Skip to main content

Advertisement

Log in

Stem cells in colon cancer. A new era in cancer theory begins

  • Review
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Introduction

Despite the various therapeutic combinations and the emergence of new targeted therapies, there is still no curative treatment for all stages of colorectal cancer. Through the query for the best possible combination and solution, a new theory approaching colorectal cancer as a stem cell disease appeared, with a continuously growing body of evidence supporting this idea. The inability to directly recognize cancer stem cells has led researchers to an attempt of distinguishing those using indirect markers.

Discussion

This review focuses on colon cancer stem cell theory, the various findings supporting and contradicting this hypothesis, and the markers used up to now in characterizing stem cell populations in colorectal cancer. Despite the numerous unanswered questions on this new cancer hypothesis, it appears to have a justifiable role to play in colorectal cancer tumor biology, and furthermore, it may be the basis for the development of new therapeutic agents of the future. Therefore, every surgeon, oncologist, and physician who is implicated with this disease should be familiar with this novel colorectal cancer theory.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Ferlay J, Autier P, Heanue M et al (2007) Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 18:581–592

    Article  CAS  PubMed  Google Scholar 

  2. Boman BM, Wicha MS (2008) Cancer stem cells: a step toward the cure. J Clin Oncol 26:2795–2799

    Article  PubMed  Google Scholar 

  3. Potten CS, Loeffler M (1990) Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons from a crypt. Development 110:1001–1020

    CAS  PubMed  Google Scholar 

  4. Brittan M, Wright NA (2002) Gastrointestinal stem cells. J Pathol 197:492–509

    Article  PubMed  Google Scholar 

  5. Reya T, Clevers H (2005) Wnt signalling in stem cells and cancer. Nature 434:843–850

    Article  CAS  PubMed  Google Scholar 

  6. Willis ND, Przyborski SA, Hutchison CJ et al (2008) Colonic and colorectal cancer stem cells: progress in the search for putative biomarkers. J Anat 213:59–65

    Article  PubMed  Google Scholar 

  7. Potten CS, Grant HK (1998) The relationship between ionizing radiation-induced apoptosis and stem cells in the small and large intestine. Brit J Cancer 78:993–1003

    CAS  PubMed  Google Scholar 

  8. Meritt AJ, Potten CS, Watson AJM et al (1995) Differential expression of bcl-2 in intestinal epithelia. Correlation with attenuation of apoptosis in colonic crypts and the incidence of colonic neoplasia. J Cell Sci 198:2261–2271

    Google Scholar 

  9. O’Brien CA, Pollett A, Gallinger S et al (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445:106–110

    Article  PubMed  Google Scholar 

  10. Nguyen NP, Almeida FS, Chi A et al (2010) Molecular biology of breast cancer stem cells: potential clinical applications. Cancer Treat Rev 2010 (In press)

  11. Oliveira LR, Jeffrey SS, Ribeiro-Silva A (2010) Stem cells in human breast cancer. Histol Histopathol 25:371–385

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Kim CF, Jackson EL, Woolfenden AE et al (2005) Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121:823–835

    Article  CAS  PubMed  Google Scholar 

  14. Ma S, Chan KW, Hu L et al (2007) Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132:2542–2556

    Article  CAS  PubMed  Google Scholar 

  15. Schatton T, Murphy GF, Frank NY et al (2008) Identification of cells initiating human melanomas. Nature 451:345–349

    Article  CAS  PubMed  Google Scholar 

  16. Li C, Heidt DG, Dalerba P et al (2007) Identification of pancreatic cancer stem cells. Cancer Res 67:1030–1037

    Article  CAS  PubMed  Google Scholar 

  17. Pardal R, Clarke MF, Morrison SJ (2003) Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3:895–902

    Article  CAS  PubMed  Google Scholar 

  18. Gaziova I, Bhat KM (2007) Generating asymmetry: with and without renewal. Prog Mol Subcell Biol 45:143–178

    Article  CAS  PubMed  Google Scholar 

  19. Bach S, Renehan A, Potten C (2000) Stem cells: the intestinal stem cell as a paradigm. Carcinogenesis 21:469–476

    Article  CAS  PubMed  Google Scholar 

  20. Karam SM (1999) Lineage commitment and maturation of epithelial cells in the gut. Frontiers Biosci 4:286–298

    Article  Google Scholar 

  21. Fevr T, Robine S, Louvard D, Huelsken J (2007) Wnt/beta-catenin is essential for intestinal homeostasis and maintenance of intestinal stem cells. Mol Cell Biol 27:7551–7559

