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The Impact of Wound Inflammation on Cancer Progression: Studies in Fish and Patients

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Perioperative Inflammation as Triggering Origin of Metastasis Development

Abstract

There is a long history of literature suggesting parallels between wound healing and cancer growth, and similarly, much anecdotal evidence that tissue damage may impact on the growth and progression of cancers. In our recent studies we have investigated the association between wound-induced inflammation, as might be triggered post biopsy or surgery, and the subsequent proliferation and migratory tumour cell characteristics in zebrafish and human ulcerated melanoma. The translucent zebrafish allowed us to live visualise the behaviour of inflammatory cells around a wound, which we made in the vicinity of clones of early pre-neoplastic cells. These studies showed that neutrophils and macrophages are sequentially recruited to sites of tissue wounding, and subsequently distracted from the wound by competing attractants from the nearby pre-neoplastic cells. The interaction between inflammatory cells, largely neutrophils, and pre-neoplastic cells directly led to increased proliferation of the pre-neoplastic cells, through release of trophic/growth factors including prostaglandin (PGE2). Complementary clinical data showed that the density of infiltrating neutrophils correlates with increasing size of wound, in this instance extent of ulceration, and with tumour-cell proliferation in human melanoma, whilst there was no correlation between infiltrating macrophages and proliferation or prognosis. In addition to the demonstrated inflammation induced tumour-cell proliferation we showed an independent prognostic link between neutrophil influx and melanoma specific survival, supporting the hypothesis that wound-induced inflammation may be detrimental to patient survival. Reactivation of developmental and migratory cell behaviours of melanocytes may be an essential link between inflammation and tumour progression, equivalent to what is conventionally described as epithelial to mesenchymal transition (EMT) in epithelial-derived tumours. In what has been found from zebrafish studies, both melanoblasts and mature melanocytes migrate towards sites of tissue wounding, under the influence of innate immune cells. In ulcerated melanomas, the infiltration of neutrophils in ulcerated areas is associated with migratory tumour cell characteristics such as spindle shaped morphology and loss of e-cadherin expression and extravascular migratory metastasis (angiotropism), linking inflammation to a pro-migratory microenvironment.

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Author information

Authors and Affiliations

  1. Department of Plastic and Breast Surgery, Aarhus University Hospital, Nørrebrogade 44, 8000, Aarhus, Denmark

    Marie Louise Bønnelykke-Behrndtz M.D., Ph.D.

  2. Department of Oncology, Aarhus University Hospital, Aarhus, Denmark

    Henrik Schmidt M.D., Dr.Med.

  3. Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

    Henrik Schmidt M.D., Dr.Med.

  4. MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK

    Yi Feng

  5. School of Biochemistry, University of Bristol, Bristol, UK

    Paul Martin

  6. School of Physiology and Pharmacology, University of Bristol, Bristol, UK

    Paul Martin

  7. School of Medicine, University of Cardiff, Cardiff, UK

    Paul Martin

Authors
  1. Marie Louise Bønnelykke-Behrndtz M.D., Ph.D.
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  2. Henrik Schmidt M.D., Dr.Med.
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  3. Yi Feng
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  4. Paul Martin
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Corresponding author

Correspondence to Marie Louise Bønnelykke-Behrndtz M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Harvard TH Chan School of Public Health, Boston, Massachusetts, USA

    Michael W. Retsky

  2. Istituto Nazionale Tumori di Milano, Fondazione IRCCS, Milan, Italy

    Romano Demicheli

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Bønnelykke-Behrndtz, M.L., Schmidt, H., Feng, Y., Martin, P. (2017). The Impact of Wound Inflammation on Cancer Progression: Studies in Fish and Patients. In: Retsky, M., Demicheli, R. (eds) Perioperative Inflammation as Triggering Origin of Metastasis Development. Springer, Cham. https://doi.org/10.1007/978-3-319-57943-6_8

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