understandingcancer stem cell (CSC) biology in head and neck squamous cell cancer. Oral Oncol47:237-243.
46. Rahman, M., Deleyrolle, L., Vedam-Mai, V., Azari, H., Abd-El-Barr, M., andReynolds, B.A.2011. The cancer stem cell hypothesis: failures and pitfalls.Neurosurgery68:531-545; discussion545.
47. Merlos-Suarez, A., Barriga, F.M., Jung, P., Iglesias, M., Cespedes, M.V., Rossell, D.,Sevillano, M., Hernando-Momblona, X., da Silva-Diz, V., Munoz, P., et al.2011.The intestinal stem cell signature identifies colorectal cancer stem cells and predictsdisease relapse. Cell Stem Cell8:511-524.
48. Nie, D.2010. Cancer stem cell and niche. Front Biosci (Schol Ed)2:184-193.
49. Bomken, S., Fiser, K., Heidenreich, O., and Vormoor, J.2010. Understanding thecancer stem cell. Br J Cancer103:439-445.
50. Tang, C., Ang, B.T., and Pervaiz, S.2007. Cancer stem cell: target for anti-cancertherapy. FASEB J21:3777-3785.
51. Pelechano, V., Wei, W., and Steinmetz, L.M.2013. Extensive transcriptionalheterogeneity revealed by isoform profiling. Nature497:127-131.
52. Hu, J., Locasale, J.W., Bielas, J.H., O'Sullivan, J., Sheahan, K., Cantley, L.C.,Heiden, M.G., and Vitkup, D.2013. Heterogeneity of tumor-induced geneexpression changes in the human metabolic network. Nat Biotechnol.
53. Holzel, M., Bovier, A., and Tuting, T.2013. Plasticity of tumour and immune cells:a source of heterogeneity and a cause for therapy resistance? Nat Rev Cancer13:365-376.
54. Alderton, G.K.2013. Tumour heterogeneity: The rise of the minority. Nat RevCancer13:225.
55. Wang, Z.A., Mitrofanova, A., Bergren, S.K., Abate-Shen, C., Cardiff, R.D.,Califano, A., and Shen, M.M.2013. Lineage analysis of basal epithelial cellsreveals their unexpected plasticity and supports a cell-of-origin model for prostatecancer heterogeneity. Nat Cell Biol15:274-283.
56. Valent, P., Bonnet, D., Wohrer, S., Andreeff, M., Copland, M., Chomienne, C., andEaves, C.2013. Heterogeneity of neoplastic stem cells: theoretical, functional, andclinical implications. Cancer Res73:1037-1045.
57. Zhang, J., Grubor, V., Love, C.L., Banerjee, A., Richards, K.L., Mieczkowski, P.A.,Dunphy, C., Choi, W., Au, W.Y., Srivastava, G., et al.2013. Genetic heterogeneityof diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A110:1398-1403.
58. Raza, A., and Galili, N.2012. The genetic basis of phenotypic heterogeneity inmyelodysplastic syndromes. Nat Rev Cancer12:849-859.
59. MacArthur, B.D., Sevilla, A., Lenz, M., Muller, F.J., Schuldt, B.M., Schuppert, A.A.,Ridden, S.J., Stumpf, P.S., Fidalgo, M., Ma'ayan, A., et al.2012. Nanog-dependentfeedback loops regulate murine embryonic stem cell heterogeneity. Nat Cell Biol14:1139-1147.
60. Dooley, J., Erickson, M., and Farr, A.G.2009. Lessons from thymic epithelialheterogeneity: FoxN1and tissue-restricted gene expression by extrathymic,endodermally derived epithelium. J Immunol183:5042-5049.
61. Shackleton, M., Quintana, E., Fearon, E.R., and Morrison, S.J.2009. Heterogeneityin cancer: cancer stem cells versus clonal evolution. Cell138:822-829.
62. Magee, J.A., Piskounova, E., and Morrison, S.J.2012. Cancer stem cells: impact,heterogeneity, and uncertainty. Cancer Cell21:283-296.
63. Salerno, M., Avnet, S., Bonuccelli, G., Eramo, A., De Maria, R., Gambarotti, M.,Gamberi, G., and Baldini, N.2013. Sphere-forming cell subsets with cancer stemcell properties in human musculoskeletal sarcomas. Int J Oncol.
64. Ma, L., Zhang, G., Miao, X.B., Deng, X.B., Wu, Y., Liu, Y., Jin, Z.R., Li, X.Q., Liu,Q.Z., Sun, D.X., et al.2013. Cancer stem-like cell properties are regulated byEGFR/AKT/beta-catenin signaling and preferentially inhibited by gefitinib innasopharyngeal carcinoma. FEBS J280:2027-2041.
65. Nishi, M., Sakai, Y., Akutsu, H., Nagashima, Y., Quinn, G., Masui, S., Kimura, H.,Perrem, K., Umezawa, A., Yamamoto, N., et al.2013. Induction of cells with cancerstem cell properties from nontumorigenic human mammary epithelial cells bydefined reprogramming factors. Oncogene.
