title: Hypoxia promotes vasculogenic mimicry formation by inducing epithelial-mesenchymal transition in ovarian carcinoma.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, PR China; Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin 300070, PR China; Department of Pathology, Tianjin Central Hospital of Gynecology Obstetrics, Tianjin 300100, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, PR China; Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin 300070, PR China; Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin 300070, PR China. Electronic address: baocunsun@gmail.com.
authors.forename: Baocun
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, PR China; Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin 300070, PR China.
authors.forename: Xiulan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, PR China; Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin 300070, PR China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gu
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, PR China; Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin 300070, PR China.
authors.forename: Xueyi
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Mo
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, PR China.
authors.forename: Junyan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, PR China.
authors.forename: Ran
authors.initials: R
authors.lastname: Sun
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, PR China.
authors.forename: Yanrong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000098:blood supply / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009687:Nuclear Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000378:metabolism; D014746:Vimentin / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D015820:Cadherins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D012333:RNA, Messenger; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D014746:Vimentin
keywords: Epithelial–mesenchymal transition; HIF-1α; Hypoxia; Ovarian cancer; Vasculogenic mimicry