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Ultraviolet (UV) radiation from the sun is known to induce DNA muta- tions in melanocytes that can result in the development of melanoma. However, the main cause of death in patients with melanoma is tumour metastasis to the lungs; so, what causes the melanoma cells to spread? Reporting in Nature, Bald et al. show that, in addition to inducing mutations, repeated UV irradiation of developing melanoma tumours drives an inflammatory response that promotes tumour metastasis to the lungs. To examine the tumour- promoting effects of UV radiation on melanomas independently of its tumour-initiating effects, tumours were first induced by administering the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) to the back skin of geneti- cally engineered mice that develop invasive and metastatic melanomas (HGF-CDK4(R24C) mice), and then these mice were exposed to UV radia- tion. UV irradiation did not affect the incidence or growth of primary melanomas, but UV-irradiated mice had increased growth of tumour cells along dermal blood vessels and increased lung metastases compared with control mice. UV irradiation of the skin is asso- ciated with an inflammatory infiltrate that consists mainly of neutrophils. This skin inflammation was shown to be dependent on the release of the nuclear protein HMGB1 from dam- aged keratinocytes, which induced a Toll-like receptor 4 (TLR4)–MYD88- dependent feedforward inflam- matory pathway, predominantly in neutrophils. To determine whether the UV radiation-induced neutrophilic inflammatory response influenced the angiotropism and metastatic dissemination of mela- noma cells, the authors transplanted melanoma tumours into wild-type or Tlr4 –/– mice, which were then exposed to UV radiation. UV irradiation induced an increase in skin melanoma metastasis in wild- type mice but not in Tlr4 –/– mice. Furthermore, antibody-mediated depletion of neutrophils or inhibition of extracellular HMGB1 abolished the UV radiation-dependent increase in angiotropism and lung metastasis that was observed in wild-type mice. Next, the authors assessed the effects of inflammation on melanoma–endothelial cell inter- actions in vitro. They found that tumour necrosis factor (TNF), which is secreted by activated neutrophils, enhances the migration of both mouse and human melanoma cells towards endothelial cells. Furthermore, both mouse and human melanoma cells were shown to closely associate with blood vessel endothelial cells in inflamed mouse ear tissue explants from UV-irradiated mice. Taken together, this study shows that exposure to UV radiation induces the release of HMGB1 from damaged keratinocytes, resulting in TLR4–MYD88-driven neutrophilic inflammation. This inflammatory response, mediated at least in part by TNF, stimulates melanoma cells to migrate towards endothelial cells and metastasize to the lungs. Olive Leavy TUMOUR IMMUNOLOGY Inflaming tumour spread ORIGINAL RESEARCH PAPER Bald, T. et al. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature 507, 109–113 (2014) inhibition of extracellular HMGB1 abolished the UV radiation- dependent increase in angiotropism and lung metastasis Paul Glendell/Alamy RESEARCH HIGHLIGHTS NATURE REVIEWS | IMMUNOLOGY VOLUME 14 | APRIL 2014 © 2014 Macmillan Publishers Limited. All rights reserved
