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The Inflammatory Cytokine Tumor Necrosis Factor- Generates an Autocrine Tumor-Promoting Network in Epithelial Ovarian Cancer Cells

¹ Centre for Translational Oncology, Institute of Cancer and the Cancer Research-UK Clinical Centre and ² Bone and Joint Research Unit, William Harvey Research Institute, Barts and The London, Queen Mary's School of Medicine and Dentistry, London, United Kingdom and ³ Department of Pathology, Hacettepe University School of Medicine, Ankara, Turkey

Requests for reprints: Frances Balkwill, Biological Therapy Laboratory, Imperial Cancer Research Fund, P.O. Box 123, London WC2A 3PX, United Kingdom. Phone: 44-207-882-6106; E-mail: frances.balkwill{at}cancer.org.uk.

Constitutive expression of the inflammatory cytokine tumor necrosis factor- (TNF-) is characteristic of malignant ovarian surface epithelium. We investigated the hypothesis that this autocrine action of TNF- 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-, constitutive production of TNF- 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- 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- 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- was achieved. Tumors derived from TNF- 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- knockdown tumors. Furthermore, culture supernatants from such cells failed to stimulate endothelial cell growth in vitro. We conclude that autocrine production of TNF- 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. [Cancer Res 2007;67(2):585–92]

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