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Colorectal Cancer Stem Cells: Biology and Therapeutic Implications

  • Published:
Current Colorectal Cancer Reports

Abstract

The hypothesis that cancer is driven by a subpopulation of tumor-initiating or cancer stem cells (CSC), defined by their selective ability for extensive self-renewal and capacity to give rise to nontumorigenic cancer cell progeny through differentiation, has been validated experimentally in diverse human malignancies. Translational relevance of the CSC hypothesis is underlined by emerging novel strategies designed to target all subpopulations within a given tumor in order to effect cancer eradication and improve patient outcomes. Colorectal cancer stem cells (CRSCs) have been identified and successfully isolated by several research groups based on distinct cell-surface marker characteristics. Identification of CRSC populations has led to a wave of discoveries describing novel self-renewal and drug resistance mechanisms in colorectal cancer that represent novel future therapeutic targets. In this review, we will discuss emerging CRSC-specific pathways and the therapeutic promise of targeting this cancer population in colorectal cancer patients.

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References

Papers of particular interest, published recently, have been highlighted as: ••Of major importance

  1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71–96.

    Article  PubMed  Google Scholar 

  2. Markowitz SD, Bertagnolli MM. Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med. 2009;361:2449–60.

    Article  PubMed  CAS  Google Scholar 

  3. Frank NY, Schatton T, Frank MH: The therapeutic promise of the cancer stem cell concept. J Clin Invest. 2010;120:41–50.

    Google Scholar 

  4. Zhou BB, Zhang H, Damelin M, et al. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov. 2009;8:806–23.

    Article  PubMed  CAS  Google Scholar 

  5. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319:525–32.

    Article  PubMed  CAS  Google Scholar 

  6. Kinzler KW, Nilbert MC, Vogelstein B, et al. Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science. 1991;251:1366–70.

    Article  PubMed  CAS  Google Scholar 

  7. Nishisho I, Nakamura Y, Miyoshi Y, et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science. 1991;253:665–9.

    Article  PubMed  CAS  Google Scholar 

  8. Morin PJ, Sparks AB, Korinek V, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 1997;275:1787–90.

    Article  PubMed  CAS  Google Scholar 

  9. Howe JR, Bair JL, Sayed MG, et al. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet. 2001;28:184–7.

    Article  PubMed  CAS  Google Scholar 

  10. Howe JR, Roth S, Ringold JC, et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science. 1998;280:1086–8.

    Article  PubMed  CAS  Google Scholar 

  11. Thiagalingam S, Lengauer C, Leach FS, et al. Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers. Nat Genet. 1996;13:343–6.

    Article  PubMed  CAS  Google Scholar 

  12. Bellacosa A, Genuardi M, Anti M, et al. Hereditary nonpolyposis colorectal cancer: review of clinical, molecular genetics, and counseling aspects. Am J Med Genet. 1996;62:353–64.

    Article  PubMed  CAS  Google Scholar 

  13. Bruce WR, Van Der Gaag H. A quantitative assay for the number of murine lymphoma cells capable of proliferation in vivo. Nature. 1963;199:79–80.

    Article  PubMed  CAS  Google Scholar 

  14. Hamburger AW, Salmon SE. Primary bioassay of human tumor stem cells. Science. 1977;197:461–3.

    Article  PubMed  CAS  Google Scholar 

  15. Brunschwig A, Southam CM, Levin AG. Host resistance to cancer. Clinical experiments by homotransplants, autotransplants and admixture of autologous leucocytes. Ann Surg. 1965;162:416–25.

    Article  PubMed  CAS  Google Scholar 

  16. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11.

    Article  PubMed  CAS  Google Scholar 

  17. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100:3983–8.

    Article  PubMed  CAS  Google Scholar 

  18. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature. 2004;432:396–401.

    Article  PubMed  CAS  Google Scholar 

  19. •• O’Brien CA, Pollett A, Gallinger S, Dick JE: A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007;445:106–110.

    Article  PubMed  Google Scholar 

  20. •• Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al.: Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445:111–115.

    Article  PubMed  CAS  Google Scholar 

  21. •• Dalerba P, Dylla SJ, Park IK, et al.: Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A. 2007;104:10158–10163. Studies 19–21 provided initial evidence to support the existence of cancer stem cells in human colorectal cancer.

