The Role of Angiogenesis in the Persistence of Chemoresistance in Epithelial Ovarian Cancer.
Chemoresistance remains a major challenge in the treatment of ovarian cancer. As part of a survival mechanism, tumor cells have been shown to release proangiogenic factors, such as vascular endothelial growth factor (VEGF), through a mechanism that involves the upregulation of hypoxia-induced factor (HIF)-1α. The objective of this study was to compare the expression of VEGF and its receptors (R1 and R2) as well as HIF-1α in chemoresistant epithelial ovarian cancer (EOC) cells to their chemosensitive counterparts and determine their impact on angiogenesis.



Two human EOC cell lines, MDAH-2774 and SKOV-3, and their cisplatin- or taxotere-resistant counterparts were used. Total RNA and protein were subjected to real-time reverse transcriptase-polymerase chain reaction, immunoprecipitation/Western blot and enzyme-linked immunosorbent assay to evaluate the expression of VEGF, VEGF receptors (R1 and R2), and HIF-1α. Angiogenesis was assessed with an in vitro angiogenesis assay. Data were analyzed using independent Student t tests and chi-square.



Both taxotere- and cisplatin-resistant MDAH-2774 and SKOV-3 EOC cell lines manifested a significant decrease in VEGF, VEGF receptors, HIF-1α messenger RNA, and protein levels as compared to their chemosensitive counterparts. There was a significant decrease in the number and thickness of polygon blood vessel formation in chemoresistant EOC cells compared to chemosensitive counterparts.



Cisplatin- and taxotere-resistant EOC cells are characterized by lower VEGF, VEGF receptors, and HIF-1α, and decreased angiogenesis. These findings may indicate a decrease in drug delivery at the tumor site, hence allowing the persistence of chemoresistant EOC cells.
Department of Obstetrics and Gynecology, The C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI, USA.
Osama
O
Nusrat
Department of Obstetrics and Gynecology, The C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI, USA.
Jimmy
J
Belotte
Department of Obstetrics and Gynecology, The C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI, USA.
Nicole M
NM
Fletcher
Department of Obstetrics and Gynecology, The C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI, USA.
Ira
I
Memaj
Department of Obstetrics and Gynecology, The C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI, USA.
Mohammed G
MG
Saed
Department of Obstetrics and Gynecology, Georgia Regents University, Augusta, GA, USA.
Michael P
MP
Diamond
Department of Obstetrics and Gynecology, The C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI, USA gsaed@med.wayne.edu.
Ghassan M
GM
Saed
D000970:Antineoplastic Agents / Q000008:administration & dosage; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D000077143:Docetaxel; D004351:Drug Resistance; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism*; D043823:Taxoids / Q000008:administration & dosage; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D043823:Taxoids; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077143:Docetaxel; C501162:FLT1 protein, human; C000588866:KDR protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D002945:Cisplatin
and hypoxia-inducible factor-1α; chemoresistance; ovarian cancer; vascular endothelial growth factor