The angiogenic and lymphangiogenic factor vascular endothelial growth factor-D exhibits a paracrine mode of action in cancer.
Vascular endothelial growth factor-D (VEGF-D) promotes angiogenesis, lymphangiogenesis and metastatic spread via the lymphatics, however, the mode of VEGF-D action (e.g. paracrine vs. autocrine) was unknown. We analyzed VEGF-D action in human tumors and a mouse model of metastasis. VEGF-D was localized in tumor cells and endothelium in human non-small cell lung carcinoma and breast ductal carcinoma in situ. Tumor vessels positive for VEGF-D were also positive for its receptors, VEGF receptor-2 (VEGFR-2) and/or VEGFR-3 but negative for VEGF-D mRNA, indicating that VEGF-D is secreted by tumor cells and subsequently associates with endothelium via receptor-mediated uptake. The mature form of VEGF-D was detected in tumors demonstrating that VEGF-D is proteolytically processed and bioactive. In a mouse model of metastasis, VEGF-D synthesized in tumor cells became localized on the endothelium and thereby promoted metastatic spread. These data indicate that VEGF-D promotes tumor angiogenesis, lymphangiogenesis and metastatic spread by a paracrine mechanism.
Achen
Marc G
MG
Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria, Australia. Marc.achen@ludwig.edu.au
Williams
Richard A
RA
Baldwin
Megan E
ME
Lai
Patricia
P
Roufail
Sally
S
Alitalo
Kari
K
Stacker
Steven A
SA
D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008175:Lung Neoplasms / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D011233:Precipitin Tests; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042643:Vascular Endothelial Growth Factor D; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
D016228:Endothelial Growth Factors; D012333:RNA, Messenger; D042643:Vascular Endothelial Growth Factor D; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3