title: A dynamic inflammatory cytokine network in the human ovarian cancer microenvironment.
abstract: Constitutive production of inflammatory cytokines is a characteristic of many human malignant cell lines; however, the in vitro and in vivo interdependence of these cytokines, and their significance to the human cancer microenvironment, are both poorly understood. Here, we describe for the first time how three key cytokine/chemokine mediators of cancer-related inflammation, TNF, CXCL12, and interleukin 6, are involved in an autocrine cytokine network, the "TNF network," in human ovarian cancer. We show that this network has paracrine actions on angiogenesis, infiltration of myeloid cells, and NOTCH signaling in both murine xenografts and human ovarian tumor biopsies. Neutralizing antibodies or siRNA to individual members of this TNF network reduced angiogenesis, myeloid cell infiltration, and experimental peritoneal ovarian tumor growth. The dependency of network genes on TNF was shown by their downregulation in tumor cells from patients with advanced ovarian cancer following the infusion of anti-TNF antibodies. Together, the findings define a network of inflammatory cytokine interactions that are crucial to tumor growth and validate this network as a key therapeutic target in ovarian cancer.
authors: Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, Cancer Research UK, Bioinformatics and Biostatistics Service, London, United Kingdom.
authors: Hagen
authors: H
authors: Kulbe
authors: Probir
authors: P
authors: Chakravarty
authors: D Andrew
authors: DA
authors: Leinster
authors: Kellie A
authors: KA
authors: Charles
authors: Joseph
authors: J
authors: Kwong
authors: Richard G
authors: RG
authors: Thompson
authors: Jermaine I
authors: JI
authors: Coward
authors: Tiziana
authors: T
authors: Schioppa
authors: Stephen C
authors: SC
authors: Robinson
authors: William M
authors: WM
authors: Gallagher
authors: Laura
authors: L
authors: Galletta
authors: Michael A
authors: MA
authors: Salako
authors: John F
authors: JF
authors: Smyth
authors: Thorsten
authors: T
authors: Hagemann
authors: Donal J
authors: DJ
authors: Brennan
authors: David D
authors: DD
authors: Bowtell
authors: Frances R
authors: FR
authors: Balkwill
mesh_terms: D000818:Animals; D001706:Biopsy; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016207:Cytokines