title: Elevated VEGF-D Modulates Tumor Inflammation and Reduces the Growth of Carcinogen-Induced Skin Tumors.
abstract: Vascular endothelial growth factor D (VEGF-D) promotes the lymph node metastasis of cancer by inducing the growth of lymphatic vasculature, but its specific roles in tumorigenesis have not been elucidated. We monitored the effects of VEGF-D in cutaneous squamous cell carcinoma (cSCC) by subjecting transgenic mice overexpressing VEGF-D in the skin (K14-mVEGF-D) and VEGF-D knockout mice to a chemical skin carcinogenesis protocol involving 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate treatments. In K14-mVEGF-D mice, tumor lymphangiogenesis was significantly increased and the frequency of lymph node metastasis was elevated in comparison with controls. Most notably, the papillomas regressed more often in K14-mVEGF-D mice than in littermate controls, resulting in a delay in tumor incidence and a remarkable reduction in the total tumor number. Skin tumor growth and metastasis were not obviously affected in the absence of VEGF-D; however, the knockout mice showed a trend for reduced lymphangiogenesis in skin tumors and in the untreated skin. Interestingly, K14-mVEGF-D mice showed an altered immune response in skin tumors. This consisted of the reduced accumulation of macrophages, mast cells, and CD4(+) T-cells and an increase of cytotoxic CD8(+) T-cells. Cytokine profiling by flow cytometry and quantitative real time PCR revealed that elevated VEGF-D expression results in an attenuated Th2 response and promotes M1/Th1 and Th17 polarization in the early stage of skin carcinogenesis, leading to an anti-tumoral immune environment and the regression of primary tumors. Our data suggest that VEGF-D may be beneficial in early-stage tumors since it suppresses the pro-tumorigenic inflammation, while at later stages VEGF-D-induced tumor lymphatics provide a route for metastasis.
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, FIN-90014, University of Oulu, Oulu, Finland.
authors.forename: Hanne-Kaisa
authors.initials: HK
authors.lastname: Honkanen
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, FIN-90014, University of Oulu, Oulu, Finland.
authors.forename: Valerio
authors.initials: V
authors.lastname: Izzi
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, FIN-90014, University of Oulu, Oulu, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Petäistö
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, FIN-00290, Helsinki, Finland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Holopainen
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, FIN-90014, University of Oulu, Oulu, Finland; Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, FIN-00290, Helsinki, Finland.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Harjunen
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, FIN-90014, University of Oulu, Oulu, Finland.
authors.forename: Taina
authors.initials: T
authors.lastname: Pihlajaniemi
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, FIN-00290, Helsinki, Finland.
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, FIN-90014, University of Oulu, Oulu, Finland. Electronic address: ritva.heljasvaara@oulu.fi.
authors.forename: Ritva
authors.initials: R
authors.lastname: Heljasvaara
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002273:Carcinogens / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000473:pathology*; D005434:Flow Cytometry; D008198:Lymph Nodes / Q000098:blood supply*; D042583:Lymphangiogenesis / Q000187:drug effects*; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000473:pathology; D018655:Lymphocyte Count; D008264:Macrophages / Q000276:immunology; D008407:Mast Cells / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D042643:Vascular Endothelial Growth Factor D; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate