Stem cell dynamics in homeostasis and cancer of the intestine

Key Points

  • Intestinal stem cells (ISCs) are not static entities but are instead involved in many dynamical processes.

  • ISCs are equipotent and continuously replace each other in neutral events.

  • The ISC phenotype is the sum of all markers and features that are commonly associated with stem cells in the intestine. Therefore, the ISC phenotype is continuously changing as new markers and features are being identified.

  • ISC activity is the ability of cells to initiate clonal long-term, multipotent lineages and is typically assessed by lineage tracing experiments.

  • ISC potential refers to the display of ISC activity solely in a specific context but not during homeostasis; for example, during regeneration after tissue injury. Examples of intestinal cells with ISC potential are label-retaining Paneth cell precursors and Delta-like 1-positive (DLL1+) secretory precursors.

  • The functional ISC compartment is the number of cells with ISC activity corrected for their relative contribution to the total output of the stem cell compartment.

  • Mutations that are commonly found in colorectal cancer (CRC), such as adenomatous polyposis coli (APC) inactivation and KRAS activation, act on ISC dynamics and give a competitive advantage to the cell in which they occur.

  • The benefit of mutated ISCs over wild-type ISCs is not absolute, and mutated ISCs are frequently outcompeted by wild-type ISCs.

  • CRCs contain cells with stem cell-like activity; however, the frequency of these cells remains unknown, as does the importance of these cells for the biology of CRCs.

  • Differentiated cancer cells and cancer stem cells are in constant flux, which is influenced by signals that emanate from the tumour stroma.

Abstract

Intestinal stem cells (ISCs) and colorectal cancer (CRC) biology are tightly linked in many aspects. It is generally thought that ISCs are the cells of origin for a large proportion of CRCs and crucial ISC-associated signalling pathways are often affected in CRCs. Moreover, CRCs are thought to retain a cellular hierarchy that is reminiscent of the intestinal epithelium. Recent studies offer quantitative insights into the dynamics of ISC behaviour that govern homeostasis and thereby provide the necessary baseline parameters to begin to apply these analyses during the various stages of tumour development.

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Figure 1: Intestinal epithelium.
Figure 2: Intestinal stem cell (ISC) phenotype, activity, potential and functionality.
Figure 3: Intestinal homeostasis results from neutral competition between intestinal stem cells (ISCs).
Figure 4: Competitive behaviour of cancer mutations.
Figure 5: Adenoma and cancer stem cells (CSCs).

References

  1. 1

    Cheng, H. & Leblond, C. P. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian Theory of the origin of the four epithelial cell types. Am. J. Anat. 141, 537–561 (1974).

    CAS  PubMed  Google Scholar 

  2. 2

    Sato, T. et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469, 415–418 (2011).

    CAS  Google Scholar 

  3. 3

    Siegel, R., Naishadham, D. & Jemal, A. Cancer statistics, 2012. CA Cancer J. Clin. 62, 10–29 (2012).

    Google Scholar 

  4. 4

    Zeki, S. S., Graham, T. A. & Wright, N. A. Stem cells and their implications for colorectal cancer. Nature Rev. Gastroenterol. Hepatol 8, 90–100 (2011).

    Google Scholar 

  5. 5

    Fearon, E. R. Molecular genetics of colorectal cancer. Annu. Rev. Pathol. 6, 479–507 (2011).

    CAS  Google Scholar 

  6. 6

    Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).

    CAS  Google Scholar 

  7. 7

    Henderson, K. & Kirkland, S. C. Multilineage differentiation of cloned HRA-19 cells in serum-free medium: a model of human colorectal epithelial differentiation. Differentiation 60, 259–268 (1996).

    CAS  PubMed  Google Scholar 

  8. 8

    Vermeulen, L. et al. Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc. Natl Acad. Sci. USA 105, 13427–13432 (2008).

    CAS  PubMed  Google Scholar 

  9. 9

    Tian, H. et al. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478, 255–259 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Takeda, N. et al. Interconversion between intestinal stem cell populations in distinct niches. Science 334, 1420–1424 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Buczacki, S. J. et al. Intestinal label-retaining cells are secretory precursors expressing Lgr5. Nature 495, 65–69 (2013).

