Abstract
Colorectal cancer (CRC) is the third most common form of cancer and the second cause of cancer-related death in the Western world, leading to 655,000 deaths worldwide per year (Jemal et al. in CA Cancer J Clin 56:106–130, 2006). Despite the emergence of new targeted agents and the use of various therapeutic combinations, none of the treatment options available is curative in patients with advanced cancer. A growing body of evidence is increasingly supporting the idea that human cancers can be considered as a stem cell disease. According to the cancer stem cell model, malignancies originate from a small fraction of cancer cells that show self-renewal and pluripotency and are capable of initiating and sustaining tumor growth (Boman and Wicha in J Clin Oncol 26:2795–2799, 2008). The cancer-initiating cells or “cancer stem cells” were first identified in hematologic malignancies and most recently in several solid tumors, including CRC. The hypothesis of stem cell-driven tumorigenesis in colon cancer raises questions as to whether current treatments are able to efficiently target the tumorigenic cell population that is responsible for tumor growth and maintenance. This review will focus on the different aspects of stem cell biology in the context of CRC, which might help to understand the mechanisms that give rise to tumor development and resistance to therapy. First, we will briefly revise the knowledge available on normal intestinal stem cells and recent advances in understanding crypt biology, which have led to new theory on the origins of colon adenomas and cancers. Then, we will summarize the evidence and current status on colon cancer stem cells, focusing on their relevance and promises for the treatment of colorectal carcinoma.
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References
Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ (2006) Cancer statistics, 2006. CA Cancer J Clin 56:106–130
Boman BM, Wicha MS (2008) Cancer stem cells: a step toward the cure. J Clin Oncol 26:2795–2799
Potten CS, Kellett M, Rew DA, Roberts SA (1992) Proliferation in human gastrointestinal epithelium using bromodeoxyuridine in vivo: data for different sites, proximity to a tumour, and polyposis coli. Gut 33:524–529
Cheng H, Bjerknes M, Amar J (1984) Methods for the determination of epithelial cell kinetic parameters of human colonic epithelium isolated from surgical and biopsy specimens. Gastroenterology 86:78–85
Radtke F, Clevers H (2005) Self-renewal and cancer of the gut: two sides of a coin. Science 307:1904–1909
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
Kosinski C, Li VS, Chan AS, Zhang J, Ho C, Tsui WY, Chan TL, Mifflin RC, Powell DW, Yuen ST, Leung SY, Chen X (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
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
van Es JH, Clevers H (2005) Notch and Wnt inhibitors as potential new drugs for intestinal neoplastic disease. Trends Mol Med 11:496–502
Batlle E, Henderson JT, Beghtel H, van den Born MM, Sancho E, Huls G, Meeldijk J, Robertson J, van de Wetering M, Pawson T, Clevers H (2002) Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 111:251–263
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
Potten CS, Owen G, Booth D (2002) Intestinal stem cells protect their genome by selective segregation of template DNA strands. J Cell Sci 115:2381–2388
Kim SJ, Cheung S, Hellerstein MK (2004) Isolation of nuclei from label-retaining cells and measurement of their turnover rates in rat colon. Am J Physiol Cell Physiol 286:C1464–C1473
Kiel MJ, He S, Ashkenazi R, Gentry SN, Teta M, Kushner JA, Jackson TL, Morrison SJ (2007) Haematopoietic stem cells do not asymmetrically segregate chromosomes or retain BrdU. Nature 449:238–242
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
Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML, Wu L, Lindeman GJ, Visvader JE (2006) Generation of a functional mammary gland from a single stem cell. Nature 439:84–88
Nakamura M, Okano H, Blendy JA, Montell C (1994) Musashi, a neural RNA-binding protein required for Drosophila adult external sensory organ development. Neuron 13:67–81
Nishimura S, Wakabayashi N, Toyoda K, Kashima K, Mitsufuji S (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
Kayahara T, Sawada M, Takaishi S, Fukui H, Seno H, Fukuzawa H, Suzuki K, Hiai H, Kageyama R, Okano H, Chiba T (2003) Candidate markers for stem and early progenitor cells, Musashi-1 and Hes1, are expressed in crypt base columnar cells of mouse small intestine. FEBS Lett 535:131–135
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
Holmberg J, Genander M, Halford MM, Anneren C, Sondell M, Chumley MJ, Silvany RE, Henkemeyer M, Frisen J (2006) EphB receptors coordinate migration and proliferation in the intestinal stem cell niche. Cell 125:1151–1163
