title: Autocrine and paracrine roles of VEGF/VEGFR-2 and VEGF-C/VEGFR-3 signaling in angiosarcomas of the scalp and face.
abstract: Angiosarcoma of the skin is an extremely rare malignant tumor of vascular origin that usually arises in the scalp and face of elderly persons. To clarify its characteristic features and cell cycle kinetics, we quantitatively evaluated the expression of cell cycle-related molecules and vascular endothelial growth factors using immunohistochemical staining, for comparison with 2 benign vascular tumors of the skin, the capillary hemangioma and the cavernous hemangioma. Cell proliferation, determined with reference to the Ki-67 labeling index, was highest in angiosarcomas and lowest in cavernous hemangiomas (angiosarcomas versus capillary hemangioma, P = .014; capillary hemangioma versus cavernous hemangiomas, P = 1.4 x 10(-4)). Similar differences were also found in cyclin A, cyclin E, and p21(Waf1) expression. Expressions of cyclin D1 and p16(INK4A) were also significantly higher in angiosarcoma than in cavernous hemangioma. Expressions of these 5 proteins showed significant positive correlations with Ki-67 labeling indices (Spearman rho = 0.91-0.43). Expression levels of vascular endothelial growth factor and its receptor, VEGFR-2, were highest in angiosarcomas. VEGF-C expression in angiosarcomas was significantly higher than in cavernous hemangiomas, and its receptor VEGFR-3 expression was highest in angiosarcomas. Furthermore, significant positive correlations of these protein expression with Ki-67 labeling indices were noted (Spearman rho = 0.88-0.40). Among them, VEGFR-3 showed the highest correlation coefficient. These results suggest that not only VEGFR-2-mediated signal but also VEGFR-3-mediated signal may contribute to proliferation of vascular tumor cells as autocrine and paracrine signaling factors.
authors.affiliation: Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa 228-8555, Japan. tokuyama@med.kitasato-u.ac.jp
authors.forename: Wataru
authors.initials: W
authors.lastname: Tokuyama
authors.forename: Tetuo
authors.initials: T
authors.lastname: Mikami
authors.forename: Mikio
authors.initials: M
authors.lastname: Masuzawa
authors.forename: Isao
authors.initials: I
authors.lastname: Okayasu
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000502:physiology; D019898:Autocrine Communication / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation; D019925:Cyclin A / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D005145:Face / Q000473:pathology; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006394:Hemangiosarcoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019899:Paracrine Communication / Q000502:physiology; D012535:Scalp / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*
chemical_list: D019925:Cyclin A; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3