Review Article | Published:

Stem cell dynamics in homeostasis and cancer of the intestine

Nature Reviews Cancer volume 14, pages 468480 (2014) | Download Citation

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.

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & 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).

  2. 2.

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

  3. 3.

    , & Cancer statistics, 2012. CA Cancer J. Clin. 62, 10–29 (2012).

  4. 4.

    , & Stem cells and their implications for colorectal cancer. Nature Rev. Gastroenterol. Hepatol 8, 90–100 (2011).

  5. 5.

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

  6. 6.

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

  7. 7.

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

  8. 8.

    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).

  9. 9.

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

  10. 10.

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

  11. 11.

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

  12. 12.

    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.

  13. 13.

    , , & Intestinal stem cell replacement follows a pattern of neutral drift. Science 330, 822–825 (2010).

  14. 14.

    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.

  15. 15.

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

  16. 16.

    , , , & 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.

  17. 17.

    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).

  18. 18.

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

  19. 19.

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

  20. 20.

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

  21. 21.

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

  22. 22.

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

  23. 23.

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

  24. 24.

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

  25. 25.

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

  26. 26.

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

  27. 27.

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

  28. 28.

    , , & Lgr5 stem cells are indispensable for radiation-induced intestinal regeneration. Cell Stem Cell 14, 149–159 (2013).

  29. 29.

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

  30. 30.

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

  31. 31.

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

  32. 32.

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

  33. 33.

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

  34. 34.

    , & 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).

  35. 35.

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

  36. 36.

    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).

  37. 37.

    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).

  38. 38.

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

  39. 39.

    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.

  40. 40.

    , & A comparison of cell replacement in bone marrow, testis and three regions of surface epithelium. Biochim. Biophys. Acta 560, 281–299 (1979).

  41. 41.

    , , & Apoptosis differently affects lineage tracing of Lgr5 and Bmi1 intestinal stem cell populations. Cell Stem Cell 12, 298–303 (2013).

  42. 42.

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

  43. 43.

    & A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

  44. 44.

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

  45. 45.

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

  46. 46.

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

  47. 47.

    , , & Cancer heterogeneity—a multifaceted view. EMBO Rep. 14, 686–695 (2013).

  48. 48.

    & The hallmarks of cancer. Cell 100, 57–70 (2000).

  49. 49.

    & Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

  50. 50.

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

  51. 51.

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

  52. 52.

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

  53. 53.

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

  54. 54.

    & Cancer. Unwanted evolution. Science 342, 938–939 (2013).

  55. 55.

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

  56. 56.

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

  57. 57.

    , & 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).

  58. 58.

    , , , & Regeneration of intestinal stem/progenitor cells following doxorubicin treatment of mice. Am. J. Physiol. Gastrointest. Liver Physiol. 297, G461–G470 (2009).

  59. 59.

    , , & Field cancerization, clonality, and epithelial stem cells: the spread of mutated clones in epithelial sheets. J. Pathol. 187, 61–81 (1999).

  60. 60.

    , & Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 6, 963–968 (1953).

  61. 61.

    , , , & Occult progression by Apc-deficient intestinal crypts as a target for chemoprevention. Carcinogenesis 35, 237–246 (2014).

  62. 62.

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

  63. 63.

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

  64. 64.

    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).

  65. 65.

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

  66. 66.

    & The bone marrow niche for haematopoietic stem cells. Nature 505, 327–334 (2014).

  67. 67.

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

  68. 68.

    , , , & Natural history of paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 333, 1253–1258 (1995).

  69. 69.

    & 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).

  70. 70.

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

  71. 71.

    , & The nonsteroidal anti-inflammatory drugs aspirin and indomethacin attenuate β-catenin/TCF-4 signaling. Oncogene 20, 645–653 (2001).

  72. 72.

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

  73. 73.

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

  74. 74.

    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).

  75. 75.

    , & 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).

  76. 76.

    , , & 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).

  77. 77.

    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).

  78. 78.

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

  79. 79.

    , , & 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.

  80. 80.

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

  81. 81.

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

  82. 82.

    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).

  83. 83.

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

  84. 84.

    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).

  85. 85.

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

  86. 86.

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

  87. 87.

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

  88. 88.

    , , , & DCAMKL-1 expression identifies Tuft cells rather than stem cells in the adult mouse intestinal epithelium. Gastroenterology 137, 2179–2180 (2009).

  89. 89.

    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.

  90. 90.

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

  91. 91.

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

  92. 92.

    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).

  93. 93.

    , , , & 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.

  94. 94.

    , , , & Inferring clonal expansion and cancer stem cell dynamics from DNA methylation patterns in colorectal cancers. Proc. Natl Acad. Sci. USA 106, 4828–4833 (2009).

  95. 95.

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

  96. 96.

    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.

  97. 97.

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

  98. 98.

    , de , & The developing cancer stem-cell model: clinical challenges and opportunities. Lancet Oncol. 13, e83–89 (2012).

  99. 99.

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

  100. 100.

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

  101. 101.

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

  102. 102.

    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).

  103. 103.

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

  104. 104.

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

  105. 105.

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

  106. 106.

    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).

  107. 107.

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

  108. 108.

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

  109. 109.

    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.

  110. 110.

    & The Biology of Epithelial Cell Populations. Vol. 2 (Oxford Univ. Press, 1984).

  111. 111.

    , , & Cellular inheritance of a Cre-activated reporter gene to determine Paneth cell longevity in the murine small intestine. Dev. Dyn. 233, 1332–1336 (2005).

  112. 112.

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

  113. 113.

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

  114. 114.

    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).

  115. 115.

    , , , & OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology 137, 15–17 (2009).

  116. 116.

    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).

  117. 117.

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

  118. 118.

    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).

  119. 119.

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

  120. 120.

    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).

  121. 121.

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

  122. 122.

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

  123. 123.

    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).

  124. 124.

    , , & Exploring cancer stem cell niche directed tumor growth. Cell Cycle 9, 1472–1479 (2010).

Download references

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.

Author information

Affiliations

  1. Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

    • Louis Vermeulen
  2. Cancer Research UK — Cambridge Institute, University of Cambridge, Robinson Way, CB2 0RE, Cambridge, UK.

    • Louis Vermeulen
  3. Molecular Cancer Research and Cancer Genomics Netherlands, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.

    • Hugo J. Snippert

Authors

  1. Search for Louis Vermeulen in:

  2. Search for Hugo J. Snippert in:

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Louis Vermeulen or Hugo J. Snippert.

Supplementary information

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.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrc3744

Further reading