Sangiorgi E, Capecchi MR (2008) Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet 40:915–920
Gregorieff A, Clevers H (2005) Wnt signaling in the intestinal epithelium: from endoderm to cancer. Genes Dev 19:877–890
Katoh M (2007) WNT signaling pathway and stem cell signaling network. Clin Cancer Res 13:4042–4045
Korinek V, Barker N, Moerer P, van Donselaar E, Huls G, Peters PJ, Clevers H (1998) Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet 19:379–383
Pinto D, Gregorieff A, Begthel H, Clevers H (2003) Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev 17:1709–1713
Kuhnert F, Davis CR, Wang HT, Chu P, Lee M, Yuan J, Nusse R, Kuo CJ (2004) Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1. Proc Natl Acad Sci USA 101:266–271
Batlle E, Bacani J, Begthel H, Jonkheer S, Gregorieff A, van de Born M, Malats N, Sancho E, Boon E, Pawson T, Gallinger S, Pals S, Clevers H (2005) EphB receptor activity suppresses colorectal cancer progression. Nature 435:1126–1130
Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449:1003–1007
Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, Clevers H (2009) Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459:262–265
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
Campbell F, Williams GT, Appleton MA, Dixon MF, Harris M, Williams ED (1996) Post-irradiation somatic mutation and clonal stabilisation time in the human colon. Gut 39:569–573
Nakamura S, Kino I (1984) Morphogenesis of minute adenomas in familial polyposis coli. J Natl Cancer Inst 73:41–49
Preston SL, Wong WM, Chan AO, Poulsom R, Jeffery R, Goodlad RA, Mandir N, Elia G, Novelli M, Bodmer WF, Tomlinson IP, Wright NA (2003) Bottom-up histogenesis of colorectal adenomas: origin in the monocryptal adenoma and initial expansion by crypt fission. Cancer Res 63:3819–3825
Taylor RW, Barron MJ, Borthwick GM, Gospel A, Chinnery PF, Samuels DC, Taylor GA, Plusa SM, Needham SJ, Greaves LC, Kirkwood TB, Turnbull DM (2003) Mitochondrial DNA mutations in human colonic crypt stem cells. J Clin Invest 112:1351–1360
Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445:111–115
O'Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445:106–110
Corbeil D, Roper K, Hellwig A, Tavian M, Miraglia S, Watt SM, Simmons PJ, Peault B, Buck DW, Huttner WB (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
Corbeil D, Roper K, Fargeas CA, Joester A, Huttner WB (2001) Prominin: a story of cholesterol, plasma membrane protrusions and human pathology. Traffic 2:82–91
Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, Hoey T, Gurney A, Huang EH, Simeone DM, Shelton AA, Parmiani G, Castelli C, Clarke MF (2007) Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA 104:10158–10163
Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, Milde T, St Clair R, Baljevic M, White I, Jin DK, Chadburn A, Murphy AJ, Valenzuela DM, Gale NW, Thurston G, Yancopoulos GD, D'Angelica M, Kemeny N, Lyden D, Rafii S (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
Horst D, Kriegl L, Engel J, Kirchner T, Jung A (2008) CD133 expression is an independent prognostic marker for low survival in colorectal cancer. Br J Cancer 99:1285–1289
Horst D, Kriegl L, Engel J, Jung A, Kirchner T (2009) CD133 and nuclear beta-catenin: the marker combination to detect high risk cases of low stage colorectal cancer. Eur J Cancer 45:2034–2040
Huang EH, Hynes MJ, Zhang T, Ginestier C, Dontu G, Appelman H, Fields JZ, Wicha MS, Boman BM (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
Zhu L, Gibson P, Currle DS, Tong Y, Richardson RJ, Bayazitov IT, Poppleton H, Zakharenko S, Ellison DW, Gilbertson RJ (2009) Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 457:603–607
Dylla SJ, Beviglia L, Park IK, Chartier C, Raval J, Ngan L, Pickell K, Aguilar J, Lazetic S, Smith-Berdan S, Clarke MF, Hoey T, Lewicki J, Gurney AL (2008) Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS ONE 3:e2428
Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760
Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F, Tripodo C, Russo A, Gulotta G, Medema JP, Stassi G (2007) Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell 1:389–402
Acknowledgements
We thank the Italian Ministry of Health, the Italian Ministry for University and Research (FIRB_RBIP06ZJ78), and the Italian Association for Cancer Research (AIRC) for supporting the colon cancer stem cell research.
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The authors declare that they have no conflicting interests related to this study.
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Ricci-Vitiani, L., Fabrizi, E., Palio, E. et al. Colon cancer stem cells. J Mol Med 87, 1097–1104 (2009). https://doi.org/10.1007/s00109-009-0518-4
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DOI: https://doi.org/10.1007/s00109-009-0518-4