title: Vascular endothelial growth factor-a promotes peritumoral lymphangiogenesis and lymphatic metastasis.
abstract: Metastases are commonly found in the lymphatic system. The molecular mechanism of lymphatic metastasis is, however, poorly understood. Here we report that vascular endothelial growth factor (VEGF)-A stimulated lymphangiogenesis in vivo and that overexpression of VEGF-A in murine T241 fibrosarcomas induced the growth of peritumoral lymphatic vessels, which occasionally penetrated into the tumor tissue. As a result of peritumoral lymphangiogenesis, metastases in lymph nodes of mice were detected. VEGF-A-overexpressing tumors contained high numbers of infiltrating inflammatory cells such as macrophages, which are known to express VEGF receptor (VEGFR)-1. It seemed that in the mouse cornea, VEGF-A stimulated lymphangiogenesis through a VEGF-C/-D/VEGFR-3-independent pathway as a VEGFR-3 antagonist selectively inhibited VEGF-C-induced, but not VEGF-A-induced, lymphangiogenesis. Our data show that VEGF-A contributes to lymphatic mestastasis. Thus, blockage of VEGF-A-induced lymphangiogenesis may provide a novel approach for prevention and treatment of lymphatic metastasis.
authors.affiliation: Laboratory of Angiogenesis Research, Microbiology and Tumor Biology Center, David Geffen School of Medicine at University of California, Los Angeles, CA, USA.
authors.forename: Meit A
authors.initials: MA
authors.lastname: Björndahl
authors.forename: Renhai
authors.initials: R
authors.lastname: Cao
authors.forename: Jeremy B
authors.initials: JB
authors.lastname: Burton
authors.forename: Ebba
authors.initials: E
authors.lastname: Brakenhielm
authors.forename: Piotr
authors.initials: P
authors.lastname: Religa
authors.forename: Dagmar
authors.initials: D
authors.lastname: Galter
authors.forename: Lily
authors.initials: L
authors.lastname: Wu
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016510:Corneal Neovascularization; D042783:Endothelial Cells; D005354:Fibrosarcoma / Q000098:blood supply / Q000473:pathology; D006801:Humans; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis / Q000473:pathology*; D042601:Lymphatic Vessels; D051379:Mice; D013552:Swine; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D000906:Antibodies; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040321:Vascular Endothelial Growth Factor Receptor-3