Hypoxia promotes vasculogenic mimicry formation by inducing epithelial–mesenchymal transition in ovarian carcinoma

• Published in: Gynecologic oncology Vol. 133; no. 3; pp. 575 - 583
• Main Authors: Du, Jing, Sun, Baocun, Zhao, Xiulan, Gu, Qiang, Dong, Xueyi, Mo, Jing, Sun, Tao, Wang, Junyan, Sun, Ran, Liu, Yanrong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2014
• Subjects: Adult; Aged; Aged, 80 and over; Cadherins - genetics; Cadherins - metabolism; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Epithelial-Mesenchymal Transition - physiology; Epithelial–mesenchymal transition; Female; Hematology, Oncology and Palliative Medicine; HIF-1α; Humans; Hypoxia; Hypoxia - genetics; Hypoxia - metabolism; Hypoxia - physiopathology; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Middle Aged; Neoplasms, Glandular and Epithelial - blood supply; Neoplasms, Glandular and Epithelial - genetics; Neoplasms, Glandular and Epithelial - metabolism; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - physiopathology; Nuclear Proteins - metabolism; Obstetrics and Gynecology; Ovarian cancer; Ovarian Neoplasms - blood supply; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; RNA, Messenger - analysis; Snail Family Transcription Factors; Transcription Factors - metabolism; Twist-Related Protein 1 - metabolism; Vasculogenic mimicry; Vimentin - genetics; Vimentin - metabolism; Young Adult; Hypoxia; Epithelial–mesenchymal transition; HIF-1α; Ovarian cancer; Vasculogenic mimicry
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2014.02.034

Abstract Objectives The functions of hypoxia and subsequent hypoxia-inducible factor-1α (HIF-1α) activation in vasculogenic mimicry (VM) are currently unclear. This study aimed to investigate the effects of hypoxia on VM formation in ovarian cancer, and explore the possible mechanism involved. Methods The expression levels of HIF-1α, E-cadherin, vimentin, Twist1, Slug, and VE-cadherin proteins were analyzed by immunohistochemistry in 71 specimens of epithelial ovarian cancer. The results were correlated with VM and survival analysis. We used a well-established in vitro model of a three-dimensional culture to compare VM formation under hypoxia and normoxia in ovarian cancer cell lines SKOV3 and OVCAR3. To explore the potential mechanism, we examined the effects of hypoxia on the mRNA and protein expression levels of both E-cadherin and vimentin. Results HIF-1α expression was correlated with loss of E-cadherin expression and up-regulated vimentin expression in 11 of the 18 VM-positive patients. Ovarian cancer with evidence of VM was significantly more likely to have high Twist1, Slug, and VE-cadherin expression levels. VM was observed in vitro under hypoxia. The ovarian cancer cells presented morphological epithelial–mesenchymal transition (EMT)-like changes (more fibroblastoid morphology and loss of cellular cohesiveness) under hypoxic conditions. The mRNA and protein levels demonstrated the induction of EMT after hypoxia. Clinicopathological analysis revealed that both VM and HIF-1α expression levels presented shorter survival durations. Conclusions Hypoxia contributed to VM formation by inducing EMT. These results may offer new insights for consideration in ovarian cancer treatment strategies.