    CAS  Google Scholar 

  12. 12

    van Es, J. H. et al. Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nature Cell Biol. 14, 1099–1104 (2012). References 11 and 12 are the first studies to report on ISC potential in progenitor cells following injury.

    CAS  PubMed  Google Scholar 

  13. 13

    Lopez-Garcia, C., Klein, A. M., Simons, B. D. & Winton, D. J. Intestinal stem cell replacement follows a pattern of neutral drift. Science 330, 822–825 (2010).

    CAS  Google Scholar 

  14. 14

    Snippert, H. J. et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134–144 (2010). References 13 and 14 provide the first quantitative description of neutral stochastic competition between ISCs.

    CAS  Google Scholar 

  15. 15

    Vermeulen, L. et al. Defining stem cell dynamics in models of intestinal tumor initiation. Science 342, 995–998 (2013).

    CAS  Google Scholar 

  16. 16

    Snippert, H. J., Schepers, A. G., van Es, J. H., Simons, B. D. & Clevers, H. Biased competition between Lgr5 intestinal stem cells driven by oncogenic mutation induces clonal expansion. EMBO Rep. 15, 62–69 (2014). References 15 and 16 provide quantitative insight into the effect of common oncogenic mutations in intestinal tumour initiation.

    CAS  Google Scholar 

  17. 17

    Wright, N. A. Epithelial stem cell repertoire in the gut: clues to the origin of cell lineages, proliferative units and cancer. Int. J. Exp. Pathol. 81, 117–143 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Barker, N. Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nature Rev. Mol. Cell Biol. 15, 19–33 (2014).

    CAS  Google Scholar 

  19. 19

    Blanpain, C. & Simons, B. D. Unravelling stem cell dynamics by lineage tracing. Nature Rev. Mol. Cell Biol. 14, 489–502 (2013).

    CAS  Google Scholar 

  20. 20

    Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).

    CAS  Google Scholar 

  21. 21

    Munoz, J. et al. The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent '+4' cell markers. EMBO J. 31, 3079–3091 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Sangiorgi, E. & Capecchi, M. R. Bmi1 is expressed in vivo in intestinal stem cells. Nature Genet. 40, 915–920 (2008).

    CAS  PubMed  Google Scholar 

  23. 23

    Montgomery, R. K. et al. Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells. Proc. Natl Acad. Sci. USA 108, 179–184 (2011).

    CAS  Google Scholar 

  24. 24

    van der Flier, L. G. et al. Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell 136, 903–912 (2009).

    CAS  PubMed  Google Scholar 

  25. 25

    Zhu, L. et al. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 457, 603–607 (2009).

    CAS  PubMed  Google Scholar 

  26. 26

    Snippert, H. J. et al. Prominin-1/CD133 marks stem cells and early progenitors in mouse small intestine. Gastroenterology 136, 2187–2194 e2181 (2009).

    CAS  PubMed  Google Scholar 

  27. 27

    Itzkovitz, S. et al. Single-molecule transcript counting of stem-cell markers in the mouse intestine. Nature Cell Biol. 14, 106–114 (2012).

    CAS  Google Scholar 

  28. 28

    Metcalfe, C., Kljavin, N. M., Ybarra, R. & de Sauvage, F. J. Lgr5 stem cells are indispensable for radiation-induced intestinal regeneration. Cell Stem Cell 14, 149–159 (2013).

    PubMed  Google Scholar 

  29. 29

    Kim, T. H. et al. Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity. Nature 506, 511–515 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Kaaij, L. T. et al. DNA methylation dynamics during intestinal stem cell differentiation reveals enhancers driving gene expression in the villus. Genome Biol. 14, R50 (2013).

    PubMed  PubMed Central  Google Scholar 

  31. 31

    Butler, J. S. & Dent, S. Y. The role of chromatin modifiers in normal and malignant hematopoiesis. Blood 121, 3076–3084 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Ritsma, L. et al. Intestinal crypt homeostasis revealed at single stem cell level by in vivo live-imaging. Nature 507, 362–365 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Ponder, B. A. et al. Derivation of mouse intestinal crypts from single progenitor cells. Nature 313, 689–691 (1985).

