Cancer as an overhealing wound: an old hypothesis revisited

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. The hypothesis that “tumor production is a possible overhealing” has recently been verified in several studies. In vivo analysis of genes that are involved in tissue repair combined with gene-expression analysis in wounds and tumours have highlighted remarkable similarities between wound healing and cancer. 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 invol