Elsevier

Neoplasia

Volume 16, Issue 4, April 2014, Pages 343-353.e2
Neoplasia

VEGFR3 Inhibition Chemosensitizes Ovarian Cancer Stemlike Cells through Down-Regulation of BRCA1 and BRCA21,2

https://doi.org/10.1016/j.neo.2014.04.003Get rights and content
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Abstract

In ovarian cancer, loss of BRCA gene expression in tumors is associated with improved response to chemotherapy and increased survival. A means to pharmacologically downregulate BRCA gene expression could improve the outcomes of patients with BRCA wild-type tumors. We report that vascular endothelial growth factor receptor 3 (VEGFR3) inhibition in ovarian cancer cells is associated with decreased levels of both BRCA1 and BRCA2. Inhibition of VEGFR3 in ovarian tumor cells was associated with growth arrest. CD133+ ovarian cancer stemlike cells were preferentially susceptible to VEGFR3-mediated growth inhibition. VEGFR3 inhibition–mediated down-regulation of BRCA gene expression reversed chemotherapy resistance and restored chemosensitivity in resistant cell lines in which a BRCA2 mutation had reverted to wild type. Finally, we demonstrate that tumor-associated macrophages are a primary source of VEGF-C in the tumor microenvironment. Our studies suggest that VEGFR3 inhibition may be a pharmacologic means to downregulate BRCA genes and improve the outcomes of patients with BRCA wild-type tumors.

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1

This work was supported by grant 1-R01-CA163345-01 from the National Institutes of Health. Core facilities used to perform this work were supported by the National Institutes of Health through the University of Michigan Cancer Center Support grant (P30 CA046592). The authors have no conflicts of interest to report.

2

This article refers to supplementary materials, which are designated by Table W1, Table W2 and Figure W1 and are available online at www.neoplasia.com.