    CAS  PubMed  Google Scholar 

  34. 34

    Hermiston, M. L., Green, R. P. & Gordon, J. I. Chimeric-transgenic mice represent a powerful tool for studying how the proliferation and differentiation programs of intestinal epithelial cell lineages are regulated. Proc. Natl Acad. Sci. USA 90, 8866–8870 (1993).

    CAS  PubMed  Google Scholar 

  35. 35

    Novelli, M. R. et al. Polyclonal origin of colonic adenomas in an XO/XY patient with FAP. Science 272, 1187–1190 (1996).

    CAS  PubMed  Google Scholar 

  36. 36

    Gutierrez-Gonzalez, L. et al. Analysis of the clonal architecture of the human small intestinal epithelium establishes a common stem cell for all lineages and reveals a mechanism for the fixation and spread of mutations. J. Pathol. 217, 489–496 (2009).

    CAS  PubMed  Google Scholar 

  37. 37

    Greaves, L. C. et al. Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission. Proc. Natl Acad. Sci. USA 103, 714–719 (2006).

    CAS  Google Scholar 

  38. 38

    Taylor, R. W. et al. Mitochondrial DNA mutations in human colonic crypt stem cells. J. Clin. Invest. 112, 1351–1360 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Kozar, S. et al. Continuous clonal labeling reveals small numbers of functional stem cells in intestinal crypts and adenomas. Cell Stem Cell 13, 626–633 (2013). This is the first study to use a continuous, marker-independent system to describe the functional stem cell compartment in normal murine intestine and adenomas.

    CAS  PubMed  Google Scholar 

  40. 40

    Potten, C. S., Schofield, R. & Lajtha, L. G. A comparison of cell replacement in bone marrow, testis and three regions of surface epithelium. Biochim. Biophys. Acta 560, 281–299 (1979).

    CAS  PubMed  Google Scholar 

  41. 41

    Zhu, Y., Huang, Y. F., Kek, C. & Bulavin, D. V. Apoptosis differently affects lineage tracing of Lgr5 and Bmi1 intestinal stem cell populations. Cell Stem Cell 12, 298–303 (2013).

    CAS  PubMed  Google Scholar 

  42. 42

    de Navascues, J. et al. Drosophila midgut homeostasis involves neutral competition between symmetrically dividing intestinal stem cells. EMBO J. 31, 2473–2485 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

    CAS  Google Scholar 

  44. 44

    Visvader, J. E. Cells of origin in cancer. Nature 469, 314–322 (2011).

    CAS  Google Scholar 

  45. 45

    Schwitalla, S. et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152, 25–38 (2013).

    CAS  Google Scholar 

  46. 46

    Jansen, M. et al. LKB1 as the ghostwriter of crypt history. Fam. Cancer 10, 437–446 (2011).

    PubMed  PubMed Central  Google Scholar 

  47. 47

    De Sousa, E. M. F., Vermeulen, L., Fessler, E. & Medema, J. P. Cancer heterogeneity—a multifaceted view. EMBO Rep. 14, 686–695 (2013).

    Google Scholar 

  48. 48

    Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    CAS  Google Scholar 

  49. 49

    Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  Google Scholar 

  50. 50

    Nowell, P. C. The clonal evolution of tumor cell populations. Science 194, 23–28 (1976).

    CAS  Google Scholar 

  51. 51

    Li, Q. et al. Oncogenic Nras has bimodal effects on stem cells that sustainably increase competitiveness. Nature 504, 143–147 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Wang, D. et al. Altered dynamics of intestinal cell maturation in Apc1638N/+ mice. Cancer Res. 70, 5348–5357 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Yeung, A. T. et al. One-hit effects in cancer: altered proteome of morphologically normal colon crypts in familial adenomatous polyposis. Cancer Res. 68, 7579–7586 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Bozic, I. & Nowak, M. A. Cancer. Unwanted evolution. Science 342, 938–939 (2013).

    CAS  PubMed  Google Scholar 

  55. 55

    Cheng, H. & Bjerknes, M. Whole population cell kinetics and postnatal development of the mouse intestinal epithelium. Anat. Rec. 211, 420–426 (1985).

