Editors' ChoiceCancer

Neutrophils mediate surgery-induced cancer formation

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Sci. Signal.  15 Sep 2015:
Vol. 8, Issue 394, pp. ec261
DOI: 10.1126/scisignal.aad4082

Both inflammation and wounding are associated with the development and recurrence of cancers (see Wculek and Malanchi). This has potential clinical implications for patients who undergo biopsies or tumor resection surgeries. Antonio et al. used a zebrafish model to investigate the effects of wounding on nearby precancerous cells. In this model, transgenic fish expressed the fluorescent protein dsRed in neutrophils and RasG12VeGFP, an oncogenic form of the small GTPase Ras fused to green fluorescent protein, in melanocytes. Compared with unwounded controls, repeated laser wounding of the tail fin promoted the subsequent development of melanomas specifically on the tail fin. There were few neutrophils near these tumors, but partial surgical removal of these melanomas caused neutrophils to accumulate at the remaining tumor tissue. Live imaging of wounds made on the flank epidermis revealed that neutrophils were recruited to wound sites, as expected, but then migrated away from the wounds to nearby RasG12eGFP-expressing (preneoplastic) cells. In contrast, neutrophils remained at the wound site when there were no preneoplastic cells nearby. Although some neutrophils associated with preneoplastic cells in unwounded fish, many more were present at the preneoplastic cells in wounded fish. The recruitment of neutrophils correlated with increased proliferation of preneoplastic cells, and interfering with immune cell differentiation reduced the proliferation of preneoplastic cells near wound sites. Neutrophils and macrophages release prostaglandin E2 (PGE2), which stimulates the proliferation of transformed cells. When an inhibitor of the PGE2 biosynthetic enzyme Cox-2 was added to the water, preneoplastic cells near wound sites exhibited the same amount of proliferation as preneoplastic cells in unwounded control larvae that had not been treated with the Cox-2 inhibitor. Addition of synthetic PGE2 to the wound site stimulated preneoplastic cell proliferation in immune cell–depleted fish. These results do not exclude the involvement of additional neutrophil-secreted trophic factors in stimulating tumor formation, but they do suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit PGE2 synthesis, such as aspirin, administered before and after tumor resection surgery, might help reduce the chances of tumor recurrence due to stimulation of preneoplastic cells near the wound site.

N. Antonio, M. L. Bønnelykke-Behrndtz, L. Chloe Ward, J. Collin, I. J. Christensen, T. Steiniche, H. Schmidt, Y. Feng, P. Martin, The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer. EMBO J. 34, 2219–2236 (2015). [PubMed]

S. K. Wculek, I. Malanchi, Neutrophils fan cancer’s flames. EMBO J. 34, 2211–2212 (2015). [PubMed]