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Epithelial stem cells, wound healing and cancer

Nature Reviews Cancer volume 12, pages 170–180 (2012)Cite this article

Subjects

Key Points

  • Wound healing and tumorigenesis are two processes that rely on similar molecular mechanisms. Repair of tissue injury is a self-limiting process; whereas, tumour formation is characterized by the continuous activation of the pathways involved.

  • The interplay of different cell types, such as epithelial, mesenchymal and immune cells, is of major importance in both wound repair and tumour formation. Changes in the microenvironment caused by tissue injury can permit the development of a tumour.

  • Stem cells contribute to wound healing and tumour formation. In each case, stem cells can adopt a new location that differs from their location in undamaged tissue.

  • Several crucial pathways, such as Hedgehog and WNT signalling, are deregulated in wound healing and tumorigenesis. Deregulated Hedgehog signalling is linked to the development of basal cell carcinoma; whereas, aberrant WNT signalling can result in a variety of epidermal tumours.

  • Non-dividing, differentiating and dying epithelial cells can either positively or negatively influence tumour formation.

Abstract

It is well established that tissue repair depends on stem cells and that chronic wounds predispose to tumour formation. However, the association between stem cells, wound healing and cancer is poorly understood. Lineage tracing has now shown how stem cells are mobilized to repair skin wounds and how they contribute to skin tumour development. The signalling pathways, including WNT and Hedgehog, that control stem cell behaviour during wound healing are also implicated in tumour formation. Furthermore, tumorigenesis and wound repair both depend on communication between epithelial cells, mesenchymal cells and bone marrow-derived cells. These studies suggest ways to harness stem cells for wound repair while minimizing cancer risk.

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Figure 1: Comparison of the microenvironments of a healing wound and an invading tumour margin.
Figure 2: Different stem cell compartments in adult mouse back skin.
Figure 3: WNT and Hedgehog pathways.

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Acknowledgements

The authors thank I. Brownell, R. Toftgard, K. Kretzschmar and K. Jensen for advice on Figure 2. F.M.W. gratefully acknowledges financial support from the Wellcome Trust, Medical Research Council and Cancer Research UK. E.H. is supported by EUFP7 HEALING network. E.N.A. is a recipient of a Sir Henry Wellcome postdoctoral fellowship.

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  1. Esther N. Arwert

    Present address: Present address: Albert Einstein College of Medicine, Michael F. Price Center, 1301 Morris Park Avenue, New York NY 10461, USA.,

  2. Esther N. Arwert and Esther Hoste: These authors contributed equally to this work.

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  1. Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, CB2 ORE, Cambridge, UK

    Esther N. Arwert, Esther Hoste & Fiona M. Watt

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Glossary

Keratinocytes

Epithelial cells in a multilayered epithelium, such as the epidermis.

Squamous cell carcinoma

Malignant tumour with elements of interfollicular epidermal differentiation.

Psoriasis

Benign skin disorder that affects 2% of the world's population; characterized by epidermal hyperproliferation and skin inflammation.

Sebaceous gland

Gland that is associated with the junction between the hair follicle and the interfollicular epidermis; releases sebum that lubricates the skin surface.

Interfollicular epidermis

(IFE). Multilayered epithelium of the epidermis that lies between the hair follicles; forms the barrier that protects the skin from the external environment.

Isthmus

The region of the hair follicle that extends between the bulge and the sebaceous gland.

Junctional zone

Junction between the hair follicle, sebaceous gland and infundibulum; the location of LRIG1+ stem cells.

Basal cell carcinoma

(BCC). Very common, slow-growing epidermal tumour that lacks differentiated cell markers and that is believed to arise from hair follicles.

Infundibulum

The part of the hair follicle that lies above the sebaceous gland and that is continuous with the interfollicular epidermis.

Pilomatricomas

Benign skin tumours with elements of hair follicle matrix differentiation.

Trichofolliculomas

Benign skin tumours with multiple elements of hair follicle differentiation.

Papillomas

Benign tumours with elements of interfollicular epidermal differentiation that can convert into squamous cell carcinomas.

Full-thickness wounding

Wounding that extends through all the layers of the skin (epidermis, dermis and subdermal fat layer).

Keratoacanthomas

Low-grade squamous cell carcinomas in skin.

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Arwert, E., Hoste, E. & Watt, F. Epithelial stem cells, wound healing and cancer. Nat Rev Cancer 12, 170–180 (2012). https://doi.org/10.1038/nrc3217

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