    CAS  PubMed  Google Scholar 

  56. 56

    Dehmer, J. J. et al. Expansion of intestinal epithelial stem cells during murine development. PLoS ONE 6, e27070 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Park, H. S., Goodlad, R. A. & Wright, N. A. Crypt fission in the small intestine and colon. A mechanism for the emergence of G6PD locus-mutated crypts after treatment with mutagens. Am. J. Pathol. 147, 1416–1427 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Dekaney, C. M., Gulati, A. S., Garrison, A. P., Helmrath, M. A. & Henning, S. J. Regeneration of intestinal stem/progenitor cells following doxorubicin treatment of mice. Am. J. Physiol. Gastrointest. Liver Physiol. 297, G461–G470 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Garcia, S. B., Park, H. S., Novelli, M. & Wright, N. A. Field cancerization, clonality, and epithelial stem cells: the spread of mutated clones in epithelial sheets. J. Pathol. 187, 61–81 (1999).

    CAS  PubMed  Google Scholar 

  60. 60

    Slaughter, D. P., Southwick, H. W. & Smejkal, W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 6, 963–968 (1953).

    CAS  Google Scholar 

  61. 61

    Fischer, J. M., Schepers, A. G., Clevers, H., Shibata, D. & Liskay, R. M. Occult progression by Apc-deficient intestinal crypts as a target for chemoprevention. Carcinogenesis 35, 237–246 (2014).

    CAS  PubMed  Google Scholar 

  62. 62

    Wasan, H. S. et al. APC in the regulation of intestinal crypt fission. J. Pathol. 185, 246–255 (1998).

    CAS  PubMed  Google Scholar 

  63. 63

    Zhu, D. et al. K-ras gene mutations in normal colorectal tissues from K-ras mutation-positive colorectal cancer patients. Cancer Res. 57, 2485–2492 (1997).

    CAS  Google Scholar 

  64. 64

    Aivado, M. et al. “Field cancerization”—an additional phenomenon in development of colon tumors? K-ras codon 12 mutations in normal colonic mucosa of patients with colorectal neoplasms. Chirurg 71, 1230–1234 (2000).

    CAS  PubMed  Google Scholar 

  65. 65

    Simons, B. D. & Clevers, H. Strategies for homeostatic stem cell self-renewal in adult tissues. Cell 145, 851–862 (2011).

    CAS  PubMed  Google Scholar 

  66. 66

    Morrison, S. J. & Scadden, D. T. The bone marrow niche for haematopoietic stem cells. Nature 505, 327–334 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Sawyers, C. L. Chronic myeloid leukemia. N. Engl. J. Med. 340, 1330–1340 (1999).

    CAS  PubMed  Google Scholar 

  68. 68

    Hillmen, P., Lewis, S. M., Bessler, M., Luzzatto, L. & Dacie, J. V. Natural history of paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 333, 1253–1258 (1995).

    CAS  PubMed  Google Scholar 

  69. 69

    Algra, A. M. & Rothwell, P. M. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncol. 13, 518–527 (2012).

    CAS  Google Scholar 

  70. 70

    Barnes, C. J. & Lee, M. Chemoprevention of spontaneous intestinal adenomas in the adenomatous polyposis coli Min mouse model with aspirin. Gastroenterology 114, 873–877 (1998).

    CAS  PubMed  Google Scholar 

  71. 71

    Dihlmann, S., Siermann, A. & von Knebel Doeberitz, M. The nonsteroidal anti-inflammatory drugs aspirin and indomethacin attenuate β-catenin/TCF-4 signaling. Oncogene 20, 645–653 (2001).

    CAS  PubMed  Google Scholar 

  72. 72

    Medema, J. P. & Vermeulen, L. Microenvironmental regulation of stem cells in intestinal homeostasis and cancer. Nature 474, 318–326 (2011).

    CAS  Google Scholar 

  73. 73

    Blank, M. et al. Expression of MUC2-mucin in colorectal adenomas and carcinomas of different histological types. Int. J. Cancer 59, 301–306 (1994).

