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

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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.

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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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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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Authors and Affiliations

  1. Department of Gynaecology and Obstetrics, University of Ulm, Ulm, Germany

    Melanie Weigand, Pia Hantel & Rolf Kreienberg

  2. Department of Interventional Cardiology, University of Maastricht, Maastricht, The Netherlands

    Johannes Waltenberger

  3. Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Melanie Weigand

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  1. Melanie Weigand
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  2. Pia Hantel
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Correspondence to: Melanie Weigand, Department of Cancer Biology, University of Massachusetts Medical School, LRB-470X, 364 Plantation St, Worcester, MA, USA. Tel: +1-508-856-2579; Fax: +1-508-856-1310; E-Mail: melanie_weigand@hotmail.de

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Weigand, M., Hantel, P., Kreienberg, R. et al. Autocrine vascular endothelial growth factor signalling in breast cancer. Evidence from cell lines and primary breast cancer cultures in vitro . Angiogenesis 8, 197–204 (2005). https://doi.org/10.1007/s10456-005-9010-0

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  • DOI: https://doi.org/10.1007/s10456-005-9010-0

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