66. Yamazaki, H., Naito, M., Ghani, F.I., Dang, N.H., Iwata, S., and Morimoto, C.2012.Characterization of cancer stem cell properties of CD24and CD26-positive humanmalignant mesothelioma cells. Biochem Biophys Res Commun419:529-536.
67. Zucchi, I., Sanzone, S., Astigiano, S., Pelucchi, P., Scotti, M., Valsecchi, V., Barbieri,O., Bertoli, G., Albertini, A., Reinbold, R.A., et al.2007. The properties of amammary gland cancer stem cell. Proc Natl Acad Sci U S A104:10476-10481.
68. Ponti, D., Costa, A., Zaffaroni, N., Pratesi, G., Petrangolini, G., Coradini, D., Pilotti,S., Pierotti, M.A., and Daidone, M.G.2005. Isolation and in vitro propagation oftumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res65:5506-5511.
69. Adhikari, A.S., Agarwal, N., and Iwakuma, T.2011. Metastatic potential oftumor-initiating cells in solid tumors. Front Biosci16:1927-1938.
70. Hiraga, T., Ito, S., and Nakamura, H.2013. Cancer Stem-like Cell Marker CD44Promotes Bone Metastases by Enhancing Tumorigenicity, Cell Motility andHyaluronan Production. Cancer Res.
71. Schneider, M., Huber, J., Hadaschik, B., Siegers, G.M., Fiebig, H.H., and Schuler, J.
2012. Characterization of colon cancer cells: a functional approach characterizingCD133as a potential stem cell marker. BMC Cancer12:96.
72. Takaishi, S., Okumura, T., Tu, S., Wang, S.S., Shibata, W., Vigneshwaran, R.,Gordon, S.A., Shimada, Y., and Wang, T.C.2009. Identification of gastric cancerstem cells using the cell surface marker CD44. Stem Cells27:1006-1020.
73. Gopisetty, G., Xu, J., Sampath, D., Colman, H., and Puduvalli, V.K.2012.Epigenetic regulation of CD133/PROM1expression in glioma stem cells bySp1/myc and promoter methylation. Oncogene.
74. Zhang, L., Sun, H., Zhao, F., Lu, P., Ge, C., Li, H., Hou, H., Yan, M., Chen, T.,Jiang, G., et al.2012. BMP4administration induces differentiation of CD133+hepatic cancer stem cells, blocking their contributions to hepatocellular carcinoma.Cancer Res72:4276-4285.
75. Taylor, R.A., Toivanen, R., Frydenberg, M., Pedersen, J., Harewood, L., AustralianProstate Cancer, B., Collins, A.T., Maitland, N.J., and Risbridger, G.P.2012. Humanepithelial basal cells are cells of origin of prostate cancer, independent of CD133status. Stem Cells30:1087-1096.
76. Tang, K.H., Ma, S., Lee, T.K., Chan, Y.P., Kwan, P.S., Tong, C.M., Ng, I.O., Man,K., To, K.F., Lai, P.B., et al.2012. CD133(+) liver tumor-initiating cells promotetumor angiogenesis, growth, and self-renewal throughneurotensin/interleukin-8/CXCL1signaling. Hepatology55:807-820.
77. Shmelkov, S.V., Butler, J.M., Hooper, A.T., Hormigo, A., Kushner, J., Milde, T., StClair, R., Baljevic, M., White, I., Jin, D.K., et al.2008. CD133expression is notrestricted to stem cells, and both CD133+and CD133-metastatic colon cancer cellsinitiate tumors. J Clin Invest118:2111-2120.
78. LaBarge, M.A., and Bissell, M.J.2008. Is CD133a marker of metastatic coloncancer stem cells? J Clin Invest118:2021-2024.
79. Fedorchenko, O., Stiefelhagen, M., Peer Zada, A.A., Barthel, R., Mayer, P., Eckei,L., Breuer, A., Crispatzu, G., Rosen, N., Landwehr, T., et al.2013. CD44regulatesthe apoptotic response and promotes disease development in chronic lymphocyticleukemia. Blood.
80. Du, L., Rao, G., Wang, H., Li, B., Tian, W., Cui, J., He, L., Laffin, B., Tian, X., Hao,C., et al.2013. CD44-Positive Cancer Stem Cells Expressing Cellular Prion ProteinContribute to Metastatic Capacity in Colorectal Cancer. Cancer Res73:2682-2694.
81. Nagano, O., Okazaki, S., and Saya, H.2013. Redox regulation in stem-like cancercells by CD44variant isoforms. Oncogene.
82. Zhao, P., Damerow, M.S., Stern, P., Liu, A.H., Sweet-Cordero, A., Siziopikou, K.,Neilson, J.R., Sharp, P.A., and Cheng, C.2012. CD44promotes Kras-dependentlung adenocarcinoma. Oncogene.
83. Dallas, M.R., Liu, G., Chen, W.C., Thomas, S.N., Wirtz, D., Huso, D.L., andKonstantopoulos, K.2012. Divergent roles of CD44and carcinoembryonic antigenin colon cancer metastasis. FASEB J26:2648-2656.
84. Szabo, A.Z., Fong, S., Yue, L., Zhang, K., Strachan, L.R., Scalapino, K., Mancianti,M.L., and Ghadially, R.2012. The CD44+ALDH+population of humankeratinocytes is enriched for epidermal stem cells with long-term repopulatingability. Stem Cells31:786-799.
