Abstract
Intestinal stem cell (ISC) population at crypts base displays extraordinary capability for organized renewal and regeneration of intestinal epithelium. Complex interplay among stem cells, its progeny and niche balances between self-renewal and differentiation to maintain intestinal homeostasis. Involvement of various interactions to regulate intestinal epithelium rapid renewal, presents with high risk of developing cancer. Intestinal stem cells (ISCs) biology and cancer development is closely related in various aspects. Studies have shown, ISCs as the cells of origin for majority of intestinal cancer where signaling pathways regulating ISC are often deregulated, giving rise to cancer stem cell (CSC). Moreover, intestinal cancers are shown to maintain cellular hierarchy similar to intestinal epithelium with presence of CSC at apex. CSCs are cell subpopulation with ISC like features involved in tumor genesis. Here we present common and different features of ISC and CSC with special emphasis on differential regulation of Wnt, Notch and BMP signaling pathways in both stem cell populations. Recent identification of both ISC and CSC markers along with technological development to track stem cell lineage and endogenous activity in vivo with possibility to generate ex vivo intestinal organoids, has broaden our understanding regarding ISC driven intestinal epithelium homeostasis, repair and cancer. Basic understanding of intestinal stem cell biology and its role in carcinogenesis opens up exciting opportunity to develop stem cell based therapeutics for cancer treatment.
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References
Al-Hajj M, Wicha MS et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100(7):3983–3988
Anderson EC, Wong MH (2010) Caught in the Akt: regulation of Wnt signaling in the intestine. Gastroenterology 139(3):718–722
Andoh A, Bamba S et al (2005) Colonic subepithelial myofibroblasts in mucosal inflammation and repair: contribution of bone marrow-derived stem cells to the gut regenerative response. J Gastroenterol 40(12):1089–1099
Andoh A, Bamba S et al (2007) Role of intestinal subepithelial myofibroblasts in inflammation and regenerative response in the gut. Pharmacol Ther 114(1):94–106
Andriatsilavo M, Gervais L et al (2013) The Drosophila midgut as a model to study adult stem cells. Med Sci (Paris) 29(1):75–81
Ashley N (2013) Regulation of intestinal cancer stem cells. Cancer Lett 338(1):120–126
Baker A-M, Graham TA et al (2015) Characterization of LGR5 stem cells in colorectal adenomas and carcinomas. Sci Rep 5:8654
Barker N (2014) Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nat Rev Mol Cell Biol 15(1):19–33
Barker N, Clevers H (2007) Tracking down the stem cells of the intestine: strategies to identify adult stem cells. Gastroenterology 133(6):1755–1760
Barker N, Clevers H (2010) Leucine-rich repeat-containing G-protein-coupled receptors as markers of adult stem cells. Gastroenterology 138(5):1681–1696
Barker N, van Es JH et al (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449(7165):1003–1007
Barker N, van de Wetering M et al (2008) The intestinal stem cell. Genes Dev 22(14):1856–1864
Barker N, Ridgway RA et al (2009) Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457(7229):608–611
Barker N, van Oudenaarden A et al (2012) Identifying the stem cell of the intestinal crypt: strategies and pitfalls. Cell Stem Cell 11(4):452–460
Batts LE, Polk DB et al (2006) Bmp signaling is required for intestinal growth and morphogenesis. Dev Dyn 235(6):1563–1570
Bitarte N, Bandres E et al (2011) MicroRNA-451 is involved in the self-renewal, tumorigenicity, and chemoresistance of colorectal cancer stem cells. Stem Cells 29(11):1661–1671
Biteau B, Hochmuth CE et al (2008) JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut. Cell Stem Cell 3(4):442–455
Biteau B, Hochmuth CE et al (2011) Maintaining tissue homeostasis: dynamic control of somatic stem cell activity. Cell Stem Cell 9(5):402–411
