Expression and regulation of tumor necrosis factor A in normal and malignant ovarian epithelium

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