Intermittent intense ultraviolet (UV) exposure represents an importantaetiological factor in the development of malignant melanoma1.The ability ofUVradiation to cause tumour-initiatingDNAmutationsin melanocytes is now firmly established2, but how the microenvironmentaleffects ofUVradiation3,4 influencemelanomapathogenesisis not fully understood. Here we report that repetitive UV exposureof primary cutaneous melanomas in a genetically engineeredmousemodel5 promotesmetastatic progression, independent of its tumourinitiatingeffects.UVirradiation enhanced the expansion of tumourcells along abluminal blood vessel surfaces and increased the numberof lung metastases. This effect depended on the recruitment andactivation of neutrophils, initiated by the release of high mobilitygroup box 1 (HMGB1) fromUV-damaged epidermal keratinocytesand driven by Toll-like receptor 4 (TLR4). The UV-induced neutrophilicinflammatory response stimulated angiogenesis and promotedthe ability of melanoma cells to migrate towards endothelial cellsand use selective motility cues on their surfaces.Our results not onlyreveal how UV irradiation of epidermal keratinocytes is sensed bythe innate immune system, but also show that the resulting inflammatoryresponse catalyses reciprocalmelanoma–endothelial cell interactionsleading to perivascular invasion, a phenomenon originallydescribed as angiotropism in human melanomas by histopathologists6.Angiotropism represents a hitherto underappreciated mechanismof metastasis7 that also increases the likelihood of intravasationand haematogenous dissemination. Consistent with our findings,ulcerated primary human melanomas with abundant neutrophilsand reactive angiogenesis frequently show angiotropism and a highrisk for metastases. Our work indicates that targeting the inflammation-induced phenotypic plasticity of melanoma cells and theirassociation with endothelial cells represent rational strategies tospecifically interfere with metastatic progression.
Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma
BIANCHI , MARCO EMILIO;
2014-01-01
Abstract
Intermittent intense ultraviolet (UV) exposure represents an importantaetiological factor in the development of malignant melanoma1.The ability ofUVradiation to cause tumour-initiatingDNAmutationsin melanocytes is now firmly established2, but how the microenvironmentaleffects ofUVradiation3,4 influencemelanomapathogenesisis not fully understood. Here we report that repetitive UV exposureof primary cutaneous melanomas in a genetically engineeredmousemodel5 promotesmetastatic progression, independent of its tumourinitiatingeffects.UVirradiation enhanced the expansion of tumourcells along abluminal blood vessel surfaces and increased the numberof lung metastases. This effect depended on the recruitment andactivation of neutrophils, initiated by the release of high mobilitygroup box 1 (HMGB1) fromUV-damaged epidermal keratinocytesand driven by Toll-like receptor 4 (TLR4). The UV-induced neutrophilicinflammatory response stimulated angiogenesis and promotedthe ability of melanoma cells to migrate towards endothelial cellsand use selective motility cues on their surfaces.Our results not onlyreveal how UV irradiation of epidermal keratinocytes is sensed bythe innate immune system, but also show that the resulting inflammatoryresponse catalyses reciprocalmelanoma–endothelial cell interactionsleading to perivascular invasion, a phenomenon originallydescribed as angiotropism in human melanomas by histopathologists6.Angiotropism represents a hitherto underappreciated mechanismof metastasis7 that also increases the likelihood of intravasationand haematogenous dissemination. Consistent with our findings,ulcerated primary human melanomas with abundant neutrophilsand reactive angiogenesis frequently show angiotropism and a highrisk for metastases. Our work indicates that targeting the inflammation-induced phenotypic plasticity of melanoma cells and theirassociation with endothelial cells represent rational strategies tospecifically interfere with metastatic progression.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
