Live imaging of the earliest inflammatory response to transformed cells within tissues – studies in zebrafish


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Paul Martin
University of Bristol, UK

Abstract

There are numerous cell and tissue migrations that underpin the morphogenetic and organ building phases of embryogenesis and it seems that when adult tissues heal a wound, much of the same motility machinery is reactivated, and the same is true at sites of cancer growth also. Besides epithelial sheet movements and fibroblast migration and contraction, adult tissue repair invariably triggers a wound inflammatory response which we believe leads to pathological collagen deposition at the wound site and ultimately to fibrosis and scarring. Recently we have begun investigating parallels between the inflammatory response to a wound and to cancer. Just as for wounds, we find H2O2 to be the key attractant enabling immune cells to sense early clones of transformed cells before they progress to cancers. Subsequently, our movies reveal neutrophils "nibbling" at the transformed cells, while macrophages phagocytose whole living transformed cells. However, despite this feasting of immune cells, we find that clones of transformed cells deprived of immune cells proliferate at a slower rate suggesting that trophic signals are delivered to the transformed cells by immune cells. We now find that exogenous addition of the stable prostaglandin, dmPGE2, can in part rescue growth of transformed cells after transient depletion of immune cells; moreover, morpholino knockdown of the rate-limiting prostaglandin synthesizing enzyme, mPGES, mimics loss of leukocytes in reducing transformed cell number suggesting that prostaglandins might be a component of the trophic signal. This observation may, in part, explain recent studies showing how low dose aspirin can stave off the onset of gut and other cancers. Since surgery is one of the most effective means of treating cancer we have begun to use larval and adult zebrafish to model cancer surgery, in particular investigating how the wound inflammatory response impacts on immune cell recruitment to nearby transformed cells and what might be the downstream consequences of this.

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