    CAS  PubMed  Google Scholar 

  74. 74

    Grabowski, P. et al. Heterogeneous expression of neuroendocrine marker proteins in human undifferentiated carcinoma of the colon and rectum. Ann. NY Acad. Sci. 1014, 270–274 (2004).

    CAS  PubMed  Google Scholar 

  75. 75

    Marsh, K. A., Stamp, G. W. & Kirkland, S. C. Isolation and characterization of multiple cell types from a single human colonic carcinoma: tumourigenicity of these cell types in a xenograft system. J. Pathol. 170, 441–450 (1993).

    CAS  PubMed  Google Scholar 

  76. 76

    Pierce, G. B., Nakane, P. K., Martinez-Hernandez, A. & Ward, J. M. Ultrastructural comparison of differentiation of stem cells of murine adenocarcinomas of colon and breast with their normal counterparts. J. Natl Cancer Inst. 58, 1329–1345 (1977).

    CAS  PubMed  Google Scholar 

  77. 77

    West, A. B. et al. Localization of villin, a cytoskeletal protein specific to microvilli, in human ileum and colon and in colonic neoplasms. Gastroenterology 94, 343–352 (1988).

    CAS  PubMed  Google Scholar 

  78. 78

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

    CAS  PubMed  Google Scholar 

  79. 79

    O'Brien, C. A., Pollett, A., Gallinger, S. & Dick, J. E. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445, 106–110 (2007). References 78 and 79 provide the first experimental evidence for the presence of rare tumour-initiating cells in CRC.

    CAS  PubMed  Google Scholar 

  80. 80

    Dalerba, P. et al. Single-cell dissection of transcriptional heterogeneity in human colon tumors. Nature Biotech. 29, 1120–1127 (2011).

    CAS  Google Scholar 

  81. 81

    Medema, J. P. Cancer stem cells: the challenges ahead. Nature Cell Biol. 15, 338–344 (2013).

    CAS  PubMed  Google Scholar 

  82. 82

    Todaro, M. et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell 1, 389–402 (2007).

    CAS  Google Scholar 

  83. 83

    Dalerba, P. et al. Phenotypic characterization of human colorectal cancer stem cells. Proc. Natl Acad. Sci. USA 104, 10158–10163 (2007).

    CAS  PubMed  Google Scholar 

  84. 84

    Shmelkov, S. V. et al. 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 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Horst, D. et al. Differential WNT activity in colorectal cancer confers limited tumorigenic potential and is regulated by MAPK signaling. Cancer Res. 72, 1547–1556 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Quintana, E. et al. Efficient tumour formation by single human melanoma cells. Nature 456, 593–598 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Schepers, A. G. et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science 337, 730–735 (2012).

    CAS  Google Scholar 

  88. 88

    Gerbe, F., Brulin, B., Makrini, L., Legraverend, C. & Jay, P. DCAMKL-1 expression identifies Tuft cells rather than stem cells in the adult mouse intestinal epithelium. Gastroenterology 137, 2179–2180 (2009).

    CAS  PubMed  Google Scholar 

  89. 89

    Nakanishi, Y. et al. Dclk1 distinguishes between tumor and normal stem cells in the intestine. Nature Genet. 45, 98–103,(2013). References 87 and 89 are the first studies to use lineage tracing in murine intestinal adenomas.

    CAS  PubMed  Google Scholar 

  90. 90

    Shibata, D. & Tavare, S. Counting divisions in a human somatic cell tree: how, what and why? Cell Cycle 5, 610–614,(2006).

    CAS  PubMed  Google Scholar 

  91. 91

    Graham, T. A. et al. Use of methylation patterns to determine expansion of stem cell clones in human colon tissue. Gastroenterology 140, 1241–1250 (2011).

    CAS  PubMed  Google Scholar 

  92. 92

    Humphries, A. et al. Lineage tracing reveals multipotent stem cells maintain human adenomas and the pattern of clonal expansion in tumor evolution. Proc. Natl Acad. Sci. USA 110, E2490–E2499 (2013).

