title: Neonatal UVB exposure accelerates melanoma growth and enhances distant metastases in Hgf-Cdk4(R24C) C57BL/6 mice.
abstract: Genetically engineered mouse models offer new opportunities to experimentally investigate the impact of UV on melanoma pathogenesis. Here we irradiated a cohort of newborn 15 Hgf-Cdk4(R24C) mice on the pigmented C57BL/6 background with one erythemogenic dose of 6 kJ/m(2) UVB and compared the development of nevi and melanoma with a cohort of 30 untreated Hgf-Cdk4(R24C) mice. Neonatal UVB exposure decreased the latency and accelerated the growth of primary melanomas resulting in a significantly decreased time from melanoma onset to melanoma-related death (61 days vs. 96 days). Interestingly, we did not observe differences in the development of melanocytic nevi. Histopathological investigations revealed that UVB irradiation shifted the spectrum of melanomas toward a more aggressive phenotype with increased tumor cell proliferation, invasive growth and enhanced angiogenesis. Accordingly, we observed distal melanoma metastases in the lungs more frequently in the UV-irradiated than in the untreated cohort of Hgf-Cdk4(R24C) mice (73% vs. 47%). UVB-induced melanomas only contained very few infiltrating immune cells and expressed very low levels of proinflammatory chemokines. Taken together, our results demonstrate that neonatal UVB exposure promoted the early appearance of rapidly enlarging primary melanomas in Hgf-Cdk4(R24C) C57BL/6 mice which showed enhanced invasive and metastatic behaviour without a persistent tumor-associated inflammatory response. The preferential impact of UVB irradiation on the progression of melanoma without an effect on the development of nevi supports the hypothesis that the molecular targets of UVB are involved in bypassing the proliferative arrest of transformed melanocytes without alerting a cellular immune response.
authors.affiliation: Department of Dermatology and Allergy, Laboratory of Experimental Dermatology, University of Bonn, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Gaffal
authors.forename: Jennifer
authors.initials: J
authors.lastname: Landsberg
authors.forename: Tobias
authors.initials: T
authors.lastname: Bald
authors.forename: Alexander
authors.initials: A
authors.lastname: Sporleder
authors.forename: Judith
authors.initials: J
authors.lastname: Kohlmeyer
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D004781:Environmental Exposure / Q000009:adverse effects*; D005260:Female; D018095:Germ-Line Mutation; D017228:Hepatocyte Growth Factor / Q000235:genetics; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D008546:Melanoma, Experimental / Q000473:pathology* / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D009381:Neoplasms, Radiation-Induced / Q000473:pathology* / Q000556:secondary; D009506:Nevus / Q000473:pathology; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: C553307:HGF protein, mouse; D017228:Hepatocyte Growth Factor; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4