Blanpain C, Simons BD (2013) Unravelling stem cell dynamics by lineage tracing. Nat Rev Mol Cell Biol 14(8):489–502
Buske P, Galle J et al (2011) A comprehensive model of the spatio-temporal stem cell and tissue organisation in the intestinal crypt. PLoS Comput Biol 7(1):e1001045
Carmon KS, Gong X et al (2011) R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling. Proc Natl Acad Sci U S A 108(28):11452–11457
Chakrabarty S, Fan D et al (1990) Modulation of differentiation and proliferation in human colon carcinoma cells by transforming growth factor beta 1 and beta 2. Int J Cancer 46(3):493–499
Chandler JM, Lagasse E (2010) Cancerous stem cells: deviant stem cells with cancer-causing misbehavior. Stem Cell Res Ther 1(2):13
Cheng H, Leblond CP (1974) Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. III. Entero-endocrine cells. Am J Anat 141(4):503–519
Clevers H (2011) The cancer stem cell: premises, promises and challenges. Nat Med 17(3):313–319
Creamer B, Shorter RG et al (1961) The turnover and shedding of epithelial cells. I. The turnover in the gastro-intestinal tract. Gut 2:110–118
Dalerba P, Dylla SJ et al (2007) Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A 104(24):10158–10163
Dalerba P, Kalisky T et al (2011) Single-cell dissection of transcriptional heterogeneity in human colon tumors. Nat Biotechnol 29(12):1120–1127
Davies PS, Dismuke AD et al (2008) Wnt-reporter expression pattern in the mouse intestine during homeostasis. BMC Gastroenterol 8:57
de Lau W, Barker N et al (2011) Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 476(7360):293–297
de Sousa EM, Vermeulen L et al (2011a) Targeting Wnt signaling in colon cancer stem cells. Clin Cancer Res 17(4):647–653
de Sousa EMF, Colak S et al (2011b) Methylation of cancer-stem-cell-associated Wnt target genes predicts poor prognosis in colorectal cancer patients. Cell Stem Cell 9(5):476–485
Dean M, Fojo T et al (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5(4):275–284
Dieter SM, Ball CR et al (2011) Distinct types of tumor-initiating cells form human colon cancer tumors and metastases. Cell Stem Cell 9(4):357–365
Forster R, Chiba K et al (2014) Human intestinal tissue with adult stem cell properties derived from pluripotent stem cells. Stem Cell Rep 2(6):838–852
Fre S, Huyghe M et al (2005) Notch signals control the fate of immature progenitor cells in the intestine. Nature 435(7044):964–968
Fre S, Pallavi SK et al (2009) Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine. Proc Natl Acad Sci U S A 106(15):6309–6314
Fuchs E (2009) The tortoise and the hair: slow-cycling cells in the stem cell race. Cell 137(5):811–819
Giannakis M, Stappenbeck TS et al (2006) Molecular properties of adult mouse gastric and intestinal epithelial progenitors in their niches. J Biol Chem 281(16):11292–11300
Greco V, Guo S (2010) Compartmentalized organization: a common and required feature of stem cell niches? Development 137(10):1586–1594
Gregorieff A, Pinto D et al (2005) Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology 129(2):626–638
Guezguez A, Pare F et al (2014) Modulation of stemness in a human normal intestinal epithelial crypt cell line by activation of the WNT signaling pathway. Exp Cell Res 322(2):355–364
Haramis AP, Begthel H et al (2004) De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science 303(5664):1684–1686
He XC, Zhang J et al (2004) BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nat Genet 36(10):1117–1121
Houthuijzen JM, Daenen LG et al (2012) The role of mesenchymal stem cells in anti-cancer drug resistance and tumour progression. Br J Cancer 106(12):1901–1906
Huang EH, Hynes MJ 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(8):3382–3389
Johnston MD, Edwards CM et al (2007) Mathematical modeling of cell population dynamics in the colonic crypt and in colorectal cancer. Proc Natl Acad Sci U S A 104(10):4008–4013
Johnston MD, Maini PK et al (2010) On the proportion of cancer stem cells in a tumour. J Theor Biol 266(4):708–711