    CAS  PubMed  Google Scholar 

  93. 93

    Sottoriva, A., Spiteri, I., Shibata, D., Curtis, C. & Tavare, S. Single-molecule genomic data delineate patient-specific tumor profiles and cancer stem cell organization. Cancer Res. 73, 41–49 (2013). References 92 and 93 provide the first convincing evidence for the presence of stem-like cells in unperturbed human adenomas and CRCs, respectively.

    CAS  PubMed  Google Scholar 

  94. 94

    Siegmund, K. D., Marjoram, P., Woo, Y. J., Tavare, S. & Shibata, D. Inferring clonal expansion and cancer stem cell dynamics from DNA methylation patterns in colorectal cancers. Proc. Natl Acad. Sci. USA 106, 4828–4833 (2009).

    CAS  Google Scholar 

  95. 95

    Gupta, P. B. et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 146, 633–644 (2011).

    CAS  Google Scholar 

  96. 96

    Vermeulen, L. et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nature Cell Biol. 12, 468–476 (2010). This is the first study to show that differentiated CRC cells can re-acquire CSC properties.

    CAS  PubMed  Google Scholar 

  97. 97

    Sottoriva, A. et al. Cancer stem cell tumor model reveals invasive morphology and increased phenotypical heterogeneity. Cancer Res. 70, 46–56 (2010).

    CAS  PubMed  Google Scholar 

  98. 98

    Vermeulen, L., de Sousa e Melo, F., Richel, D. J. & Medema, J. P. The developing cancer stem-cell model: clinical challenges and opportunities. Lancet Oncol. 13, e83–89 (2012).

    PubMed  Google Scholar 

  99. 99

    Lotti, F. et al. Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J. Exp. Med. 210, 2851–2872 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Kreso, A. et al. Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science 339, 543–548 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Kemper, K. et al. Mutations in the Ras-Raf axis underlie the prognostic value of CD133 in colorectal cancer. Clin. Cancer Res. 18, 3132–3141 (2012).

    CAS  PubMed  Google Scholar 

  102. 102

    Park, S. Y. et al. Heterogeneity for stem cell-related markers according to tumor subtype and histologic stage in breast cancer. Clin. Cancer Res. 16, 876–887 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Curtis, S. J. et al. Primary tumor genotype is an important determinant in identification of lung cancer propagating cells. Cell Stem Cell 7, 127–133 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Notta, F. et al. Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. Nature 469, 362–367 (2011).

    CAS  PubMed  Google Scholar 

  105. 105

    Budinska, E. et al. Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer. J. Pathol. 231, 63–76 (2013).

    CAS  Google Scholar 

  106. 106

    De Sousa, E. M. F. et al. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nature Med. 19, 614–618 (2013).

    Google Scholar 

  107. 107

    Marisa, L. et al. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med. 10, e1001453 (2013).

    CAS  Google Scholar 

  108. 108

    Roepman, P. et al. Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition. Int. J. Cancer 134, 552–562 (2014).

    CAS  Google Scholar 

  109. 109

    Sadanandam, A. et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nature Med. 19, 619–625 (2013). References 105 to 109 provide the first unbiased classifications of CRCs.

    CAS  PubMed  Google Scholar 

  110. 110

    Wright, N. A. & Alison, M. R. The Biology of Epithelial Cell Populations. Vol. 2 (Oxford Univ. Press, 1984).

    Google Scholar 

  111. 111

    Ireland, H., Houghton, C., Howard, L. & Winton, D. J. Cellular inheritance of a Cre-activated reporter gene to determine Paneth cell longevity in the murine small intestine. Dev. Dyn. 233, 1332–1336 (2005).

    CAS  PubMed  Google Scholar 

  112. 112

    Rothenberg, M. E. et al. Identification of a cKit+ colonic crypt base secretory cell that supports Lgr5+ stem cells in mice. Gastroenterology 142, 1195–1205 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Pellegrinet, L. et al. Dll1- and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells. Gastroenterology 140, 1230–1240 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Riccio, O. et al. Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2. EMBO Rep. 9, 377–383 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    van der Flier, L. G., Haegebarth, A., Stange, D. E., van de Wetering, M. & Clevers, H. OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology 137, 15–17 (2009).

