Angiogenesis

, Volume 8, Issue 3, pp 197–204 | Cite as

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

  • Melanie Weigand
  • Pia Hantel
  • Rolf Kreienberg
  • Johannes Waltenberger
Article

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.

Keywords

angiogenesis autocrine signalling breast cancer cell culture KDR VEGF 

Abbreviations

ATCC

American Type Culture Collection

EGFR

epidermal growth factor receptor

IGFR

insulin-like growth factor receptor

PI3-kinase

phosphatidylinositol 3′-kinase

VEGF

vascular endothelial growth factor

VEGFR

vascular endothelial growth factor receptor

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Notes

Acknowledgements

We thank Stephanie Kliche, Guido Fellbrich, Lisa Wiesmüller, Shan Wang-Gorke as well as Ulrike Mayr-Beyrle, Stephen Ethier and Arthur Mercurio for valuable discussions and technical help. This study was supported in part by the Medical Faculty of the University of Ulm (to M.W.), by a Heisenberg Scholarship of the Deutsche Forschungsgemeinschaft (Wa734/5–1) and by a project grant of the Deutsche Forschungsgemeinschaft (priority research program ȁ8angiogenesisȁ9, Wa734/6–3) (both to J.W.).

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Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Melanie Weigand
    • 1
    • 3
  • Pia Hantel
    • 1
  • Rolf Kreienberg
    • 1
  • Johannes Waltenberger
    • 2
  1. 1.Department of Gynaecology and ObstetricsUniversity of UlmUlmGermany
  2. 2.Department of Interventional CardiologyUniversity of MaastrichtMaastrichtThe Netherlands
  3. 3.Department of Cancer BiologyUniversity of Massachusetts Medical SchoolWorcesterUSA

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