UV-induced inflammation promotes angiotropism and metastasis in melanoma.
Major finding: UV-induced inflammation promotes angiotropism and metastasis in melanoma.
Mechanism: UV exposure induces melanoma cell motility via a TLR4–MYD88–HMGB1-dependent neutrophilic response.
Impact: Inhibition of motility cues or inflammation may be an effective strategy to block melanoma progression.
Ultraviolet (UV) radiation exposure is known to cause melanoma through the generation of oncogenic DNA mutations in melanocytes. UV irradiation has also been shown to trigger an inflammatory response that may be linked to reactive melanocyte proliferation, prompting Bald and colleagues to determine whether UV-mediated effects on the tumor microenvironment contribute to melanoma progression. Consistent with previous results, transient UV exposure in a genetically engineered melanoma mouse model stimulated a neutrophilic inflammatory response and melanocyte accumulation within the upper dermis. To study the role of UV-associated inflammation in tumor progression independent of tumor initiation, the authors exposed existing carcinogen-induced melanomas to UV radiation and observed no effect on tumor incidence, multiplicity, or growth kinetics compared with unirradiated mice. However, they noted enhanced frequency of lung metastases and melanoma cell expansion along vascular endothelial cell surfaces, a phenomenon known as angiotropism. Genetic deletion of various components of innate immune response pathways revealed that Tlr4 and Myd88 were required for UV-mediated neutrophil activation and angiotropism. Interestingly, UV exposure of keratinocytes also led to the cytosolic translocation and release of HMGB1, which has TLR4-dependent cytokine activity. In support of a role for an HMGB1–TLR4–MYD88 axis in inflammatory-induced tumor progression, small molecule inhibitors of extracellular HMGB1 or TLR4 reversed angiotropism and lung metastasis in UV-treated mice and melanoma skin transplant models. Extending on these findings, the authors showed that pre-incubation of mouse or human melanoma cells with the cytokine TNF, which is secreted by activated neutrophils, enhanced their ability to migrate toward and upon endothelial cell surfaces, including vascular extracellular matrix components isolated from UV-irradiated mice. Together, these results suggest that the inflammatory response generated by UV irradiation drives melanoma progression by promoting angiotropism and potentially highlight new therapeutic targets that could be exploited by selectively inhibiting specific cytokine-driven activities.