Jung P, Sato T et al (2011) Isolation and in vitro expansion of human colonic stem cells. Nat Med 17(10):1225–1227
Juno RJ, Williams JL et al (2002) A serum factor after intestinal resection stimulates epidermal growth factor receptor signaling and proliferation in intestinal epithelial cells. Surgery 132(2):377–383
Juno RJ, Knott AW et al (2003) A serum factor(s) after small bowel resection induces intestinal epithelial cell proliferation: effects of timing, site, and extent of resection. J Pediatr Surg 38(6):868–874
Katoh M (2007) WNT antagonist, DKK2, is a Notch signaling target in intestinal stem cells: augmentation of a negative regulation system for canonical WNT signaling pathway by the Notch-DKK2 signaling loop in primates. Int J Mol Med 19(1):197–201
Keith B, Simon MC (2007) Hypoxia-inducible factors, stem cells, and cancer. Cell 129(3):465–472
Kemper K, Grandela C et al (2010) Molecular identification and targeting of colorectal cancer stem cells. Oncotarget 1(6):387–395
Kemper K, Prasetyanti PR et al (2012) Monoclonal antibodies against Lgr5 identify human colorectal cancer stem cells. Stem Cells 30(11):2378–2386
Kim JE, Lee JM et al (2015) Differentiation of poorly differentiated colorectal adenocarcinomas from well- or moderately differentiated colorectal adenocarcinomas at contrast-enhanced multidetector CT. Abdom Imaging 40(1):1–10
Kirkland SC, Ying H (2008) Alpha2beta1 integrin regulates lineage commitment in multipotent human colorectal cancer cells. J Biol Chem 283(41):27612–27619
Kleist B, Xu L et al (2011) Expression of the adult intestinal stem cell marker Lgr5 in the metastatic cascade of colorectal cancer. Int J Clin Exp Pathol 4(4):327–335
Koo BK, Stange DE et al (2012) Controlled gene expression in primary Lgr5 organoid cultures. Nat Methods 9(1):81–83
Korinek V, Barker N et al (1998) Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet 19(4):379–383
Kosinski C, Li VS 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 U S A 104(39):15418–15423
Lahar N, Lei NY et al (2011) Intestinal subepithelial myofibroblasts support in vitro and in vivo growth of human small intestinal epithelium. PLoS One 6(11):e26898
Laurent E, McCoy JW 3rd et al (2008) Nox1 is over-expressed in human colon cancers and correlates with activating mutations in K-Ras. Int J Cancer 123(1):100–107
Leblond CP, Walker BE (1956) Renewal of cell populations. Physiol Rev 36(2):255–276
Levin TG, Powell AE et al (2010) Characterization of the intestinal cancer stem cell marker CD166 in the human and mouse gastrointestinal tract. Gastroenterology 139(6):2072–2082.e2075
Levin DE, Barthel ER et al (2013) Human tissue-engineered small intestine forms from postnatal progenitor cells. J Pediatr Surg 48(1):129–137
Lewis MP, Lygoe KA et al (2004) Tumour-derived TGF-beta1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells. Br J Cancer 90(4):822–832
Li L, Clevers H (2010) Coexistence of quiescent and active adult stem cells in mammals. Science 327(5965):542–545
Lombardo Y, Scopelliti A et al (2011) Bone morphogenetic protein 4 induces differentiation of colorectal cancer stem cells and increases their response to chemotherapy in mice. Gastroenterology 140(1):297–309
Mathieu J, Zhang Z et al (2011) HIF induces human embryonic stem cell markers in cancer cells. Cancer Res 71(13):4640–4652
May R, Sureban SM et al (2009) Doublecortin and CaM kinase-like-1 and leucine-rich-repeat-containing G-protein-coupled receptor mark quiescent and cycling intestinal stem cells, respectively. Stem Cells 27(10):2571–2579
Mazumdar J, O’Brien WT et al (2010) O2 regulates stem cells through Wnt/beta-catenin signalling. Nat Cell Biol 12(10):1007–1013
McCracken KW, Howell JC et al (2011) Generating human intestinal tissue from pluripotent stem cells in vitro. Nat Protoc 6(12):1920–1928
Merlos-Suarez A, Barriga FM et al (2011) The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell 8(5):511–524
Metcalfe C, Kljavin NM et al (2014) Lgr5+ stem cells are indispensable for radiation-induced intestinal regeneration. Cell Stem Cell 14(2):149–159
