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¹ Cancer Research UK Translational Oncology Laboratory, Barts and The London, Queen Mary's School of Medicine and Dentistry; ² Cancer Research UK Breast Cancer Biology Group, Guy's Hospital, London, United Kingdom; and ³ Departments of Obstetrics and Gynecology and Pathology, University of South Florida and the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida

Requests for reprints: Frances Balkwill, Cancer Research UK, Translational Oncology Laboratory, Barts and The London, Queen Mary's School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, United Kingdom. Phone: 44-20-7882-6106; Fax: 44-20-7882-6110. E-mail: frances.balkwill{at}cancer.org.uk

Epidemiologic studies implicate inflammatory stimuli in the development of ovarian cancer. The proinflammatory cytokine tumor necrosis factor (TNF-) and both its receptors (TNFRI and TNFRII) are expressed in biopsies of this malignancy. Here, we tested the hypothesis that TNF- is a regulator of the proinflammatory microenvironment of ovarian cancer. A cancer profiling array showed higher expression of TNF- in ovarian tumors compared with normal ovarian tissue, and cultured ovarian cancer cells expressed up to 1,000 times more TNF- mRNA than cultured normal ovarian surface epithelial cells; TNF- protein was only detected in the supernatant of tumor cell cultures. Treatment with TNF- induced TNF- mRNA via TNFRI in both malignant and normal cells with evidence for enhanced TNF- mRNA stability in tumor cells. TNF- induced TNF- protein in an autocrine fashion in tumor but not in normal ovarian surface epithelial cells. The TNF- neutralizing antibody infliximab reduced the constitutive levels of TNF- mRNA in tumor cell lines capable of autocrine TNF- production. Apart from TNF- mRNA expression, several other proinflammatory cytokines were constitutively expressed in malignant and normal ovarian surface epithelial cells, including interleukin (IL)-1, IL-6, CCL2, CXCL8, and M-CSF. TNF- treatment further induced these cytokines with de novo transcription of IL-6 mRNA contrasting with the increased stability of CCL2 mRNA. RNA interference directed against TNF- was highly effective in abolishing constitutive IL-6 production by ovarian tumor cells. In summary, we show that TNF- is differentially regulated in ovarian cancer cells compared with untransformed cells and modulates production of several cytokines that may promote ovarian tumorigenesis. Infliximab treatment may have a role in suppressing the TNF--driven inflammatory response associated with ovarian cancer. [Mol Cancer Ther 2006;5(2):382-90]

⁴ Dr. Charles, personal communication.

Received 8/ 4/05; revised 10/26/05; accepted 12/ 7/05.

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