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Neoplasia. 2014 Apr;16(4):343-53.e1-2. doi: 10.1016/j.neo.2014.04.003.

VEGFR3 inhibition chemosensitizes ovarian cancer stemlike cells through down-regulation of BRCA1 and BRCA2.

Author information

1
Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
2
Department of Obstetrics and Gynecology, University of California, Los Angeles, CA, USA.
3
Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Division of Gynecology and Oncology, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA. Electronic address: ronaldbu@med.umich.edu.

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.

PMID:
24862760
PMCID:
PMC4094836
DOI:
10.1016/j.neo.2014.04.003
[Indexed for MEDLINE]
Free PMC Article

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