TUMOR-NECROSIS-FACTOR-ALPHA AS AN AUTOCRINE AND PARACRINE GROWTH-FACTOR FOR OVARIAN-CANCER - MONOKINE INDUCTION OF TUMOR-CELL PROLIFERATIONAND TUMOR-NECROSIS-FACTOR-ALPHA EXPRESSION

Ovarian tumor cells produce macrophage colony stimulating factor, a po tent chemoattractant for monocytes. Monocytes and macrophages produce tumor necrosis factor alpha (TNF-alpha) and interleukin 1alpha or inte rleukin 1beta (IL-1beta) that can stimulate ovarian tumor cell growth. The present study has explored whether paracrine stimulation by monoc yte derived cytokines might induce autocrine growth stimulation of nor mal and malignant ovarian epithelial cells. Endogenous expression of T NF-alpha mRNA was detected in ascites ovarian cancer cells isolated di rectly from patients, but not in established cultures of normal or mal ignant ovarian epithelial cells. When ascites tumor cells were culture d for 7 days, TNF-alpha expression ceased but could be reinduced by tr eatment with TNF-alpha or IL-1beta. Ascites fluid contained concentrat ions of the cytokines that could mediate these effects. Similarly, tre atment of normal or malignant ovarian epithelial cells with purified r ecombinant IL-1beta or TNF-alpha induced transcription of TNF-alpha mR NA within 1 h. TNF-alpha protein could be detected by enzyme-linked im munosorbent assay in conditioned medium from IL-1beta treated ovarian cancer cells. [H-3]thymidine incorporation by normal or malignant ovar ian epithelial cells was stimulated by a 24-h incubation with IL-1beta or TNF-alpha. Stimulation of proliferation by IL-1beta could be parti ally blocked by an antibody against TNF-alpha or by soluble TNF-alpha- receptor. Thus, TNF-alpha may function as both an autocrine and a para crine growth factor in ovarian cancer.