Vascular endothelial growth factor-a promotes peritumoral lymphangiogenesis and lymphatic metastasis.
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.
Björndahl
Meit A
MA
Laboratory of Angiogenesis Research, Microbiology and Tumor Biology Center, David Geffen School of Medicine at University of California, Los Angeles, CA, USA.
Cao
Renhai
R
Burton
Jeremy B
JB
Brakenhielm
Ebba
E
Religa
Piotr
P
Galter
Dagmar
D
Wu
Lily
L
Cao
Yihai
Y
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
D000906:Antibodies; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040321:Vascular Endothelial Growth Factor Receptor-3