    Article  CAS  PubMed  Google Scholar 

  22. Crosnier C, Stamataki D, Lewis J (2006) Organizing cell renewal in the intestine: stem cells, signals and combinatorial control. Nat Rev Genet 7:349–359

    Article  CAS  PubMed  Google Scholar 

  23. van Es JH, Clevers H (2005) Notch and Wnt inhibitors as potential new drugs for intestinal neoplastic disease. Trends Mol Med 11:496–502

    Article  PubMed  Google Scholar 

  24. Kosinski C, Li VSW, Chan ASY et al (2007) Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proc Natl Acad Sci USA 104:15418–15423

    Article  CAS  PubMed  Google Scholar 

  25. Potten CS (1992) The significance of spontaneous and induced apoptosis in the gastrointestinal tract of mice. Cancer Metastasis Rev 179–195

  26. Watson AJ, Merritt AJ, Jones LS et al (1996) Evidence of reciprocity of bcl-2 and p53 expression in human colorectal adenomas and carcinomas. Br J Cancer 73:889–895

    CAS  PubMed  Google Scholar 

  27. Wilson JW, Nostro MC, Balzi M et al (2000) Bcl-w expression in colorectal adenocarcinoma. Br J Cancer 82:178–185

    Article  CAS  PubMed  Google Scholar 

  28. Kirkland SC (1988) Clonal origin of columnar, mucous, and endocrine cell lineages in human colorectal epithelium. Cancer 61:1359–1363

    Article  CAS  PubMed  Google Scholar 

  29. Yatabe Y, Tavare S, Shibata D (2001) Investigating stem cells in human colon by using methylation patterns. Proc Natl Acad Sci USA 98:10839–10844

    Article  CAS  PubMed  Google Scholar 

  30. Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111

    Article  CAS  PubMed  Google Scholar 

  31. Cicalese A, Bonizzi G, Pasi CE et al (2009) The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell 138:1083–1095

    Article  CAS  PubMed  Google Scholar 

  32. Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87:159–170

    Article  CAS  PubMed  Google Scholar 

  33. Fearon ER, Hamilton SR, Vogelstein B (1987) Clonal analysis of human colorectal tumors. Science 238:193–197

    Article  CAS  PubMed  Google Scholar 

  34. Fabian A, Barok M, Vereb G et al (2009) Die hard: are cancer stem cells the Bruce Willises of tumor biology? Cytom A 75:67–74

    Article  Google Scholar 

  35. Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737

    Article  CAS  PubMed  Google Scholar 

  36. Houghton J, Stoicov C, Nomura S et al (2004) Gastric cancer originating from bone marrow-derived cells. Science 306:1568–1571

    Article  CAS  PubMed  Google Scholar 

  37. Ricci-Vitiani L, Fabrizi E, Palio E et al (2009) Colon cancer stem cells. J Mol Med 87:1097–1104

    Article  PubMed  Google Scholar 

  38. Cotsarelis G, Sun TT, Lavker RM (1990) Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 61:1329–1337

    Article  CAS  PubMed  Google Scholar 

  39. Kiel MJ, Yilmaz OH, Iwashita T, Terhorst C, Morrison SJ (2005) SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121:1109–1121

    Article  CAS  PubMed  Google Scholar 

  40. Shackleton M, Vaillant F, Simpson KJ, Stingl J et al (2006) Generation of a functional mammary gland from a single stem cell. Nature 439:84–88

    Article  CAS  PubMed  Google Scholar 

  41. Corbeil D, Roper K, Hellwig A et al (2000) The human AC133 hematopoietic stem cell antigen is also expressed in epithelial cells and targeted to plasma membrane protrusions. J Biol Chem 275:5512–5520

