Published online before print December 13, 2007

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070181

Accepted for publication September 19, 2007.

Article

Overexpression of Vascular Endothelial Growth Factor 189 in Breast Cancer Cells Leads to Delayed Tumor Uptake with Dilated Intratumoral Vessels

Marie-Astrid Hervé^*, Hélène Buteau-Lozano^*, Roger Vassy, Ivan Bieche, Guillaume Velasco^*, Marika Pla, Gérard Perret, Samia Mourah^¶, and Martine Perrot-Applanat^*@

From INSERM U553,* INSERM U718, and INSERM U716,^¶ Institut Universitaire d'Hématologie, Hôpital Saint-Louis, University of Paris VII, Paris; the Centre National de la Recherche Scientifique UMR7033, Equipe de Pharmacologie, Bobigny; and INSERM U735, Centre René Huguenin, Saint Cloud, France

^@ To whom correspondence should be addressed. E-mail: martine.applanat{at}stlouis.inserm.fr.

	Abstract

Vascular endothelial growth factor (VEGF) is essential for breast cancer progression and is a relevant target in anti-angiogenesis. Although VEGF121 and VEGF165, the fully or partially secreted isoforms, respectively, have been the focus of intense studies, the role of the cell-associated VEGF189 isoform is not understood. To clarify the contribution of VEGF189 to human mammary carcinogenesis, we established several clones of MDA-MB-231 cells stably overexpressing VEGF189 (V189) and VEGF165 (V165). V189 and V165 clones increased tumor growth and angiogenesis in vivo. Remarkably, V165 induced the most rapid tumor uptake, whereas V189 increased vasodilation. In vitro overexpression of VEGF165 and VEGF189 increases the proliferation and chemokinesis of these cancer cells. Interestingly, overexpression of VEGF189 increased cell adhesion on fibronectin (1.9-fold) and vitronectin (1.6-fold), as compared to VEGF165, through 51 and v5 integrins. Using the BIACore system we demonstrated for the first time that VEGF189 binds directly to neuropilin-1, which is strongly expressed in MDA-MB-231 cells. In contrast, VEGF-R2 was not significantly expressed and VEGF-R1 was expressed at low level. Our in vitro results suggest an autocrine effect of VEGF189 on breast cancer cells, probably through neuropilin-1. In conclusion, our data indicate that VEGF189 participates in mammary tumor growth through both angiogenesis and nonangiogenic functions. Whether VEGF189 overexpression is correlated to prognosis in human breast tumors remains to be established.

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