85. Fleischman, A.G.2012. ALDH marks leukemia stem cell. Blood119:3376-3377.
86. Visus, C., Wang, Y., Lozano-Leon, A., Ferris, R.L., Silver, S., Szczepanski, M.J.,Brand, R.E., Ferrone, C.R., Whiteside, T.L., Ferrone, S., et al.2011. TargetingALDH(bright) human carcinoma-initiating cells with ALDH1A1-specific CD8(+) Tcells. Clin Cancer Res17:6174-6184.
87. Oelze, M., Knorr, M., Schell, R., Kamuf, J., Pautz, A., Art, J., Wenzel, P., Munzel,T., Kleinert, H., and Daiber, A.2011. Regulation of human mitochondrial aldehydedehydrogenase (ALDH-2) activity by electrophiles in vitro. J Biol Chem286:8893-8900.
88. Pierre-Louis, O., Clay, D., Brunet de la Grange, P., Blazsek, I., Desterke, C.,Guerton, B., Blondeau, C., Malfuson, J.V., Prat, M., Bennaceur-Griscelli, A., et al.
2009. Dual SP/ALDH functionalities refine the human hematopoieticLin-CD34+CD38-stem/progenitor cell compartment. Stem Cells27:2552-2562.
89. Moreb, J.S., Baker, H.V., Chang, L.J., Amaya, M., Lopez, M.C., Ostmark, B., andChou, W.2008. ALDH isozymes downregulation affects cell growth, cell motilityand gene expression in lung cancer cells. Mol Cancer7:87.
90. Visvader, J.E., and Lindeman, G.J.2012. Cancer stem cells: current status andevolving complexities. Cell Stem Cell10:717-728.
91. Visvader, J.E.2011. Cells of origin in cancer. Nature469:314-322.
92. Saito, Y., Uchida, N., Tanaka, S., Suzuki, N., Tomizawa-Murasawa, M., Sone, A.,Najima, Y., Takagi, S., Aoki, Y., Wake, A., et al.2010. Induction of cell cycle entry
eliminates human leukemia stem cells in a mouse model of AML. Nat Biotechnol
28:275-280.
1. Fuchs E, Horsley V. Ferreting out stem cells from their niches.Nature Cell Biol2011;13:513-518.
2. Medema JP, Vermulen L. Microenvironmental regulation of stem cells in intestinalhomeostasis and cancer. Nature2011;474:318-326.
3. Simons BD, Clevers H. Strategies for homeostatic stem cell self-renewal in adulttissues. Cell2011;145:851-862.
4. Li L, Clevers H. Coexistence of quiescent and active adult stem cells in mammals.Science2010;327:542-545.
5. Cotsarelis G, Cheng SZ, Dong G, Sun TT, Lavker RM. Existence of slow-cyclinglimbal epithelial basal cells that can be preferentially stimulated to proliferate:Implications on epithelial stem cells. Cell1989;57:201-209.
6. Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area ofpilosebaceous unit: implications for follicular stem cells, hair cycle, and skincarcinogenesis. Cell1990;61:1329-1337.
7. Golebiewska A, Brons NH, Bjerkvig R, Niclou SP. Critical appraisal of the sidepopulation assay in stem cell and cancer stem cell research. Cell Stem Cell2011;8:136-147.
8. Storms RW, Trujillo AP, Springer JB, et al. Isolation of primitive humanhematopoietic progenitors on the basis of aldehyde dehydrogenase activity. Proc NatlAcad Sci USA1999;96:9118-9123.
9. Passegué E, Jamieson CH, Ailles LE, Weissman IL. Normal and leukemichematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cellcharacteristics? Proc Natl Acad Sci USA2003;100(Suppl1):11842-11849.
10. Notta F, Doulatov S, Laurenti E, Poeppl A, Jurisica I, Dick JE. Isolation of singlehuman hematopoietic stem cells capable of long-term multilineage engraftment.Science2011;333:218-221.
11. Majeti R, Park CY, Weissman IL. Identification of a hierarchy of multipotenthematopoietic progenitors in human cord blood. Cell Stem Cell2007;1:635-645.
12. Osawa M, Hanada K, Hamada H, Nakauchi H. Long-term lymphohematopoieticreconstitution by a single CD34-low/negative hematopoietic stem cell. Science1996;273:242-245.
13. Kiel MJ, Yilmaz OH, Iwashita T, Yilmaz OH, Terhorst C, Morrison SJ. SLAM familyreceptors distinguish hematopoietic stem and progenitor cells and reveal endothelialniches for stem cells. Cell2005;121:1109-1121.
14. Xin L, Lawson DA, Witte ON. The Sca-1cell surface marker enriches for aprostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. ProcNatl Acad Sci USA2005;102:6942-6947.
15. Burger PE, Xiong X, Coetzee S, et al. Sca-1expression identifies stem cells in theproximal region of prostatic ducts with high capacity to reconstitute prostatic tissue.Proc Natl Acad Sci USA2005;102:7180-7185.