    Article  CAS  PubMed  Google Scholar 

  42. Corbeil D, Roper K, Fargeas CA et al (2001) Prominin: a story of cholesterol, plasma membrane protrusions and human pathology. Traffic 2:82–91

    Article  CAS  PubMed  Google Scholar 

  43. Haraguchi N, Utsunomiya T, Inoue H et al (2006) Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells 24:506–513

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  45. Hermann PC, Huber SL, Herrler T et al (2007) Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1:313–323

    Article  CAS  PubMed  Google Scholar 

  46. Zhu L, Gibson P, Currle DS et al (2009) Promini1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 457:603–607

    Article  CAS  PubMed  Google Scholar 

  47. Immervoll H, Hoem D, Sakariassen PO et al (2008) Expression of the “stem cell marker” CD133 in pancreas and pancreatic ductal adenocarcinomas. BMC Cancer 8:48

    Article  PubMed  Google Scholar 

  48. Saigusa S, Tanaka K, Toiyama Y et al (2009) Correlation of CD133, OCT4, and SOX2 in rectal cancer and their association with distant recurrence after chemoradiotherapy. Ann Surg Oncol 6(12):3488–3498

    Article  Google Scholar 

  49. Horst D, Kriegl L, Engel J et al (2008) CD133 expression is an independent prognostic marker for low survival in colorectal cancer. Br J Cancer 99(8):1285–1289

    Article  CAS  PubMed  Google Scholar 

  50. Sparks AB, Morin PJ, Vogelstein B, Kinzler KW (1998) Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. Cancer Res 58:1130–1134

    CAS  PubMed  Google Scholar 

  51. Bienz M, Clevers H (2000) Linking colorectal cancer to Wnt signaling. Cell 103:311–320

    Article  CAS  PubMed  Google Scholar 

  52. Horst D, Kriegl L, Engel J et al (2009) CD133 and nuclear β-catenin: the marker combination to detect high risk cases of low stage colorectal cancer. Eur J Cancer 45:2034–40

    Article  CAS  PubMed  Google Scholar 

  53. Corbeil D, Röper K, Hellwig A et al (2000) The human AC133 hematopoietic stem cell antigen is also expressed in epithelial cells and targeted to plasma membrane protrusions. J Biol Chem 275:5512–5520

    Article  CAS  PubMed  Google Scholar 

  54. Shmelkov SV, Butler JM, Hooper AT et al (2008) CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors. J Clin Invest 118:2111–2120

    CAS  PubMed  Google Scholar 

  55. Lin EH, Hassan M, Li Y et al (2007) Elevated circulating endothelial progenitor marker CD133 messenger RNA levels predict colon cancer recurrence. Cancer 110:534–542

    Article  CAS  PubMed  Google Scholar 

  56. Ieta K, Tanaka F, Haraguchi N et al (2008) Biological and genetic characteristics of tumor-initiating cells in colon cancer. Ann Surg Oncol 15:638–648

    Article  PubMed  Google Scholar 

  57. Choi D, Lee HW, Hur KY et al (2009) Cancer stem cell markers CD133 and CD24 correlate with invasiveness and differentiation in colorectal adenocarcinoma. World J Gastroenterol 15:2258–2264

    Article  CAS  PubMed  Google Scholar 

  58. Lim SC, Oh SH (2005) The role of CD24 in various human epithelial neoplasias. Pathol Res Pract 201:479–486

    Article  CAS  PubMed  Google Scholar 

  59. Weichert W, Denkert C, Burkhardt M et al (2005) Cytoplasmic CD24 expression in colorectal cancer independently correlates with shortened patient survival. Clin Cancer Res 11:6574–6581

    Article  CAS  PubMed  Google Scholar 

  60. Horst D, Sheel SK, Liebmann S et al (2009) The cancer stem cell marker CD133 has high prognostic impact but unknown functional relevance for the metastasis of human colon cancer. J Pathol 219:427–434

    Article  CAS  PubMed  Google Scholar 

  61. Cheng L, Sung MT, Cossu-Rocca P et al (2007) OCT4: biological functions and clinical applications as a marker of germ cell neoplasia. J Pathol 211:1–9

