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Stem cell dynamics in homeostasis and cancer of the intestine

Nature Reviews Cancer volume 14, pages 468–480 (2014)Cite this article

Subjects

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).

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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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Authors and Affiliations

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

    Louis Vermeulen

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

    Louis Vermeulen

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

    Hugo J. Snippert

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  1. Louis Vermeulen
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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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