Research Article: Vascular Endothelial Growth Factor Mediates Intracrine Survival in Human Breast Carcinoma Cells through Internally Expressed VEGFR1/FLT1

Date Published: June 5, 2007

Publisher: Public Library of Science

Author(s): Tae-Hee Lee, Seyha Seng, Masayuki Sekine, Cimona Hinton, Yigong Fu, Hava Karsenty Avraham, Shalom Avraham, Robert S Kerbel

Abstract: BackgroundWhile vascular endothelial growth factor (VEGF) expression in breast tumors has been correlated with a poor outcome in the pathogenesis of breast cancer, the expression, localization, and function of VEGF receptors VEGFR1 (also known as FLT1) and VEGFR2 (also known as KDR or FLK1), as well as neuropilin 1 (NRP1), in breast cancer are controversial.Methods and FindingsWe investigated the expression and function of VEGF and VEGF receptors in breast cancer cells. We observed that VEGFR1 expression was abundant, VEGFR2 expression was low, and NRP1 expression was variable. MDA-MB-231 and MCF-7 breast cancer cells, transfected with antisense VEGF cDNA or with siVEGF (VEGF-targeted small interfering RNA), showed a significant reduction in VEGF expression and increased apoptosis as compared to the control cells. Additionally, specifically targeted knockdown of VEGFR1 expression by siRNA (siVEGFR1) significantly decreased the survival of breast cancer cells through down-regulation of protein kinase B (AKT) phosphorylation, while targeted knockdown of VEGFR2 or NRP1 expression had no effect on the survival of these cancer cells. Since a VEGFR1-specific ligand, placenta growth factor (PGF), did not, as expected, inhibit the breast cancer cell apoptosis induced by siVEGF, and since VEGFR1 antibody also had no effects on the survival of these cells, we examined VEGFR1 localization. VEGFR1 was predominantly expressed internally in MDA-MB-231 and MCF-7 breast cancer cells. Specifically, VEGFR1 was found to be colocalized with lamin A/C and was expressed mainly in the nuclear envelope in breast cancer cell lines and primary breast cancer tumors. Breast cancer cells treated with siVEGFR1 showed significantly decreased VEGFR1 expression levels and a lack of VEGFR1 expression in the nuclear envelope.ConclusionsThis study provides, to our knowledge for the first time, evidence of a unique survival system in breast cancer cells by which VEGF can act as an internal autocrine (intracrine) survival factor through its binding to VEGFR1. These results may lead to an improved strategy for tumor therapy based on the inhibition of angiogenesis.

Partial Text: The classical role of VEGF in tumor progression is as a positive regulator of angiogenesis, the process of forming new capillaries from preexisting blood vessels [1]. Tumor growth is highly dependent on the ability of tumors to induce their own vascularization [2]. VEGF expression has been reported in a number of cancer cell lines and in several clinical specimens derived from breast, brain, and ovarian cancers [3–6]. Thus, antagonism of VEGF can effectively prevent tumor growth through incomplete blood vessel formation [7].

In this study, we found that several breast cancer cell lines expressed VEGF receptors. Furthermore, we showed that reduced endogenous VEGF or VEGFR1 expression induced the apoptosis of MDA-MB-231 and MCF-7 breast cancer cells, whereas externally acting proteins (VEGF, VEGF antibody, soluble VEGFR1, and VEGFR1-blocking antibody) had no significant effects on breast cancer cell growth or survival. We also observed that internally expressed VEGFR1 induced the survival of breast cancer cells. These results indicate that VEGF plays a role as an internal autocrine survival factor in breast cancer cells via VEGFR1 and not through VEGFR2 or NRP1, and suggest that the role of the VEGF/VEGFR1 axis in breast cancer cells may not be governed by the classical paradigm of signal transduction involving interaction between ligands and cell surface receptors.

Source:

http://doi.org/10.1371/journal.pmed.0040186

 

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