    Article  CAS  PubMed  Google Scholar 

  62. Sotomayor P, Godoy A, Smith GJ (2008) Oct4A is expressed by a subpopulation of prostate neuroendocrine cells. Prostate 69:401–410

    Article  Google Scholar 

  63. Hochedlinger K, Yamada Y, Beard C, Jaenisch R (2005) Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell 121:465–477

    Article  CAS  PubMed  Google Scholar 

  64. Yamanaka S (2008) Induction of pluripotent stem cells from mouse fibroblasts by four transcription factors. Cell Prolif 41:51–56

    Article  PubMed  Google Scholar 

  65. Ben-Porath I, Thomson MW, Carey VJ et al (2008) An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 40:499–507

    Article  CAS  PubMed  Google Scholar 

  66. Schoenhals M, Kassambara A, De Vos J et al (2009) Embryonic stem cell markers expression in cancers. Biochem Biophys Res Commun 383:157–162

    Article  CAS  PubMed  Google Scholar 

  67. Rodriguez-Pinilla SM, Sarrio D, Moreno-Bueno G et al (2007) Sox2: a possible driver of the basal-like phenotype in sporadic breast cancer. Mod Pathol 20:474–481

    Article  CAS  PubMed  Google Scholar 

  68. Gu G, Yuan J, Wills M, Kasper S (2007) Prostate cancer cells with stem cell characteristics reconstitute the original human tumor in vivo. Cancer Res 67:4807–4815

    Article  CAS  PubMed  Google Scholar 

  69. Tsukamoto T, Mizoshita T, Mihara M et al (2005) Sox2 expression in human stomach adenocarcinomas with gastric and gastric-and intestinal-mixed phenotypes. Histopathology 46:649–658

    Article  CAS  PubMed  Google Scholar 

  70. Evans PM, Liu C (2008) Roles of Kruppel-like factor 4 in normal homeostasis, cancer and stem cells. Acta Biochem Biophys Sin (Shanghai) 40:554–564

    Article  CAS  Google Scholar 

  71. McConnell BB, Ghaleb AM, Nandan MO, Yang VW (2007) The diverse functions of Kruppel-like factors 4 and 5 in epithelial biology and pathobiology. Bioessays 29:549–557

    Article  CAS  PubMed  Google Scholar 

  72. Wei D, Kanai M, Huang S, Xie K (2006) Emerging role of KLF4 in human gastrointestinal cancer. Carcinogenesis 27:23–31

    Article  CAS  PubMed  Google Scholar 

  73. Rowland BD, Peeper DS (2006) KLF4, p21 and context-dependent opposing forces in cancer. Nat Rev Cancer 6:11–23

    Article  CAS  PubMed  Google Scholar 

  74. Adhikary S, Eilers M (2005) Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol 6:635–645

    Article  CAS  PubMed  Google Scholar 

  75. Kim JB, Zaehres H, Wu G et al (2008) Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature 454:646–650

    Article  CAS  PubMed  Google Scholar 

  76. Okita K, Ichisaka T, Yamanaka S (2007) Generation of germline-competent induced pluripotent stem cells. Nature 448:313–317

    Article  CAS  PubMed  Google Scholar 

  77. Wernig M, Meissner A, Foreman R et al (2007) In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448:318–324

    Article  CAS  PubMed  Google Scholar 

  78. Eilers M, Eisenman RN (2008) Myc’s broad reach. Genes Dev 22:2755–2766

    Article  CAS  PubMed  Google Scholar 

  79. Schulein C, Eilers M (2009) An unsteady scaffold for Myc. EMBO 28:453–454

    Article  Google Scholar 

  80. Welcker M, Orian A, Jin J et al (2004) The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc Natl Acad Sci USA 101:9085–9090

    Article  CAS  PubMed  Google Scholar 

  81. Arnold HK, Zhang X, Daniel CJ et al (2009) The Axin1 scaffold protein promotes formation of a degradation complex for c-Myc. EMBO J 28:500–512

