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Colonic crypt organization and tumorigenesis

Nature Reviews Cancer volume 8, pages 415–424 (2008)Cite this article

Key Points

  • Intestinal crypts house the tissue-specific, multipotential stem cells located in the niche at the base of the crypt, capable of regenerating all intestinal cell types.

  • Intestinal crypts are clonal populations.

  • A stem cell that has acquired a mutation can expand to occupy the whole stem-cell niche, through genetic drift or by acquiring a selective advantage (niche succession); eventually their progeny can fill the whole crypt (monoclonal conversion).

  • Mutated intestinal crypts expand by crypt fission, leading to spread of the mutation within the epithelium (field cancerization).

  • Further genetic changes result in the appearance of the earliest recognizable lesion in the colon (the monocryptal adenoma); expansion by crypt fission results in the development of the premalignant lesion in the colon (the adenoma).

  • Adenomas appear to be polyclonal; short-range interactions between adjacent initiated clones might be responsible, with clonal interaction required for adenoma formation.

  • Although it is clear that many tumours arise from stem cells, there is early evidence that committed progenitor cells linger long enough in the crypt to undergo mutation and selection events that lead to neoplasia.

  • These concepts can be applied to other tissues and organs as a basis for the development of the earliest neoplastic lesions.

Abstract

An appreciation of colonic crypt organization has become essential to any understanding of tumorigenesis in the colon. Intestinal crypts house tissue-specific, multipotential stem cells, which are located in the niche at the base of the intestinal crypt and are capable of regenerating all intestinal cell types. Recent advances in our understanding of crypt biology, including how mutations in stem cells become fixed and expand within the epithelium, has led to new theories on the origins of colonic adenomas and cancers.

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Figure 1: Colonic crypt organization, patterns of stem cell divisions, niche succession and clonal conversion.
Figure 2: Niche succession and clonal conversion shown experimentally in colonic crypts.
Figure 3: A possible scheme for the development of polyclonality in colonic adenomas.

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Acknowledgements

We are grateful to S. McDonald, S. Leedham, P. Tadrous and D. Turnbull for helpful discussions and for providing figures. This work was supported by Cancer Research UK.

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  1. Histopathology Lab, London Research Institute, Cancer Research UK, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    Adam Humphries & Nicholas A. Wright

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Correspondence to Adam Humphries.

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DATABASES

National Cancer Institute

adenocarcinoma

Barrett oesophagus

colorectal carcinomas

hereditary nonpolyposis colon cancer

Glossary

Actinic keratosis

A dysplastic condition of the skin secondary to chronic sunlight exposure, which predisposes to squamous cell carcinoma.

Squamous metaplasia

The abnormal change from one defined epithelium to a squamous epithelium.

Pericryptal myofibroblasts

Mesenchymal cells that surround and support the intestinal crypt, derived from the myofibroblast lineage.

Paneth cells

Differentiated intestinal epithelial cells, mainly located in the small intestine and occasionally found in the ascending colon, that contain eosinophilic granules and secrete antibacterial proteins.

Hypomorphic variant

A variant with a reduced function compared with the wild type.

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Humphries, A., Wright, N. Colonic crypt organization and tumorigenesis. Nat Rev Cancer 8, 415–424 (2008). https://doi.org/10.1038/nrc2392

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