title: The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer.
abstract: There is a long-standing association between wound healing and cancer, with cancer often described as a "wound that does not heal". However, little is known about how wounding, such as following surgery, biopsy collection or ulceration, might impact on cancer progression. Here, we use a translucent zebrafish larval model of Ras(G12V)-driven neoplasia to image the interactions between inflammatory cells drawn to a wound, and to adjacent pre-neoplastic cells. We show that neutrophils are rapidly diverted from a wound to pre-neoplastic cells and these interactions lead to increased proliferation of the pre-neoplastic cells. One of the wound-inflammation-induced trophic signals is prostaglandin E2 (PGE2). In an adult model of chronic wounding in zebrafish, we show that repeated wounding with subsequent inflammation leads to a greater incidence of local melanoma formation. Our zebrafish studies led us to investigate the innate immune cell associations in ulcerated melanomas in human patients. We find a strong correlation between neutrophil presence at sites of melanoma ulceration and cell proliferation at these sites, which is associated with poor prognostic outcome.
authors.affiliation: School of Biochemistry, University of Bristol, Bristol, UK.
authors.forename: Nicole
authors.initials: N
authors.lastname: Antonio
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University, Aarhus, Denmark Department of Plastic and Reconstructive Surgery, Aarhus University, Aarhus, Denmark.
authors.forename: Marie Louise
authors.initials: ML
authors.lastname: Bønnelykke-Behrndtz
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
authors.forename: Laura Chloe
authors.initials: LC
authors.lastname: Ward
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
authors.forename: John
authors.initials: J
authors.lastname: Collin
authors.affiliation: Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ib Jarle
authors.initials: IJ
authors.lastname: Christensen
authors.affiliation: Department of Pathology, Aarhus University, Aarhus, Denmark Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Steiniche
authors.affiliation: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark Department of Oncology, Aarhus University, Aarhus, Denmark henrschm@rm.dk yi.feng@ed.ac.uk paul.martin@bristol.ac.uk.
authors.forename: Henrik
authors.initials: H
authors.lastname: Schmidt
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK henrschm@rm.dk yi.feng@ed.ac.uk paul.martin@bristol.ac.uk.
authors.forename: Yi
authors.initials: Y
authors.lastname: Feng
authors.affiliation: School of Biochemistry, University of Bristol, Bristol, UK School of Physiology and Pharmacology, University of Bristol, Bristol, UK School of Medicine, University of Cardiff, Cardiff, UK henrschm@rm.dk yi.feng@ed.ac.uk paul.martin@bristol.ac.uk.
authors.forename: Paul
authors.initials: P
authors.lastname: Martin
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008545:Melanoma / Q000235:genetics / Q000276:immunology*; D020125:Mutation, Missense; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D011230:Precancerous Conditions / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D014947:Wounds and Injuries / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015027:Zebrafish / Q000235:genetics / Q000276:immunology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000276:immunology; D018631:ras Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D029961:Zebrafish Proteins; D018631:ras Proteins
keywords: cancer inflammation; cancer surgery; live imaging; melanoma; wound healing