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

Abstract

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