16. Lawson DA, Xin L, Lukacs RU, Cheng D, Witte ON. Isolation and functionalcharacterization of murine prostate stem cells. Proc Natl Acad Sci USA2007;104:181-186.
17. Leong KG, Wang BE, Johnson L, Gao WQ. Generation of a prostate from a singleadult stem cell. Nature2008;456:804-808.
18. Hong SH, Rampalli S, Lee JB, et al. Cell fate potential of human pluripotent stem cellsis encoded by histone modifications. Cell Stem Cell2011;9:24-36.
19. Bergmann O, Bhardwaj RD, Bernard S, et al. Evidence for cardiomyocyte renewal inhumans. Science2009;324:98-102.
20. Spalding KL, Arner E, Westermark PO, et al. Dynamics of fat cell turnover in humans.Nature2008;453:783-787.
21. Arner P, Bernard S, Salehpour M, et al. Dynamics of human adipose lipid turnover inhealth and metabolic disease. Nature2011;478:110-113.
22. Katoh M, Shaw C, Xu Q, et al. An orderly retreat: Dedifferentiation is a regulatedprocess. Proc Natl Acad Sci USA2004;101:7005-7010.
23. Brawley C, Matunis E. Regeneration of male germline stem cells by spermatogonialdedifferentiation in vivo. Science2004;304:1331-1334.
24. Dor Y, Brown J, Martinez OI, Melton DA. Adult pancreatic beta-cells are formed byself-duplication rather than stem-cell differentiation. Nature2004;429:41-46.
25. Cobaleda C, Jochum W, Busslinger M. Conversion of mature B cells into T cells bydedifferentiation to uncommitted progenitors. Nature2007;449:473-477.
26. Heyworth C, Pearson S, May G, Enver T. Transcription factor-mediated lineageswitching reveals plasticity in primarycommitted progenitor cells. EMBO J2002;21:3770-3781.
27. Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming ofadult pancreatic exocrine cells to betacells.Nature2008;455:627-632.
28. Zhou Q, Melton DA. Extreme makeover: converting one cell into another. Cell StemCell2008;3:382-388.
29. Chambers SM, Studer L. Cell fate plug and play: Direct reprogramming and inducedpluripotency. Cell2011;145:827-830.
30. Pang ZP, Yang N, Vierbuchen T, et al. Induction of human neuronal cells by definedtranscription factors. Nature2011;476:220-223.
31. Caiazzo M, Dell’Anno MT, Dvorestskova E, et al. Direct generation of functionaldopaminergic neurons from mouse and human fibroblasts. Nature2011;476:224-227.
32. Yoo AS, Sun AX, Li L, et al. MicroRNA-mediated conversion of human fibroblasts toneurons. Nature2011;476:228-231.
33. Huang P, He, Z, Ji S, et al. Induction of functional hepatocytelike cells from mousefibroblasts by defined factors. Nature2011;475:386-389.
34. Sekiya S, Suzuki A. Direct conversion of mouse fibroblasts to hepatocyte-like cells bydefined factors. Nature2011;475:390-393.
35. Collombat P, Xu X, Ravassard P, et al. The ectopic expression of Pax4in the mousepancreas converts progenitor cells into α and subsequently β cells. Cell2009;138:449-462.
36. Kondo T, Raff M. Oligodendrocyte precursor cells reprogrammed to becomemultipotential CNS stem cells. Science2000;289:1754-1757.
37. Yamanaka S. Elite and stochastic models for induced pluripotent stem cell generation.Nature2009;460:49-52.
38. Shackleton M, Quintana E, Fearon ER, Morrison SJ. Heterogeneity in cancer: cancerstem cells versus clonal evolution. Cell2009;138:822-829.
39. Anderson K, Lutz C, van Delft FW, et al. Genetic variegation of clonal architecture andpropagating cells in leukaemia. Nature2011;469:356-361.
40. Notta F, Mullighan CG, Wang JC, et al. Evolution of human BCR-ABL1lymphoblastic leukaemia-initiating cells. Nature2011;469:362-367.
41. Visvader JE. Cells of origin in cancer. Nature2011;469:314-322.
42. Lim E, Vaillant F, Wu D, et al. Aberrant luminal progenitors as the candidate targetpopulation for basal tumor development in BRCA1mutation carriers. Nat Med2009;15:907-913.
43. Molyneux G, Geyer FC, Magnay FA, et al. BRCA1basal-like breast cancers originatefrom luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell2010;7:403-417.
44. Proia TA, Keller PJ, Gupta PB, et al. Genetic predisposition directs breast cancerphenotype by dictating progenitor cell fate. Cell Stem Cell2011;8:149-163.
45. Liu C, Sage JC, Miller MR, et al. Mosaic analysis with double markers reveals tumorcell of origin in glioma. Cell2011;146:209-221.
46. Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ. Efficienttumour formation by single human melanoma cells. Nature2008;456:593-598.
47. Ishizawa K, Rasheed ZA, Karisch R, et al. Tumor-initiating cells are rare in manyhuman tumors. Cell Stem Cell2010;7:279-282.
48. Alison MR, Guppy NJ, Lim SML, Nicholson LJ. Finding cancer stem cells: Arealdehyde dehydrogenases fit for purpose? J Pathol2010;222:335-344.