Miyamoto S, Rosenberg DW (2011) Role of Notch signaling in colon homeostasis and carcinogenesis. Cancer Sci 102(11):1938–1942
Montgomery RK, Mulberg AE et al (1999) Development of the human gastrointestinal tract: twenty years of progress. Gastroenterology 116(3):702–731
Montgomery RK, Carlone DL et al (2011) Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells. Proc Natl Acad Sci U S A 108(1):179–184
Monzo M, Navarro A et al (2008) Overlapping expression of microRNAs in human embryonic colon and colorectal cancer. Cell Res 18(8):823–833
Moore KA, Lemischka IR (2006) Stem cells and their niches. Science 311(5769):1880–1885
Munoz J, Stange DE et al (2012) The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent ‘+4’ cell markers. EMBO J 31(14):3079–3091
Ootani A, Li X et al (2009) Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat Med 15(6):701–706
Pang R, Law WL et al (2010) A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell 6(6):603–615
Pellegrinet L, Rodilla V et al (2011) Dll1- and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells. Gastroenterology 140(4):1230–1240. e1231–e1237
Pignatelli M, Bodmer WF (1989) Integrin-receptor-mediated differentiation and growth inhibition are enhanced by transforming growth factor-beta in colorectal tumour cells grown in collagen gel. Int J Cancer 44(3):518–523
Pinchuk IV, Beswick EJ et al (2011) Human colonic myofibroblasts promote expansion of CD4+ CD25high Foxp3+ regulatory T cells. Gastroenterology 140(7):2019–2030
Pinto D, Clevers H (2005) Wnt, stem cells and cancer in the intestine. Biol Cell 97(3):185–196
Pinto D, Gregorieff A et al (2003) Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev 17(14):1709–1713
Potten CS, Kovacs L et al (1974) Continuous labelling studies on mouse skin and intestine. Cell Tissue Kinet 7(3):271–283
Potten CS, Owen G et al (2002) Intestinal stem cells protect their genome by selective segregation of template DNA strands. J Cell Sci 115(Pt 11):2381–2388
Powell DW, Adegboyega PA et al (2005) Epithelial cells and their neighbors I. Role of intestinal myofibroblasts in development, repair, and cancer. Am J Physiol Gastrointest Liver Physiol 289(1):G2–G7
Radtke F, Clevers H (2005) Self-renewal and cancer of the gut: two sides of a coin. Science 307(5717):1904–1909
Reed KR, Tunster SJ et al (2012) Entopic overexpression of Ascl2 does not accelerate tumourigenesis in ApcMin mice. Gut 61(10):1435–1438
Ricci-Vitiani L, Lombardi DG et al (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445(7123):111–115
Richman PI, Bodmer WF (1988) Control of differentiation in human colorectal carcinoma cell lines: epithelial-mesenchymal interactions. J Pathol 156(3):197–211
Richman PI, Tilly R et al (1987) Colonic pericrypt sheath cells: characterisation of cell type with new monoclonal antibody. J Clin Pathol 40(6):593–600
Sancho E, Batlle E et al (2003) Live and let die in the intestinal epithelium. Curr Opin Cell Biol 15(6):763–770
Sangiorgi E, Capecchi MR (2008) Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet 40(7):915–920
Sato T, Clevers H (2013) Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science 340(6137):1190–1194
Sato T, Vries RG et al (2009) Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459(7244):262–265
Sato T, van Es JH et al (2011) Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469(7330):415–418
Schepers AG, Vries R et al (2011) Lgr5 intestinal stem cells have high telomerase activity and randomly segregate their chromosomes. EMBO J 30(6):1104–1109
Schepers AG, Snippert HJ et al (2012) Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science 337(6095):730–735
Schwank G, Koo BK et al (2013) Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell 13(6):653–658
Schwitalla S, Fingerle AA et al (2013) Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152(1–2):25–38
Scoville DH, Sato T et al (2008) Current view: intestinal stem cells and signaling. Gastroenterology 134(3):849–864
Shmelkov SV, Butler JM 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(6):2111–2120