    Article  PubMed  CAS  Google Scholar 

  22. Schatton T, Murphy GF, Frank NY, et al. Identification of cells initiating human melanomas. Nature. 2008;451:345–9.

    Article  PubMed  CAS  Google Scholar 

  23. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730–7.

    Article  PubMed  CAS  Google Scholar 

  24. Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:645–8.

    Article  PubMed  CAS  Google Scholar 

  25. Boiko AD, Razorenova OV, van de Rijn M, et al.: Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature. 2010;466:133–7.

    Google Scholar 

  26. Huang EH, Hynes MJ, Zhang T, et al. Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res. 2009;69:3382–9.

    Article  PubMed  CAS  Google Scholar 

  27. Shmelkov SV, Butler JM, Hooper AT, et al. CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors. J Clin Invest. 2008;118:2111–20.

    PubMed  CAS  Google Scholar 

  28. Li G, Liu C, Yuan J, et al. CD133(+) single cell-derived progenies of colorectal cancer cell line SW480 with different invasive and metastatic potential. Clin Exp Metastasis. 2010;27:517–27.

    Article  PubMed  Google Scholar 

  29. Vermeulen L, Todaro M, de Sousa Mello F, et al. Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc Natl Acad Sci U S A. 2008;105:13427–32.

    Article  PubMed  CAS  Google Scholar 

  30. Weichert W, Knosel T, Bellach J, et al. ALCAM/CD166 is overexpressed in colorectal carcinoma and correlates with shortened patient survival. J Clin Pathol. 2004;57:1160–4.

    Article  PubMed  CAS  Google Scholar 

  31. Frank NY, Margaryan A, Huang Y, et al. ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. Cancer Res. 2005;65:4320–33.

    Article  PubMed  CAS  Google Scholar 

  32. Haraguchi N, Ohkuma M, Sakashita H, et al. CD133 + CD44+ population efficiently enriches colon cancer initiating cells. Ann Surg Oncol. 2008;15:2927–33.

    Article  PubMed  Google Scholar 

  33. Ginestier C, Korkaya H, Dontu G, et al. The cancer stem cell: the breast cancer driver. Med Sci (Paris). 2007;23:1133–9.

    Article  Google Scholar 

  34. Barker N, van Es JH, Kuipers J, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007;449:1003–7.

    Article  PubMed  CAS  Google Scholar 

  35. Barker N, Ridgway RA, van Es JH, et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature. 2009;457:608–11.

    Article  PubMed  CAS  Google Scholar 

  36. Zhu L, Gibson P, Currle DS, et al. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature. 2009;457:603–7.

    Article  PubMed  CAS  Google Scholar 

  37. Du L, Wang H, He L, et al. CD44 is of functional importance for colorectal cancer stem cells. Clin Cancer Res. 2008;14:6751–60.

    Article  PubMed  CAS  Google Scholar 

  38. Zeilstra J, Joosten SP, Dokter M, et al. Deletion of the WNT target and cancer stem cell marker CD44 in Apc(Min/+) mice attenuates intestinal tumorigenesis. Cancer Res. 2008;68:3655–61.

    Article  PubMed  CAS  Google Scholar 

  39. Ponta H, Sherman L, Herrlich PA. CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol. 2003;4:33–45.

    Article  PubMed  CAS  Google Scholar 

  40. Ishimoto T, Oshima H, Oshima M, et al. CD44+ slow-cycling tumor cell expansion is triggered by cooperative actions of Wnt and prostaglandin E2 in gastric tumorigenesis. Cancer Sci. 2010;101:673–8.

    Article  PubMed  CAS  Google Scholar 

  41. Dissanayake SK, Wade M, Johnson CE, et al. The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition. J Biol Chem. 2007;282:17259–71.

    Article  PubMed  CAS  Google Scholar 

  42. •• Vermeulen L, De Sousa EMF, van der Heijden M, et al.: Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol. 2010;12:468–476. This study demonstrated the importance of Wnt signaling for colorectal cancer stem cell self -renewal.

    Article  PubMed  CAS  Google Scholar 

  43. Ong CW, Kim LG, Kong HH, et al. CD133 expression predicts for non-response to chemotherapy in colorectal cancer. Mod Pathol. 2010;23:450–7.