49. Pastrana E, Silva-Vargas V, Doetsch F. Eyes wide open: a critical review ofsphere-formation as an assay for stem cells. Cell Stem Cell2011;8:486-498.
50. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospectiveidentification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA2003;100:3983-3938.
51. Hirschmann-Jax C, Foster AE, Wulf GG, et al. A distinct "side population" of cellswith high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA2004;101:14228-14233.
52. Engelmann K, Shen H, Finn OJ. MCF7side population cells with characteristics ofcancer stem/progenitor cells express the tumor antigen MUC1. Cancer Res2008;68:2419-2426.
53. Ginestier C, Hur MH, Charafe-Jauffret E, et al. ALDH1is a marker of normal andmalignant human mammary stem cells and a predictor of poor clinical outcome. CellStem Cell2007;1:555-567.
54. Charafe-Jauffret E, Ginestier C, Iovino F, et al. Breast cancer cell lines containfunctional cancer stem cells with metastatic capacity and a distinct molecular signature.Cancer Res2009;69:1302-1313.
55. Pece S, Tosoni D, Confalonieri S, et al. Biological and molecular heterogeneity ofbreast cancers correlates with their cancer stem cell content. Cell2010;140:62-73.
56. Hwang-Verslues WW, Kuo WH, Chang PH, et al. Multiple lineages of human breastcancer stem/progenitor cells identified by profiling with stem cell markers. PLoS One2009;4:e8377.
57. Park SY, Lee HE, Li H, Shipitsin M, Gelman R, Polyak K. Heterogeneity for stemcell-related markers according to tumor subtype and histologic stage in breast cancer.Clin Cancer Res2010;16:876-887.
58. Deng S, Yang X, Lassus H, et al. Distinct expression levels and patterns of stem cellmarker, aldehyde dehydrogenase isoform1(ALDH1), in human epithelial cancers.PLoS One2010;5:e10277.
59. Meyer MJ, Fleming JM, Lin AF, Hussnain SA, Ginsburg E, Vonderhaar BK.CD44posCD49fhiCD133/2hi defines xenograftinitiating cells in estrogenreceptor-negative breast cancer. Cancer Res2010;70:4624-4633.
60. Cicalese A, Bonizzi G, Pasi CE, et al. The tumor suppressor p53regulates polarity ofself-renewing divisions in mammary stem cells. Cell2009;138:1083-1095.
61. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiatingcells. Nature2004;432:396-401.
62. Beier D, Hau P, Proescholdt M, et al. CD133(+) and CD133(-) glioblastoma-derivedcancer stem cells show differential growth characteristics and molecular profiles.Cancer Res2007;67:4010-4015.
63. Bleau AM, Hambardzumyan D, Ozawa T, et al. PTEN/PI3K/Akt pathway regulates theside population phenotype and ABCG2activity in glioma tumor stem-like cells. CellStem Cell2009;4:226-235.
64. Son MJ, Woolard K, Nam DH, Lee J, Fine HA. SSEA-1is an enrichment marker fortumor-initiating cells in human glioblastoma. Cell Stem Cell2009;4:440-452.
65. Piccirillo SG, Combi R, Cajola L, et al. Distinct pools of cancer stem-like cells coexistwithin human glioblastomas and display different tumorigenicity and independentgenomic evolution. Oncogene2009;28:1807-1811.
66. Chen R, Nishimura MC, Bumbaca SM, et al. A hierarchy of self-renewingtumor-initiating cell types in glioblastoma. Cancer Cell2010;17:362-375.
67. Mazzoleni S, Politi LS, Pala M, et al. Epidermal growth factor receptor expressionidentifies functionally and molecularly distinct tumor-initiating cells in humanglioblastoma multiforme and is required for gliomagenesis. Cancer Res2010;70:7500-7513.
68. Inda MM, Bonavia R, Mukasa A, et al. Tumor heterogeneity is an active processmaintained by a mutant EGFR-induced cytokine circuit in glioblastoma. Genes Dev2010;24:1731-1745.
69. Anido J, Sáez-Borderías A, Gonzàlez-Juncà A, et al. TGF-β receptor inhibitors targetthe CD44(high)/Id1(high) gliomainitiating cell population in human glioblastoma.Cancer Cell2010;18:655-668.
70. Lottaz C, Beier D, Meyer K, et al. Transcriptional profiles of CD133+and CD133-glioblastoma-derived cancer stem cell lines suggest different cells of origin. CancerRes2010;70:2030-2040.
71. Yan X, Ma L, Yi D, et al. A CD133-related gene expression signature identifies anaggressive glioblastoma subtype with excessive mutations. Proc Natl Acad Sci USA2011;108:1591-1596.
72. Eyler CE, Wu Q, Yan K, et al. Glioma stem cell proliferation and tumor growth arepromoted by nitric oxide synthase-2. Cell2011;146:53-66.
73. Broadley KW, Hunn MK, Farrand KJ, et al. Side population is not necessary orsufficient for a cancer stem cell phenotype in glioblastoma multiforme. Stem Cells2011;29:452-461.
