title: Distinct functions of epidermal and myeloid-derived VEGF-A in skin tumorigenesis mediated by HPV8.
abstract: Beta human papillomaviruses (HPV) have been suspected to be carcinogenic in nonmelanoma skin cancers (NMSC), but the basis for potential viral contributions to these cancers is poorly understood. In particular, it is unresolved how HPV-infected keratinocytes escape cell-cycle control and whether their cross-talk with immune cells is critical for tumorigenesis. In nonviral preclinical models, the angiogenic cytokine VEGF-A has been identified as a critical regulator of NMSC. In this study, we dissected the contribution of epidermal versus myeloid cell-derived VEGF-A in HPV-mediated skin cancer by interbreeding an HPV8 transgenic mouse model with a conditional disruption of VEGF-A restricted to either epidermal or myeloid cells. Although only epidermal-derived VEGF-A was essential for initiation of skin tumor development, both spontaneously and UV-light triggered, both epidermal and myeloid cell-derived VEGF-A contributed to regeneration-induced tumorigenesis upon HPV8 overexpression, partly not only through a paracrine effect on endothelial cells, but also most probably through an additional autocrine effect on epidermal cells. Our findings offer new mechanistic insights into distinct functions of epidermal versus myeloid cell-derived VEGF-A during HPV-mediated tumorigenesis, with possible implications for preventing this disease.
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Lucas
authors.affiliation: Institute of Virology, University of Cologne, Cologne, Germany.
authors.forename: Gian P
authors.initials: GP
authors.lastname: Marcuzzi
authors.affiliation: Institute of Virology, University of Cologne, Cologne, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Pfister
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. sabine.eming@uni-koeln.de.
authors.forename: Sabine A
authors.initials: SA
authors.lastname: Eming
mesh_terms: D000818:Animals; D052686:Betapapillomavirus / Q000502:physiology*; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000821:virology; D039942:Neuropilin-1 / Q000096:biosynthesis; D012878:Skin Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D039942:Neuropilin-1; D040281:Vascular Endothelial Growth Factor Receptor-1