The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer.
Bottom Line: 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.
Affiliation: School of Biochemistry, University of Bristol, Bristol, UK.Show MeSH
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Mentions: To determine what effect this increased inflammation might have on pre-neoplastic cell proliferation, we counted the number of pre-neoplastic cells 3 days post-wounding in a series of domains extending up to 250 μm away from the wound centre and corresponding approximately to the region of increased inflammation. We see a significant increase in pre-neoplastic cell number in comparison with equivalent flank regions of unwounded larvae (Fig3A, B and E) in bands extending 50–150 μm and 150–250 μm from the wound centre (Supplementary Fig S4), and this is corroborated by a significant increase in EdU-positive pre-neoplastic cells in 2-days post-wounding larvae (Fig3C and D, Supplementary Fig S5A), where the thymidine analogue EdU has been incorporated into the DNA of proliferating cells. This effect is local, rather than systemic, because we see no significant increase in numbers of Ras+ cells in the epithelium beyond 250 μm from the wound centre (Supplementary Fig S4), or overlying the yolk or in the head (Supplementary Fig S5). Moreover, only wounds that are sufficiently large to trigger a wound inflammatory response over 48 h appear to trigger a pre-neoplastic proliferative response; small wounds show no increase above background, unwounded, levels (Supplementary Fig S5C). To further test whether this increase is a consequence of the wound inflammatory response, we transiently delayed innate immune cell development by injection of PU.1 and GCSF morpholinos at the one-cell-stage embryo. This led to an almost complete depletion of neutrophils and macrophages until 4 days post-fertilisation (dpf) (Feng et al, 2012) and, as a consequence, we observed a significant decrease in pre-neoplastic cell numbers, suggesting reduced proliferation both in unwounded control fish, as previously reported (Feng et al, 2010), and in 2-days post-wounded fish, by comparison with fish with a normal wound inflammatory response (Fig3L).
Affiliation: School of Biochemistry, University of Bristol, Bristol, UK.