title: The inflammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial ovarian cancer cells.
abstract: Constitutive expression of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) is characteristic of malignant ovarian surface epithelium. We investigated the hypothesis that this autocrine action of TNF-alpha generates and sustains a network of other mediators that promote peritoneal cancer growth and spread. When compared with two ovarian cancer cell lines that did not make TNF-alpha, constitutive production of TNF-alpha was associated with greater release of the chemokines CCL2 and CXCL12, the cytokines interleukin-6 (IL-6) and macrophage migration-inhibitory factor (MIF), and the angiogenic factor vascular endothelial growth factor (VEGF). TNF-alpha production was associated also with increased peritoneal dissemination when the ovarian cancer cells were xenografted. We next used RNA interference to generate stable knockdown of TNF-alpha in ovarian cancer cells. Production of CCL2, CXCL12, VEGF, IL-6, and MIF was decreased significantly in these cells compared with wild-type or mock-transfected cells, but in vitro growth rates were unaltered. Tumor growth and dissemination in vivo were significantly reduced when stable knockdown of TNF-alpha was achieved. Tumors derived from TNF-alpha knockdown cells were noninvasive and well circumscribed and showed high levels of apoptosis, even in the smallest deposits. This was reflected in reduced vascularization of TNF-alpha knockdown tumors. Furthermore, culture supernatants from such cells failed to stimulate endothelial cell growth in vitro. We conclude that autocrine production of TNF-alpha by ovarian cancer cells stimulates a constitutive network of other cytokines, angiogenic factors, and chemokines that may act in an autocrine/paracrine manner to promote colonization of the peritoneum and neovascularization of developing tumor deposits.
authors.affiliation: Centre for Translational Oncology, Institute of Cancer and the Cancer Research-UK Clinical Centre and Bone and Joint Research Unit, William Harvey Research Institute, Barts and The London, Queen Mary's School of Medicine and Dentistry, United Kingdom.
authors.forename: Hagen
authors.initials: H
authors.lastname: Kulbe
authors.forename: Richard
authors.initials: R
authors.lastname: Thompson
authors.forename: Julia L
authors.initials: JL
authors.lastname: Wilson
authors.forename: Stephen
authors.initials: S
authors.lastname: Robinson
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hagemann
authors.forename: Rewas
authors.initials: R
authors.lastname: Fatah
authors.forename: David
authors.initials: D
authors.lastname: Gould
authors.forename: Ayse
authors.initials: A
authors.lastname: Ayhan
authors.forename: Frances
authors.initials: F
authors.lastname: Balkwill
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000378:metabolism; D014162:Transfection; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D014409:Tumor Necrosis Factor-alpha