74. Bonavia R, Inda MM, Cavenee WK, Furnari FB. Heterogeneity maintenance inglioblastoma: a social network. Cancer Res2011;71:4055-4060.
75. O'Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable ofinitiating tumour growth in immunodeficient mice. Nature2007;445:106-110.
76. Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expansion of humancolon-cancer-initiating cells. Nature2007;445:111-115.
77. Todaro M, Alea MP, Di Stefano AB, et al. Colon cancer stem cells dictate tumorgrowth and resist cell death by production of interleukin-4. Cell Stem Cell2007;1:389-402.
78. Dalerba P, Dylla SJ, Park IK, et al. Phenotypic characterization of human colorectalcancer stem cells. Proc Natl Acad Sci USA2007;04:10158-10163.
79. Du L, Wang H, He L, et al. CD44is of functional importance for colorectal cancerstem cells. Clin Cancer Res2008;14:6751-6760.
80. Odoux C, Fohrer H, Hoppo T, et al. A stochastic model for cancer stem cell origin inmetastatic colon cancer. Cancer Res2008;68:6932-6941.
81. Shmelkov SV, Butler JM, Hooper AT, et al. CD133expression is not restricted to stemcells, and both CD133+and CD133-metastatic colon cancer cells initiate tumors. JClinInvest2008;118:2111-2120.
82. Vermeulen L, Todaro M, de Sousa Mello F, et al. Aldehyde dehydrogenase1is amarker for normal and malignant human colonic stem cells (SC) and tracks SCoverpopulation during colon tumorigenesis. Cancer Res2009;69:3382-3389.
83. Kemper K, Sprick MR, de Bree M, et al. The AC133epitope, but not the CD133protein, is lost upon cancer stem cell differentiation. Cancer Res2010;70:719-729.
84. Inoda S, Hirohashi Y, Torigoe T, et al. Cytotoxic T lymphocytes efficiently recognizehuman colon cancer stem-like cells. Am J Pathol2011;178:1805-1813.
85. Wilson BJ, Schatton T, Zhan Q, et al. ABCB5identifies a therapy-refractory tumor cellpopulation in colorectal cancer patients. Cancer Res2011;71:5307-5316.
86. Medema JP, Vermeulen L. Microenvironmental regulation of stem cells in intestinalhomeostasis and cancer. Nature2011;474:318-326.
87. Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J-J, Claypool K, Tang DG. Sidepopulation (SP) is enriched in tumorigenic, stem-like cancer cells whereas ABCG2+and ABCG2–cancer cells are similarly tumorigenic. Cancer Res2005;65:6207-6219.
88. Huss WJ, Gray DR, Greenberg NM, Mohler JL, Smith GJ. Breast cancer resistanceprotein-mediated efflux of androgen in putative benign and malignant prostate stemcells. Cancer Res2005;65:6640–6650.
89. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification oftumorigenic prostate cancer stem cells. Cancer Res2005;65:10946-10951.
90. Patrawala L, Calhoun T, Schneider-Broussard R, et al. Highly purified CD44+prostatecancer cells from xenograft human tumors are enriched in tumorigenic and metastaticprogenitor cells. Oncogene2006;25:1696-1708.
91. Patrawala L, Calhoun-Davis T, Schneider-Broussard R, Tang DG. Hierarchicalorganization of prostate cancer cells in xenograft tumors: The CD44+α2β1+cellpopulation is enriched in tumor-initiating cells. Cancer Res2007;67:6796-6805.
92. Miki J, Furusato B, Li H, et al. Identification of putative stem cell markers, CD133andCXCR4, in hTERT-immortalized primary nonmalignant and malignant tumor-derivedhuman prostate epithelial cell lines and in prostate cancer specimens. Cancer Res2007;67:3153-3161.
93. Gu G, Yuan J, Wills M, Kasper S. Prostate cancer cells with stem cell characteristicsreconstitute the original human tumor in vivo. Cancer Res2007;67:4807-4815.
94. Li HW, Chen X, Calhoun-Davis T, Claypool K, Tang DG. PC3Human prostatecarcinoma cell holoclones contain selfrenewing tumor-initiating cells. Cancer Res2008;68:1820-1825.
95. Jeter C, Badeaux M, Choy G, et al. Functional evidence that the self-renewal geneNANOG regulates human tumor development. Stem Cells2009;27:993-1005.
96. Dubrovska A, Kim S, Salamone RJ, et al. The role of PTEN/Akt/PI3K signaling in themaintenance and viability of prostate cancer stem-like cell populations. Proc Natl AcadSci USA2009;106:268-273.
97. Li T, Su Y, Mei Y, et al. ALDH1A1is a marker for malignant prostate stem cells andpredictor of prostate cancer patients’outcome. Lab Invest2010;90:234-244.
98. van den Hoogen C, van der Horst G, Cheung H, et al. High aldehyde dehydrogenaseactivity identifies tumor-initiating and metastasis-initiating cells in human prostatecancer. Cancer Res2010;70:5163-5173.
99. Rajasekhar VK, Studer L, Gerald W, Socci ND, Scher HI. Tumour-initiating stem-likecells in human prostate cancer exhibit increased NF-κB signalling. Nat Commun2011;2:162.