    PubMed  Google Scholar 

  116. 116

    Fafilek, B. et al. Troy, a tumor necrosis factor receptor family member, interacts with lgr5 to inhibit wnt signaling in intestinal stem cells. Gastroenterology 144, 381–391 (2013).

    CAS  PubMed  Google Scholar 

  117. 117

    Koo, B. K. et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature 488, 665–669 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Powell, A. E. et al. The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell 149, 146–158 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Wong, V. W. et al. Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling. Nature Cell Biol. 14, 401–408 (2012).

    CAS  PubMed  Google Scholar 

  120. 120

    Batlle, E. et al. β-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 111, 251–263 (2002).

    CAS  Google Scholar 

  121. 121

    Mori-Akiyama, Y. et al. SOX9 is required for the differentiation of paneth cells in the intestinal epithelium. Gastroenterology 133, 539–546 (2007).

    CAS  Google Scholar 

  122. 122

    Lourenco, F. C. et al. Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation. Gut 63, 480–493 (2014).

    CAS  PubMed  Google Scholar 

  123. 123

    Huang, E. H. 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. 69, 3382–3389 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Sottoriva, A., Sloot, P. M., Medema, J. P. & Vermeulen, L. Exploring cancer stem cell niche directed tumor growth. Cell Cycle 9, 1472–1479 (2010).

    CAS  PubMed  Google Scholar 

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Acknowledgements

L.V. and H.J.S. are both supported by a KWF Fellowship from the Dutch Cancer Society (grant numbers 2011–4969 and 2013–6070, respectively). The authors wish to thank D. Winton and the members of his laboratory, as well as E. Morrissey, L. van der Flier and M. van de Wetering, for illuminating discussions.

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Correspondence to Louis Vermeulen or Hugo J. Snippert.

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Glossary

Self-renewal

The ability of a cell to maintain itself while producing enough offspring to repopulate the tissue. As a result of intestinal stem cell dynamics, self-renewal is achieved by the population, rather than on a single cell level.

Cancer stem cells

(CSCs). Stem cell-like cells within an adenoma or cancer that fuel tumour expansion and progression. Like normal intestinal stem cells, they are multipotent and display the ability to self-renew.

Adenomas

Benign intestinal tumours that strongly resemble the tissue architecture of the healthy tissue.

ISC activity

An intrinsic intestinal stem cell (ISC) property that is defined by multipotency and self-renewal. It can be shown using lineage tracing.

ISC potential

The ability of non-stem cells to re-obtain intestinal stem cell (ISC) activity. The degree of ISC potential probably correlates with the level of differentiation.

Multipotency

The ability of a cell to differentiate into any cell type of the tissue of residence.

Stem cell niche

A microenvironment that imposes intestinal stem cell (ISC) activity on adjacent proliferative cells via a diverse set of stimuli. The ISC niche consists of, among others, Paneth cells and mesenchymal cells along the crypt base.

Functional ISC compartment

The average number of intestinal stem cells (ISCs) per crypt that contribute to long-term homeostasis. Individual ISCs cannot be assigned as 'functional' with 100% certainty, only by probability.

Neutral drift

Continuous, on-going competition between equipotent, active dividing intestinal stem cells for positioning within the niche. Passenger mutations do not affect competitive behaviour.

Fixation

The point at which the descendants of one cell (the most recent common ancestor) have colonized a whole crypt and cannot be outcompeted anymore. Neutral drift towards clone fixation continues between relatives.

Fixation probability

(Pfix) The probability of an individual intestinal stem cell (ISC) reaching fixation.

Cell of origin

The cell that acquired the initial mutation that initiated tumour development.

Biased drift

Unequal competition between wild-type intestinal stem cells (ISCs) and mutant ISCs for positioning within the niche. Driver mutations confer a selective advantage to a clone.

Fate plasticity

The capacity of cells to dedifferentiate and re-obtain intestinal stem cell activity.

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Vermeulen, L., Snippert, H. Stem cell dynamics in homeostasis and cancer of the intestine. Nat Rev Cancer 14, 468–480 (2014). https://doi.org/10.1038/nrc3744

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