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  • Review Article
  • Published:

Cancer as an overhealing wound: an old hypothesis revisited

Nature Reviews Molecular Cell Biology volume 9, pages 628–638 (2008)Cite this article

Key Points

  • A series of clinical and preclinical findings suggest a relationship between wound repair and cancer: malignant tumours often develop at sites of chronic injury and permanent tissue damage through chronic inflammation is a major risk factor for the development of cancer.

  • Recent studies have highlighted important parallels between wound healing and cancer at the molecular and cellular level. For example, microarray analyses revealed strong similarities in the gene-expression profile of wounds and carcinomas. However, important differences were also observed, which might explain the altered metabolism, impaired differentiation capacity and invasive growth of tumour cells.

  • The wound-healing process occurs in three overlapping phases: inflammation, new tissue formation and tissue remodelling. This review summarizes the cellular and molecular events that occur during these phases and the similarities and differences to cancer.

  • The presence of a fibrin clot is a hallmark of early wounds and cancers and it initiates a healing response. This response is transient and self-limiting in wounds, but it becomes chronic in cancer.

  • Stromal cells in wounds and tumours, including fibroblasts and/or myofibroblasts, endothelial cells and inflammatory cells, are important regulators of migration and proliferation of normal epithelial cells in wounds and of malignant epithelial cells in tumours. The factors that are responsible for the stromal–epithelial cross-talk are similar in wounds and tumours and include cytokines or growth factors, matrix molecules and proteinases.

  • Most cancer therapies also inhibit the wound-healing process, but recent examples suggest that inhibition of tumour growth can be achieved without affecting the tissue-repair process.

Abstract

What is the relationship between the wound-healing process and the development of cancer? Malignant tumours often develop at sites of chronic injury, and tissue injury has an important role in the pathogenesis of malignant disease, with chronic inflammation being the most important risk factor. The development and functional characterization of genetically modified mice that lack or overexpress genes that are involved in repair, combined with gene-expression analysis in wounds and tumours, have highlighted remarkable similarities between wound repair and cancer. However, a few crucial differences were also observed, which could account for the altered metabolism, impaired differentiation capacity and invasive growth of malignant tumours.

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Figure 1: The different phases of skin wound repair.
Figure 2: Cellular parallels between a tumour and a skin wound.
Figure 3: Fibrin deposition in wounds and tumours.
Figure 4: Angiogenesis in healing skin wounds.
Figure 5: Myofibroblast differentiation in healing skin wounds.

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Acknowledgements

We are grateful to M. Detmar, ETH Zürich, Switzerland, P. Martin, University of Bristol, UK, and A. Knuth, University of Zürich, Switzerland, for helpful suggestions and critical comments on the manuscript; to U. Scheier for help with the figures and the references; and to I. Thorey for providing the micrographs shown in Figure 4 and 5. Work in the laboratory of S.W. is supported by the ETH Zürich, the Swiss National Science Foundation (grant 3100A0-109340/1), Oncosuisse (grant OCS-02017-02-2007), and the European Union (grant Ulcertherapy). M.S. is supported by an EMBO postdoctoral fellowship.

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  1. Institute of Cell Biology, ETH Zürich, Schafmattstrasse 18, Zürich, 8093, Switzerland

    Matthias Schäfer & Sabine Werner

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  1. Matthias Schäfer
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  2. Sabine Werner
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Correspondence to Sabine Werner.

Supplementary information

41580_2008_BFnrm2455_MOESM2_ESM.pdf

Supplementary information S1 (table) | Approved cancer drugs that target growth factors or their receptors: Effects on cancer and wound healing (PDF 161 kb)

Related links

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DATABASES

OMIM

recessive dystrophic epidermolysis bullosa

FURTHER INFORMATION

Sabine Werner's homepage

Glossary

Scar

A connective tissue replacement following the wounding of the dermis.

Keloid

An overgrowth of scar tissue beyond the original wound edge.

Stroma

A connective tissue component of an organ (or tumour), which includes fibroblasts, blood and lymphatic vessels, inflammatory cells and extracellular matrix.

Granulation tissue

A highly vascularized and cell-rich tissue that replaces the fibrin clot in a skin wound.

Sarcoma

A cancer that arises from mesenchymal cells.

Warburg effect

The observation that most cancer cells predominantly produce energy by anaerobic glycolysis, which results in lactate formation.

Keratinocyte

The epithelial cell of the skin.

Epidermis

The outer, protective, non-vascular layer of the skin that covers the dermis.

Re-epithelialization

Regeneration of the injured epidermis in a skin wound.

Dermis

The connective tissue layer of the skin that is located below the epidermis.

Complement

A group of more than 20 serum proteins, some of which can be serially activated and participate in a cascade that results in cell lysis.

Reactive oxygen species

(ROS). Molecules or ions that are formed by the incomplete one-electron reduction of oxygen. ROS include singlet oxygen, superoxides, peroxides, hydroxyl radicals and hypochlorous acid.

PU.1

A member of the ETS family of transcription factors that is required for the development of multiple haematopoietic lineages.

Peroxiredoxins

A family of six thiol proteins that detoxify hydrogen peroxide, lipid hydroperoxides and — in the case of peroxiredoxin-6 — also peroxinitrite.

Angiogenesis

The sprouting of new vessels from pre-existing vessels.

Matrix metalloproteinases

(MMPs). Zinc-dependent endopeptidases that cleave different extracellular matrix proteins and also growth factors, chemokines, cell-surface receptors and other proteins.

Myeloid-derived suppressor cells

(MDSCs). Heterogeneous mixture of immature myeloid cells that are potent inhibitors of anti-tumour immunity. In mice they are generally defined by the markers CD11b and GR1.

Cyclooxygenases

Enzymes responsible for the formation of prostaglandins, prostacyclins and thromboxanes.

NRF2

A Leu-zipper transcription factor that activates the expression of a battery of cytoprotective genes.

Lamellipodium

A flattened projection from the cell surface, generally associated with cell migration.

Epithelial–mesenchymal transition

(EMT). A developmental programme in which epithelial cells lose cell–cell adhesion, acquire a fibroblast-like morphology and increase their motility.

Carcinoma

A cancer that arises from epithelial cells.

STAT3

A protein that transduces the signal from activated cytokine or growth-factor receptors to the nucleus.

Psoriasis

An inflammatory skin disease that is associated with keratinocyte hyperproliferation and abnormal differentiation.

SMAD3

A signalling protein that is activated by the type I transforming growth factor-β receptor, and which transduces the signal from the plasma membrane to the nucleus.

Pericyte

A mesenchymal cell that is associated with the wall of small blood vessels.

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Schäfer, M., Werner, S. Cancer as an overhealing wound: an old hypothesis revisited. Nat Rev Mol Cell Biol 9, 628–638 (2008). https://doi.org/10.1038/nrm2455

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