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Migration-promoting role of VEGF-C and VEGF-C binding receptors in human breast cancer cells.

Abstract
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.
AuthorsA V Timoshenko, S Rastogi, P K Lala
JournalBritish journal of cancer (Br J Cancer) Vol. 97 Issue 8 Pg. 1090-8 (Oct 22 2007) ISSN: 0007-0920 [Print] England
PMID17912247 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Neuropilin-2
  • RNA, Small Interfering
  • Vascular Endothelial Growth Factor C
  • Neuropilin-1
  • Receptors, Vascular Endothelial Growth Factor
Topics
  • Breast Neoplasms (metabolism, pathology)
  • Cell Line, Tumor
  • Cell Movement
  • Female
  • Flow Cytometry
  • Humans
  • Neoplasm Metastasis (pathology)
  • Neuropilin-1 (metabolism)
  • Neuropilin-2 (metabolism)
  • RNA, Small Interfering
  • Receptors, Vascular Endothelial Growth Factor (metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transfection
  • Vascular Endothelial Growth Factor C (metabolism)

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