Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma

Bald T, Quast T, Landsberg J, Rogava M, Glodde N, Lopez-Ramos D, Kohlmeyer J, Riesenberg S, van den Boorn-Konijnenberg D, Hömig-Hölzel C, Reuten R, Schadow B, Weighardt H, Wenzel D, Helfrich I,Schadendorf D, Bloch W, Bianchi ME, Lugassy C, Barnhill RL, Koch M, Fleischmann BK, Förster I, Kastenmüller W, Kolanus W, Hölzel M, Gaffal E, Tüting T

Nature 507: 109-13, 2014

Speaker: Cheng-Hao Chen (陳正豪)                            Time: 13:00~14:00, Nov 12, 2014

Commentator: Dr. Yao Chang (張堯 老師)            Place: Room 601

Abstract:

    Ultraviolet (UV) radiation is known to induce melanoma through DNA damage of melanocyte. UV radiation also triggers an inflammatory response which could be linked to melanoma cell proliferation and migration. However, the microenvironmental effects and inflammatory response of UV radiation influence in melanoma progression is unclear. To study the mechanism of UV-induced inflammation in melanoma progression without its tumor initiating effects, authors initiated a carcinogen-induced melanoma model by UV radiation in hepatocyte growth factor and cyclin-dependent kinase 4 (HGF-CDK4) mutation mice. Results have showed that UV exposure did not affect growth kinetics of melanoma but rather trigger lung metastasis through migrating along with vascular endothelial cell surfaces, a phenomenon known as angiotropism. Genetic deletion of several molecules of innate immune pathways determined that Myd88-dependant Toll-like receptor4 (TLR4)-signaling is involved in UV-regulated neutrophilic inflammatory response and angiotropism. Interestingly, the authors observed that UV-damaged keratinocytes released high mobility group box 1 (HMGB1) protein, which has TLR4-dependent inflammatory cytokine activities. To further investigate the role of HMGB1-TLR4-Myd88 mediating inflammatory response in tumor progression, specific inhibitors of HMGB1 and TLR4 signaling were used. Results determined that inhibiting of HMGB1 and TLR4 signaling reversed angiotropism-associated lung metastasis in UV-treated melanoma bearing mie. In addition, the authors also showed that TNF, which is secreted by activated neutrophils, enhanced the ability of melanoma to migrate towards and upon endothelial cell surfaces in inflamed ear tissue explants from UV-irradiated mice. Taken together, UV radiation exposure induces angiotopism and metastasis of melanoma via a HMGB1–TLR4–Myd88-mediated neutrophilic inflammatory response.

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