    Article  CAS  PubMed  Google Scholar 

  82. Yada M, Hatakeyama S, Kamura T et al (2004) Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO J 23:2116–2125

    Article  CAS  PubMed  Google Scholar 

  83. Rajagopalan H, Jallepalli PV, Rago C, Velculescu VE, Kinzler KW, Vogelstein B, Lengauer C (2004) Inactivation of hCDC4 can cause chromosomal instability. Nature 428:77–81

    Article  CAS  PubMed  Google Scholar 

  84. Popov N, Wanzel M, Madiredjo M et al (2007) The ubiquitin-specific protease USP28 is required for MYC stability. Nat Cell Biol 9:765–774

    Article  CAS  PubMed  Google Scholar 

  85. Haegebarth A, Clevers H (2009) Wnt signaling, Lgr5, and stem cells in the intestine and the skin. Am J Pathol 174:715–21

    Article  CAS  PubMed  Google Scholar 

  86. Barker N, van Es JH, Kuipers J et al (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449:1003–1007

    Article  CAS  PubMed  Google Scholar 

  87. Sato T, Vries RG, Snippert HJ et al (2009) Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459:262–265

    Article  CAS  PubMed  Google Scholar 

  88. Barker N, Ridgway RA, van Es JH et al (2009) Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457:608–612

    Article  CAS  PubMed  Google Scholar 

  89. Kaneko Y, Sakakibara S, Imai T et al (2000) Musashi1: an evolutionally conserved marker for CNS progenitor cells including neural stem cells. Dev Neurosci 22:139–153

    Article  CAS  PubMed  Google Scholar 

  90. Booth C, Potten CS (2000) Gut instincts: thoughts on intestinal epithelial stem cells. J Clin Invest 105:1493–1499

    Article  CAS  PubMed  Google Scholar 

  91. Nishimura S, Wakabayashi N, Toyoda K et al (2003) Expression of Musashi-1 in human normal colon crypt cells: a possible stem cell marker of human colon epithelium. Dig Dis Sci 48:1523–1529

    Article  CAS  PubMed  Google Scholar 

  92. Fujimoto K, Beauchamp RD, Whitehead RH (2002) Identification and isolation of candidate human colonic clonogenic cells based on cell surface integrin expression. Gastroenterology 123:1941–1948

    Article  CAS  PubMed  Google Scholar 

  93. Howe A, Aplin AE, Alahari SK et al (1998) Integrin signaling and cell growth control. Curr Opin Cell Biol 10:220–231

    Article  CAS  PubMed  Google Scholar 

  94. Huang EH, Hynes MJ, Zhang T et al (2009) Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res 69:3382–3389

    Article  CAS  PubMed  Google Scholar 

  95. Bao S, Wu Q, McLendon RE et al (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760

    Article  CAS  PubMed  Google Scholar 

  96. Todaro M, Perez Alea M, Scopelliti A et al (2008) IL-4-mediated drug resistance in colon cancer stem cells. Cell Cycle 7:309–313

    Article  CAS  PubMed  Google Scholar 

  97. Donnenberg VS, Landreneau RJ, Donnenberg AD (2007) Tumorigenic stem and progenitor cells: implications for the therapeutic index of anti-cancer agents. J Control Release 122:385–391

    Article  CAS  PubMed  Google Scholar 

  98. May R, Riehl TE, Hunt C, Sureban SM, Anant S, Houchen CW (2008) Identification of a novel putative gastrointestinal stem cell and adenoma stem cell marker, doublecortin and CaM kinase-like-1, following radiation injury and in adenomatous polyposis coli/multiple intestinal neoplasia mice. Stem Cells 26:630–337

    Article  PubMed  Google Scholar 

  99. Dalebra P, Dylla SJ, Park IK et al (2007) Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA 104:10158–10163

    Article  Google Scholar 

  100. Todaro M, Francipane MG, Medema JP, Stassi G (2001) Colon cancer stem cells: promise of targeted therapy. Gastroenterology 138:2151–2162

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joanna Papailiou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Papailiou, J., Bramis, K.J., Gazouli, M. et al. Stem cells in colon cancer. A new era in cancer theory begins. Int J Colorectal Dis 26, 1–11 (2011). https://doi.org/10.1007/s00384-010-1022-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-010-1022-6

Keywords

Navigation