The risk of developing malignant melanoma as a result of sunburn is well established: ultraviolet (UV) radiation produces DNA adducts that can lead to DNA mutations in melanocytes that initiate melanoma development. However, independent of its mutagenic effects, UV radiation can induce an inflammatory response in exposed skin that can promote angiotropism (the interaction of melanoma cells with blood vessels) and metastasis of primary melanomas.

Credit: Lara Crow/NPG

Using a genetically engineered melanoma-prone mouse model, Thomas Tüting and colleagues exposed mouse skin to two doses of UV radiation to induce skin reddening (erythema). The exposed skin showed an increase in the recruitment of neutrophils, monocytes and macrophages, and after 6 weeks of UV exposure twice-weekly, melanocytes were present in the upper dermis. Importantly, UV exposure in mice with established melanomas (induced by chemical treatment) did not affect the growth of the primary melanoma but did increase the incidence of lung metastases. Moreover, in four of 20 UV-treated mice, melanoma cells in the primary tumour were clearly in contact with the external surface of local blood vessels.

depletion of neutrophils but not of macrophages also reduced metastasis and angiotropic behaviour

Further experiments, both in vitro and in vivo, showed that the recruitment of neutrophils into the primary tumour was essential for both the angiotropic effects and the pro-metastatic effects of UV radiation. Neutrophil recruitment was initiated through the release of high mobility group box 1 (HMGB1) protein from UV-damaged epidermal keratinocytes and its activation of the Toll-like receptor 4 (TLR4) signalling pathway in local myeloid immune cells. Inhibitors of either HMGB1 or TLR4, or genetic knockout of Tlr4, suppressed metastasis and prevented the migration of melanoma cells towards endothelial cells. Moreover, depletion of neutrophils but not of macrophages also reduced metastasis and angiotropic behaviour in vivo in UV-irradiated mice.

An analysis of patients with melanoma showed that ulcerated melanomas with neutrophils present in large numbers had evidence of angiotropism and metastasis to sentinal lymph nodes.

These findings indicate that the activation of an innate inflammatory response by UV radiation contributes to the metastatic behaviour of melanoma cells.