    Article  PubMed  CAS  Google Scholar 

  44. Liu Z, Qiu M, Tang QL, et al. Establishment and biological characteristics of oxaliplatin-resistant human colon cancer cell lines. Chin J Cancer. 2010;29:661–7.

    PubMed  CAS  Google Scholar 

  45. •• Dallas NA, Xia L, Fan F, et al.: Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. Cancer Res. 2009;69:1951–1957.

    Article  PubMed  CAS  Google Scholar 

  46. •• Todaro M, Alea MP, Di Stefano AB, et al.: Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell. 2007;1:389–402.

    Article  PubMed  CAS  Google Scholar 

  47. •• Cammareri P, Scopelliti A, Todaro M, et al.: Aurora-a is essential for the tumorigenic capacity and chemoresistance of colorectal cancer stem cells. Cancer Res. 2010;70:4655–4665.

  48. •• Song B, Wang Y, Xi Y, et al.: Mechanisms of chemoresistance mediated by mIR-140 in human osteosarcoma and colon cancer cells. Oncogene. 2010, 28:4065–4074.

    Article  Google Scholar 

  49. •• Song B, Wang Y, Titmus MA, et al.: Molecular mechanism of chemoresistance by miR-215 in osteosarcoma and colon cancer cells. Mol Cancer. 2010;9:96. Studies 45–49 describe novel chemoresistance mechanisms of colorectal cancer stem cells.

    Article  PubMed  CAS  Google Scholar 

  50. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002;2:48–58.

    Article  PubMed  CAS  Google Scholar 

  51. Riordan JR, Deuchars K, Kartner N, et al. Amplification of P-glycoprotein genes in multidrug-resistant mammalian cell lines. Nature. 1985;316:817–9.

    Article  PubMed  CAS  Google Scholar 

  52. Frank NY, Pendse SS, Lapchak PH, et al. Regulation of progenitor cell fusion by ABCB5 P-glycoprotein, a novel human ATP-binding cassette transporter. J Biol Chem. 2003;278:47156–65.

    Article  PubMed  CAS  Google Scholar 

  53. Huang Y, Anderle P, Bussey KJ, et al. Membrane transporters and channels: role of the transportome in cancer chemosensitivity and chemoresistance. Cancer Res. 2004;64:4294–301.

    Article  PubMed  CAS  Google Scholar 

  54. Elliott AM, Al-Hajj MA. ABCB8 mediates doxorubicin resistance in melanoma cells by protecting the mitochondrial genome. Mol Cancer Res. 2009;7:79–87.

    Article  PubMed  CAS  Google Scholar 

  55. Cheung ST, Cheung PF, Cheng CK, et al.: Granulin-Epithelin Precursor and ATP-Dependent Binding Cassette (ABC)B5 Regulate Liver Cancer Cell Chemoresistance. Gastroenterology. 2010;140:344–55.

    Google Scholar 

  56. Fukunaga-Kalabis M, Martinez G, Nguyen TK, et al.: Tenascin-C promotes melanoma progression by maintaining the ABCB5-positive side population. Oncogene. 2010;29:6115–24.

    Google Scholar 

  57. Frank NY, Frank MH. ABCB5 gene amplification in human leukemia cells. Leuk Res. 2009;33:1303–5.

    Article  PubMed  Google Scholar 

  58. Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756–60.

    Article  PubMed  CAS  Google Scholar 

  59. Saigusa S, Tanaka K, Toiyama Y, et al.: Clinical Significance of CD133 and Hypoxia Inducible Factor-1alpha Gene Expression in Rectal Cancer after Preoperative Chemoradiotherapy. Clin Oncol (R Coll Radiol) In-Press.

  60. Saigusa S, Tanaka K, Toiyama Y, et al. Immunohistochemical features of CD133 expression: association with resistance to chemoradiotherapy in rectal cancer. Oncol Rep. 2010;24:345–50.

    Article  PubMed  CAS  Google Scholar 

  61. Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med. 2005;352:476–87.

    Article  PubMed  CAS  Google Scholar 

  62. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337–45.

    Article  PubMed  CAS  Google Scholar 

  63. Takahashi Y, Kitadai Y, Bucana CD, et al. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res. 1995;55:3964–8.

    PubMed  CAS  Google Scholar 

  64. Fan F, Wey JS, McCarty MF, et al. Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene. 2005;24:2647–53.

    Article  PubMed  CAS  Google Scholar 

  65. Fodde R, Smits R, Clevers H. APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer. 2001;1:55–67.

    Article  PubMed  CAS  Google Scholar 

  66. •• Lepourcelet M, Chen YN, France DS, et al.: Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell. 2004;5:91–102.

