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

Jaeyoung J Lim; Kun Yang; Barbie Taylor-Harding; W Ruprecht Wiedemeyer; Ronald J Buckanovich

doi:10.1016/j.neo.2014.04.003

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

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

Authors

Jaeyoung J Lim¹, Kun Yang¹, Barbie Taylor-Harding², W Ruprecht Wiedemeyer², Ronald J Buckanovich³

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

AC133 Antigen
Animals
Antigens, CD / metabolism
Cell Line, Tumor
Disease Models, Animal
Drug Resistance, Neoplasm / genetics
Female
Gene Expression Regulation, Neoplastic / drug effects*
Genes, BRCA1*
Genes, BRCA2*
Glycoproteins / metabolism
Humans
Neoplastic Stem Cells / metabolism*
Ovarian Neoplasms / genetics*
Ovarian Neoplasms / metabolism*
Ovarian Neoplasms / pathology
Peptides / metabolism
Protein Kinase Inhibitors / pharmacology*
Signal Transduction / drug effects
Tumor Burden / drug effects
Vascular Endothelial Growth Factor C / genetics
Vascular Endothelial Growth Factor C / metabolism
Vascular Endothelial Growth Factor D / genetics
Vascular Endothelial Growth Factor D / metabolism
Vascular Endothelial Growth Factor Receptor-3 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-3 / genetics
Vascular Endothelial Growth Factor Receptor-3 / metabolism
Xenograft Model Antitumor Assays

Substances

AC133 Antigen
Antigens, CD
Glycoproteins
PROM1 protein, human
Peptides
Protein Kinase Inhibitors
Vascular Endothelial Growth Factor C
Vascular Endothelial Growth Factor D
Vascular Endothelial Growth Factor Receptor-3

Abstract

Publication types

MeSH terms

Substances

Grants and funding