100. Liu C, Kelnar K, Liu B, et al. The microRNA miR-34a inhibits prostate cancer stemcells and metastasis by directly repressing CD44. Nature Med2011;17:211-215.
101. Ho MM, Ng AV, Lam S, Hung JY. Side population in human lung cancer cell linesand tumors is enriched with stem-like cancer cells. Cancer Res2007;67:4827-4833.
102. Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M. Identification and expansion of thetumorigenic lung cancer stem cell population. Cell Death Differ2008;15:504-414.
103. Jiang T, Collins BJ, Jin N, Watkins DN, Brock MV. Achaetescute complex homologue1regulates tumor-initiating capacity in human small cell lung cancer. Cancer Res2009;69:845-854.
104. Bertolini G, Roz L, Perego P, Tortoreto M, Fontanella E. Highly tumorigenic lungcancer CD133+cells display stemlike features and are spared by cisplatin treatment.Proc Natl Acad Sci USA2009;106:16281-16286.
105. Levina V, Marrangoni A, Wang T, et al. Elimination of human lung cancer stem cellsthrough targeting of the stem cell factor-c-kit autocrine signaling loop. Cancer Res2010;70:338-346.
106. Eramo A, Haas TL, De Maria R. Lung cancer stem cells: tools and targets to fight lungcancer. Oncogene2010;29:4625-4635.
107. Sullivan JP, Spinola M, Dodge M, et al. Aldehyde dehydrogenase activity selects forlung adenocarcinoma stem cells dependent on notch signaling. Cancer Res2010;70:9937-9948.
108. Chiou SH, Wang ML, Chou YT, et al. Coexpression of Oct4and Nanog enhancesmalignancy in lung adenocarcinoma by inducing cancer stem cell-like properties andepithelial-mesenchymal transdifferentiation. Cancer Res2010;70:10433-10444.
109. Leung EL, Fiscus RR, Tung JW, et al. Non-small cell lung cancer cells expressingCD44are enriched for stem cell-like properties. PLoS One2010;5:e14062.
110. Curtis SJ, Sinkevicius KW, Li D, et al. Primary tumor genotype is an importantdeterminant in identification of lung cancer propagating cells. Cell Stem Cell2010;7:127-133.
111. Damelin M, Geles KG, Follettie MT, et al. Delineation of a cellular hierarchy in lungcancer reveals an oncofetal antigen expressed on tumor-initiating cells. Cancer Res2011;71:4236-4246.
112. Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemiaafter transplantation into SCID mice. Nature1994;367:645-648.
113. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy thatoriginates from a primitive hematopoietic cell. Nat Med1997;3:730-737.
114. Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy ofleukemic stem cell classes that differ in self-renewal capacity. Nat Immunol2004;5:738-743.
115. Sarry JE, Murphy K, Perry R, et al. Human acute myelogenous leukemia stemcells are rare and heterogeneous when assayed in NOD/SCID/IL2Rγc-deficient mice. JClin Invest2011;121:384-395.
116. Shipitsin M, Campbell LL, Argani P, et al. Molecular definition of breast tumorheterogeneity. Cancer Cell2007;11:259-273.
117. Park SY, G nen M, Kim HJ, Michor F, Polyak K. Cellular and genetic diversity in theprogression of in situ human breast carcinomas to an invasive phenotype. J Clin Invest2010;120:636-644.
118. Lotem J, Sachs L. Epigenetics and the plasticity of differentiation in normal and cancerstem cells. Oncogene2006;25:7663-7672.
119. Hendrix MJ, Seftor EA, Hess AR, Seftor RE. Molecular plasticity of human melanomacells. Oncogene2003;22:3070-3075.
120. Casal C, Torres-Collado AX, Plaza-Calonge Mdel C, et al. ADAMTS1contributes tothe acquisition of an endotheliallike phenotype in plastic tumor cells. Cancer Res2010;70:4676-4686.
121. Wang R, Chadalavada K, Wilshire J, et al. Glioblastoma stem-like cells give rise totumour endothelium. Nature2010;468:829-833.
122. Ricci-Vitiani L, Pallini R, Biffoni M, et al. Tumour vascularization via endothelialdifferentiation of glioblastoma stemlike cells. Nature2010;468:824-828.
123. Sharma SV, Lee DY, Li B, et al. A chromatin-mediated reversible drug-tolerant state incancer cell subpopulations. Cell2010;141:69-80.
124. Yan H, Chen X, Zhang Q, et al. Drug-tolerant cancer cells show reducedtumor-initiating capacity: Depletion of CD44+cells and evidence for epigeneticmechanisms. PLoS One2011;6:e24397.
125. Chaffer CL, Brueckmann I, Scheel C, et al. Normal and neoplastic nonstem cells canspontaneously convert to a stem-like state. Proc Natl Acad Sci USA2011;108:7950-7955.
126. Gupta PB, Fillmore CM, Jiang G, et al. Stochastic state transitions give rise tophenotypic equilibrium in populations of cancer cells. Cell2011;146:633-644.
127. Das B, Tsuchida R, Malkin D, et al. Hypoxia enhances tumor stemness by increasingthe invasive and tumorigenic side population fraction. Stem Cells2008;26:1818-1830.
