Migration-promoting role of VEGF-C and VEGF-C binding receptors in human breast cancer cells.
Vascular endothelial growth factor C (VEGF-C) is a lymphangiogenic factor over-expressed in highly metastatic, cyclooxygenase (COX)-2 expressing breast cancer cells. We tested the hypothesis that tumour-derived VEGF-C may play an autocrine role in metastasis by promoting cellular motility through one or more VEGF-C-binding receptors VEGFR-2, VEGFR-3, neuropilin (NRP)-1, NRP-2, and integrin alpha9beta1. We investigated the expression of these receptors in several breast cancer cell lines (MDA-MB-231, Hs578T, SK-BR-3, T-47D, and MCF7) and their possible requirement in migration of two VEGF-C-secreting, highly metastatic lines MDA-MB-231 and Hs578T. While cell lines varied significantly in their expression of above VEGF-C receptors, migratory activity of MDA-MB-231 and Hs578T cells was linked to one or more of these receptors. Depletion of endogenous VEGF-C by treatments with a neutralising antibody, VEGF-C siRNA or inhibitors of Src, EGFR/Her2/neu and p38 MAP kinases which inhibited VEGF-C production, inhibited cellular migration, indicating the requirement of VEGF-C for migratory function. Migration was differentially attenuated by blocking or downregulation of different VEGF-C receptors, for example treatment with a VEGFR-2 tyrosine kinase inhibitor, NRP-1 and NRP-2 siRNA or alpha9beta1 integrin antibody, indicating the participation of one or more of the receptors in cell motility. This novel role of tumour-derived VEGF-C indicates that breast cancer metastasis can be promoted by coordinated stimulation of lymphangiogenesis and enhanced migratory activity of breast cancer cells.
Timoshenko
A V
AV
Department of Anatomy, The University of Western Ontario, London, Ontario N6A5C1, Canada.
Rastogi
S
S
Lala
P K
PK
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D009362:Neoplasm Metastasis / Q000473:pathology*; D039942:Neuropilin-1 / Q000378:metabolism; D039943:Neuropilin-2 / Q000378:metabolism; D034741:RNA, Small Interfering; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*
D039943:Neuropilin-2; D034741:RNA, Small Interfering; D042582:Vascular Endothelial Growth Factor C; D039942:Neuropilin-1; D040262:Receptors, Vascular Endothelial Growth Factor