Exposure to ultraviolet radiation (UVR) represents the
principal etiologic factor in the development of melanoma, the most deadly form
of skin cancer with a rising incidence. Recent studies firmly established the
ability of UVR to cause tumour-initiating genomic DNA alterations in
melanocytes and to activate the innate immune system in the microenvironment.
UVR-induced mutations promote transformation and at the same time give rise to
neo-antigens that can be recognised by T-cells. Sun-burning UVR doses
additionally induce inflammatory responses in the skin which suppress cellular
immunity and promote the reactive proliferation and migration of UV-damaged
melanocytes. Using the UV-sensitive Hgf-Cdk4 melanoma mouse model we could
experimentally show that a TLR4-driven neutrophilic inflammatory response
initiated by UV-damaged epidermal keratinocytes enhances the expansion of
melanoma cells along abluminal blood vessel surfaces and increases the number
of lung metastases (Bald et al. Nature 2014). Our observations support a
tumour-promoting role of neutrophils in the perivascular niche, consistent with
clinical findings in melanoma patients. Future studies will have to address how
the divergent effects of UVR-induced genomic alterations and UVR-induced
inflammatory responses shape the complex reciprocal and dynamic interactions
between melanoma, endothelial and immune cells during metastatic progression
and in response to (immuno-)therapeutic intervention.