128. Mathieu J, Zhang Z, Zhou W, et al. HIF induces human embryonic stem cell markersin cancer cells. Cancer Res2011;71:4640-4652.
129. Koh MY, Lemos R Jr, Liu X, Powis G. The hypoxia-associated factor switches cellsfrom HIF-1α-to HIF-2α-dependent signaling promoting stem cell characteristics,aggressive tumor growth and invasion. Cancer Res2011;71:4015-4027.
130. Mani SA, Guo W, Liao MJ, et al. The epithelial-mesenchymal transition generatescells with properties of stem cells. Cell2008;133:704-715.
131. Santisteban M, Reiman JM, Asiedu MK, et al. Immuneinduced epithelial tomesenchymal transition in vivo generates breast cancer stem cells. Cancer Res2009;69:2887-2895.
132. Iliopoulos D, Hirsch HA, Struhl K. An epigenetic switch involving NF-kappaB, Lin28,Let-7MicroRNA, and IL6links inflammation to cell transformation. Cell2009;139:693-706.
133. Iliopoulos D, Lindahl-Allen M, Polytarchou C, Hirsch HA, Tsichlis PN, Struhl K. Lossof miR-200inhibition of Suz12leads to polycomb-mediated repression required for theformation and maintenance of cancer stem cells. Mol Cell2010;39:761-772.
134. Asiedu MK, Ingle JN, Behrens MD, Radisky DC, Knutson KL. TGFβ/TNFα-mediatedepithelial-mesenchymal transition generates breast cancer stem cells with a claudin-lowphenotype. Cancer Res2011;71:4707-4719.
135. Iliopoulos D, Hirsch HA, Wang G, Struhl K. Inducible formation of breast cancer stemcells and their dynamic equilibrium with non-stem cancer cells via IL6secretion. ProcNatl Acad Sci USA2011;108:1397-1402.
136. Jeter CR, Liu B, Liu X, et al. NANOG promotes cancer stemcell characteristics andprostate cancer resistance to androgen deprivation. Oncogene2011;30:3833-3845.
137. Arzumanyan A, Friedman T, Ng IO, Clayton MM, Lian Z, Feitelson MA. Does thehepatitis B antigen HBx promote the appearance of liver cancer stem cells? Cancer Res2011;71:3701-3708.
138. Su YJ, Lai HM, Chang YW, Chen GY, Lee JL. Direct reprogramming of stem cellproperties in colon cancer cells by CD44. EMBO J2011;30:3186-3199.
139. Scaffidi P, Misteli T. In vitro generation of human cells with cancer stem cellproperties. Nat Cell Biol2011;13:1051-1061.
140. Hwang WL, Yang MH, Tsai ML, et al. SNAIL regulates interleukin-8expression, stemcell-like activity, and tumorigenicity of human colorectal carcinoma cells.Gastroenterology2011;141:279-291.
141. Paranjape AN, Mandal T, Mukherjee G, Kumar MV, Sengupta K, Rangarajan A.Introduction of SV40ER and hTERT into mammospheres generates breast cancer cellswith stem cell properties. Oncogene2011Aug29. doi:10.1038/onc.2011.378
142. Bissell MJ, Labarge MA. Context, tissue plasticity, and cancer: are tumor stem cellsalso regulated by the microenvironment? Cancer Cell2005;7:17-23.
143. Liu S, Ginestier C, Ou SJ, et al. Breast cancer stem cells are regulated by mesenchymalstem cells through cytokine networks. Cancer Res2011;71:614-624.
144. Li X, Lewis MT, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cellsto chemotherapy. J Natl Cancer Inst2008;100:672-679.
145. Reim F, Dombrowski Y, Ritter C, et al. Immunoselection of breast and ovarian cancercells with trastuzumab and natural killer cells: selective escape ofCD44high/CD24low/HER2low breast cancer stem cells. Cancer Res2009;69:8058-8066.
146. Liu H, Patel MR, Prescher JA, et al. Cancer stem cells from human breast tumors areinvolved in spontaneous metastases in orthotopic mouse models. Proc Natl Acad SciUSA2010;107:18115-18120.
147. Yu F, Yao H, Zhu P, et al. let-7regulates self renewal and tumorigenicity of breastcancer cells. Cell2007;131:1109-1123.
148. Emmink BL, Van Houdt WJ, Vries RG, et al. Differentiated human colorectal cancercells protect tumor-initiating cells from irinotecan. Gastroenterology2011;141:269-278.
149. Dubrovska A, Elliott J, Salamone RJ, et al. Combination therapy targeting bothtumor-initiating and differentiated cell populations in prostate carcinoma. Clin CancerRes2010;16:5692-5702.
150. Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancerstem cells, and acts together with chemotherapy to block tumor growth and prolongremission. Cancer Res2009;69:7507-7511.
151. Shats I, Gatza ML, Chang JT, et al. Using a stem cell-based signature to guidetherapeutic selection in cancer. Cancer Res2011;71:1772-1780.
152. Eppert K, Takenaka K, Lechman ER, et al. Stem cell gene expression programsinfluence clinical outcome in human leukemia. Nat Med2011;17:1086-1093.