Tumor necrosis factor alpha as an autocrine and paracrine growth factor for ovarian cancer: monokine induction of tumor cell proliferation and tumor necrosis factor alpha expression.

Ovarian tumor cells produce macrophage colony stimulating factor, a potent chemoattractant for monocytes. Monocytes and macrophages produce tumor necrosis factor alpha (TNF-alpha) and interleukin 1 alpha or interleukin 1 beta (IL-1 beta) that can stimulate ovarian tumor cell growth. The present study has explored whether paracrine stimulation by monocyte derived cytokines might induce autocrine growth stimulation of normal and malignant ovarian epithelial cells. Endogenous expression of TNF-alpha mRNA was detected in ascites ovarian cancer cells isolated directly from patients, but not in established cultures of normal or malignant ovarian epithelial cells. When ascites tumor cells were cultured for 7 days, TNF-alpha expression ceased but could be reinduced by treatment with TNF-alpha or IL-1 beta. Ascites fluid contained concentrations of the cytokines that could mediate these effects. Similarly, treatment of normal or malignant ovarian epithelial cells with purified recombinant IL-1 beta or TNF-alpha induced transcription of TNF-alpha mRNA within 1 h. TNF-alpha protein could be detected by enzyme-linked immunosorbent assay in conditioned medium from IL-1 beta treated ovarian cancer cells. [3H]thymidine incorporation by normal or malignant ovarian epithelial cells was stimulated by a 24-h incubation with IL-1 beta or TNF-alpha. Stimulation of proliferation by IL-1 beta could be partially blocked by an antibody against TNF-alpha or by soluble TNF-alpha-receptor. Thus, TNF-alpha may function as both an autocrine and a paracrine growth factor in ovarian cancer.