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The Role of Angiogenesis in the Persistence of Chemoresistance in Epithelial Ovarian Cancer

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Abstract

Objective

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.

Methods

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.

Results

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.

Conclusion

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.

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Authors and Affiliations

  1. Departments of Obstetrics and Gynecology, Cell Biology and Anatomy, and Physiology, Member in the Karmanos Cancer Institute, Molecular Biology and Genetics Program, Wayne State University School of Medicine, 275 East Hancock St, Detroit, MI, 48202, USA

    Osama Nusrat MD, Jimmy Belotte MD, Nicole M. Fletcher PhD, Ira Memaj, Mohammed G. Saed BA & Ghassan M. Saed PhD

  2. Department of Obstetrics and Gynecology, Georgia Regents University, Augusta, GA, USA

    Michael P. Diamond MD

Authors
  1. Osama Nusrat MD
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  2. Jimmy Belotte MD
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  3. Nicole M. Fletcher PhD
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  4. Ira Memaj
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  5. Mohammed G. Saed BA
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  6. Michael P. Diamond MD
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  7. Ghassan M. Saed PhD
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Correspondence to Ghassan M. Saed PhD.

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Nusrat, O., Belotte, J., Fletcher, N.M. et al. The Role of Angiogenesis in the Persistence of Chemoresistance in Epithelial Ovarian Cancer. Reprod. Sci. 23, 1484–1492 (2016). https://doi.org/10.1177/1933719116645191

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