Autocrine vascular endothelial growth factor signalling in breast cancer. Evidence from cell lines and primary breast cancer cultures in vitro

Angiogenesis. 2005;8(3):197-204. doi: 10.1007/s10456-005-9010-0. Epub 2005 Nov 19.

Abstract

Inhibition of angiogenesis has become a major target in experimental cancer therapies. Vascular endothelial growth factor (VEGF) and its receptors are essential for breast cancer progression and relevant targets in experimental anti-angiogenesis. VEGF, produced by carcinoma cells, acts in a paracrine fashion on endothelial cells and displays autocrine activity on carcinoma cells. Breast cancer cells express VEGF-A, VEGF-B, VEGF-C and their receptors VEGFR-1 (Flt-1), VEGFR-2 (Flk-1/KDR) and neuropilin (NP-1/NP-2). VEGF-A triggers cellular signalling, an invasive phenotype of certain breast cancer cell lines and influences cell survival. However, such an autocrine VEGF/VEGFR signalling loop remains to be established. We demonstrate production of VEGF-A in cell lines MDA-MB-468, T47d, MCF-7, HBL-100 and in a primary breast cancer culture. Moreover, these cells showed baseline VEGFR-2 tyrosine-phosphorylation that could be enhanced by VEGF-A stimulation. In addition, VEGF-A leads to increased phosphorylation of ERK1/2 and Akt indicating that VEGF-A stimulation plays a crucial role in the regulation of cell growth, apoptosis, survival and differentiation. Moreover, we have established a novel breast cancer cell culture MW1 that expresses high levels of VEGF-A. We demonstrate that VEGFR-2 on the surface of breast cancer cells is functional and is capable of being stimulated by external VEGF-A. VEGF-A production by and VEGFR-2 activation on the surface of breast cancer cells indicates the presence of a distinct autocrine signalling loop that enables breast cancer cells to promote their own growth and survival by phosphorylation and activation of VEGFR-2. Moreover, this autocrine loop represents an attractive therapeutic target.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autocrine Communication / physiology*
  • Blotting, Western
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / therapy
  • Cell Line, Tumor
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • Neovascularization, Pathologic / metabolism*
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*

Substances

  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-2