title: An HCG-rich microenvironment contributes to ovarian cancer cell differentiation into endothelioid cells in a three-dimensional culture system.
abstract: We investigated the expression of human chorionic gonadotropin (HCG) and its effects on vasculogenic mimicry (VM) formation in ovarian cancer cells under normoxic and hypoxic conditions in three-dimensional matrices preconditioned by an endothelial-trophoblast cell co-culture system. The co-culture model was established using human umbilical vein endothelial cells (HUVECs) and HTR-8 trophoblast cells in a three-dimensional culture system. The co-cultured cells were removed with NH4OH, and ovarian cancer cells were implanted into the preconditioned matrix. VM was identified morphologically and by detecting vascular markers expressed by cancer cells. The specificity of the effects of exogenous HCG in the microenvironment was assessed by inhibition with a neutralizing anti-HCG antibody. HCG siRNA was used to knock down endogenous HCG expression in OVCAR-3 ovarian cancer cells. HTR-8 cells 'fingerprinted' HUVECs to form capillary-like tube structures in co-cultures. In the preconditioned HCG-rich microenvironment, the number of vessel-like network structures formed by HCG receptor-positive OVCAR-3 cells and the expression levels of CD31, VEGF and factor VIII were significantly increased. The preconditioned HCG-rich microenvironment significantly increased the expression of hypoxia inducible factor-1α (HIF‑1α) and VM formation in OVCAR-3 cells under hypoxic conditions. Treatment with a neutralizing anti-HCG antibody but not HCG siRNA significantly inhibited the formation of vessel-like network structures. HCG in the microenvironment contributes to OVCAR-3 differentiation into endothelioid cells in three-dimensional matrices preconditioned with an endothelial-trophoblast cell co-culture system. HCG may synergistically enhance hypoxia-induced vascular markers and HIF-1α expression. These findings would provide perspectives on new therapeutic targets for ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynecology, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Su
authors.affiliation: Department of Obstetrics and Gynecology, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Fan
authors.affiliation: Department of Obstetrics and Gynecology, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China.
authors.forename: Sainan
authors.initials: S
authors.lastname: Gao
authors.affiliation: The Immunology Laboratory of Nantong University, Nantong, Jiangsu 226001, P.R. China.
authors.forename: Aiguo
authors.initials: A
authors.lastname: Shen
authors.affiliation: The Immunology Laboratory of Nantong University, Nantong, Jiangsu 226001, P.R. China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D006063:Chorionic Gonadotropin / Q000502:physiology*; D018920:Coculture Techniques; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000473:pathology*; D011974:Receptors, LH / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D006063:Chorionic Gonadotropin; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011974:Receptors, LH