Sikandar SS, Pate KT et al (2010) 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 70(4):1469–1478
Spence JR, Mayhew CN et al (2011) Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470(7332):105–109
Tajbakhsh S (2014) Ballroom dancing with stem cells: placement and displacement in the intestinal crypt. Cell Stem Cell 14(3):271–273
Takahashi H, Ishii H et al (2011) Significance of Lgr5(+ve) cancer stem cells in the colon and rectum. Ann Surg Oncol 18(4):1166–1174
Takeda N, Jain R et al (2011) Interconversion between intestinal stem cell populations in distinct niches. Science 334(6061):1420–1424
Tian H, Biehs B et al (2011) A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478(7368):255–259
Todaro M, Alea MP et al (2007) Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell 1(4):389–402
Todaro M, Francipane MG et al (2010) Colon cancer stem cells: promise of targeted therapy. Gastroenterology 138(6):2151–2162
van der Flier LG, Clevers H (2009) Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 71:241–260
van der Flier LG, Haegebarth A et al (2009a) OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology 137(1):15–17
van der Flier LG, van Gijn ME et al (2009b) Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell 136(5):903–912
Vermeulen L, Todaro M et al (2008) Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc Natl Acad Sci U S A 105(36):13427–13432
Vermeulen L, De Sousa EMF et al (2010) Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol 12(5):468–476
von Furstenberg RJ, Gulati AS et al (2011) Sorting mouse jejunal epithelial cells with CD24 yields a population with characteristics of intestinal stem cells. Am J Physiol Gastrointest Liver Physiol 300(3):G409–G417
Walker F, Zhang HH et al (2011) LGR5 is a negative regulator of tumourigenicity, antagonizes Wnt signalling and regulates cell adhesion in colorectal cancer cell lines. PLoS One 6(7):e22733
Watson CL, Mahe MM et al (2014) An in vivo model of human small intestine using pluripotent stem cells. Nat Med 20(11):1310–1314
Webber J, Steadman R et al (2010) Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res 70(23):9621–9630
Weissman IL (2000) Stem cells: units of development, units of regeneration, and units in evolution. Cell 100(1):157–168
Wells JM, Spence JR (2014) How to make an intestine. Development 141(4):752–760
Widschwendter M, Fiegl H et al (2007) Epigenetic stem cell signature in cancer. Nat Genet 39(2):157–158
Yeung TM, Gandhi SC et al (2010) Cancer stem cells from colorectal cancer-derived cell lines. Proc Natl Acad Sci U S A 107(8):3722–3727
Yeung TM, Gandhi SC et al (2011) Hypoxia and lineage specification of cell line-derived colorectal cancer stem cells. Proc Natl Acad Sci U S A 108(11):4382–4387
Yokoyama S, Takifuji K et al (2010) Moderately differentiated colorectal adenocarcinoma as a lymph node metastatic phenotype: comparison with well differentiated counterparts. BMC Surg 10:8
Yu T, Chen X et al (2012a) Regulation of the potential marker for intestinal cells, Bmi1, by beta-catenin and the zinc finger protein KLF4: implications for colon cancer. J Biol Chem 287(6):3760–3768
Yu Y, Kanwar SS et al (2012b) MicroRNA-21 induces stemness by downregulating transforming growth factor beta receptor 2 (TGFbetaR2) in colon cancer cells. Carcinogenesis 33(1):68–76
Zagouras P, Stifani S et al (1995) Alterations in Notch signaling in neoplastic lesions of the human cervix. Proc Natl Acad Sci U S A 92(14):6414–6418
Zhang Y, Li B et al (2010) Notch1 regulates the growth of human colon cancers. Cancer 116(22):5207–5218
Zhu L, Gibson P et al (2009) Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 457(7229):603–607
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Singh, S., Sasikala, M., Rao, G.V., Reddy, D.N. (2016). Intestinal Stem Cells in Homeostasis and Cancer. In: Steinhoff, G. (eds) Regenerative Medicine - from Protocol to Patient. Springer, Cham. https://doi.org/10.1007/978-3-319-27610-6_9
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