    Article  PubMed  CAS  Google Scholar 

  67. Sikandar SS, Pate KT, Anderson S, et al.: NOTCH signaling is required for formation and self-renewal of tumor-initiating cells and for repression of secretory cell differentiation in colon cancer. Cancer Res. 2010;70:1469–78.

    Google Scholar 

  68. •• van Es JH, van Gijn ME, Riccio O, et al.: Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature. 2005;435:959–963.

    Article  PubMed  Google Scholar 

  69. Haramis AP, Begthel H, van den Born M, et al. De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science. 2004;303:1684–6.

    Article  PubMed  CAS  Google Scholar 

  70. Kodach LL, Bleuming SA, Musler AR, et al. The bone morphogenetic protein pathway is active in human colon adenomas and inactivated in colorectal cancer. Cancer. 2008;112:300–6.

    Article  PubMed  CAS  Google Scholar 

  71. •• Lombardo Y, Scopelliti A, Cammareri P, et al.: Bone Morphogenetic Protein 4 Induces Differentiation of Colorectal Cancer Stem Cells and Increases Their Response to Chemotherapy in Mice. Gastroenterology. 2011;140:297–309.

  72. Leavitt J, Gunning P, Kedes L, Jariwalla R. Smooth muscle alpha-action is a transformation-sensitive marker for mouse NIH 3 T3 and Rat-2 cells. Nature. 1985;316:840–2.

    Article  PubMed  CAS  Google Scholar 

  73. •• Ricci-Vitiani L, Mollinari C, di Martino S, et al.: Thymosin beta4 targeting impairs tumorigenic activity of colon cancer stem cells. FASEB J. 2010;24:4291–4301. Studies 66, 68, 71, and 73 describe novel CRSC pathways that can be targeted for successful cancer eradication.

  74. Bui T, Thompson CB. Cancer’s sweet tooth. Cancer Cell. 2006;9:419–20.

    Article  PubMed  CAS  Google Scholar 

  75. Kim JW, Dang CV. Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res. 2006;66:8927–30.

    Article  PubMed  CAS  Google Scholar 

  76. Mantel C, Broxmeyer HE. Sirtuin 1, stem cells, aging, and stem cell aging. Curr Opin Hematol. 2008;15:326–31.

    Article  PubMed  CAS  Google Scholar 

  77. Akao Y, Noguchi S, Iio A, et al.: Dysregulation of microRNA-34a expression causes drug-resistance to 5-FU in human colon cancer DLD-1 cells. Cancer Lett. 2011;300:197–204.

    Google Scholar 

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Acknowledgment

This work was supported by funds provided by the NIH/NINDS K08 NS051349 to N.Y. Frank and the NIH/NCI 1R01CA113796 to M.H. Frank.

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No potential conflicts of interest relevant to this article were reported.

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Authors and Affiliations

  1. Transplantation Research Center, Children’s Hospital Boston and Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, 300 Longwood Avenue, Enders 814, Boston, MA, 02115, USA

    Brian J. Wilson

  2. Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women’s Hospital and Transplantation Research Center, Children’s Hospital Boston, Harvard Medical School, 77 Avenue Louis Pasteur, HIM 660, Boston, MA, 02115, USA

    Tobias Schatton

  3. Transplantation Research Center, Children’s Hospital Boston and Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, 300 Longwood Avenue, Enders 816, Boston, MA, 02115, USA

    Markus H. Frank

  4. Department of Medicine, Boston VA Healthcare System, Transplantation Research Center, Children’s Hospital Boston and Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, 300 Longwood Avenue, Enders 814, Boston, MA, 02115, USA

    Natasha Y. Frank

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  1. Brian J. Wilson
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  2. Tobias Schatton
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Correspondence to Natasha Y. Frank.

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Wilson, B.J., Schatton, T., Frank, M.H. et al. Colorectal Cancer Stem Cells: Biology and Therapeutic Implications. Curr Colorectal Cancer Rep 7, 128–135 (2011). https://doi.org/10.1007/s11888-011-0093-2

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