PRESENCE OF ACTIVIN, INHIBIN, AND FOLLISTATIN IN EPITHELIAL OVARIAN-CARCINOMA

Activin induces proliferation in epithelial ovarian carcinoma cell lin es, whereas follistatin (FS), an activin binding protein, inhibits thi s action. To test the hypothesis that activin production, in excess of inhibin and FS, results in cell proliferation in epithelial ovarian t umors, messenger RNA (mRNA) expression of the activin family of protei ns, FS, and activin type I and II receptors was examined in 25 primary epithelial ovarian tumors and tumor epithelium in culture (n = 7) usi ng RT-PCR. Activin A was measured in the serum of ovarian cancer patie nts, and activin A, total inhibin, and FS protein secretion was measur ed from primary epithelial tumors in vitro. The effect of activin and FS on cell proliferation was assessed by measuring [H-3]thymidine inco rporation. All results were compared with normal ovarian epithelium. A ll epithelial ovarian tumors expressed mRNA for the alpha, beta A, and beta B subunits; FS 288 and 315; and the activin type IA, IB, II, and IIB receptors. beta A mRNA expression, as assessed using semiquantita tive RT-PCR, was 3-fold greater in cultured tumor epithelium than in p rimary tumors (band density 0.86 +/- 0.17 vs. 0.28 +/- 0.09; P < 0.01) . In addition, beta A mRNA was abundantly expressed in normal epitheli um in culture (n = 2), whereas only trace amounts were seen in 2/9 pri mary epithelial samples. Activin protein was secreted by 24/25 primary epithelial ovarian tumors (range 0.2-155.8 ng/mL). In contrast, total inhibin was secreted by only 2/25 (range 0.01-0.92 ng/mL), whereas fr ee FS was not detectable in the medium of any tumor (< 0.5 ng/mL). Tre atment with activin or FS did not consistently affect cell growth. Mea surement of serum activin A in a subset of subjects and in 27 addition al subjects with epithelial ovarian carcinoma (n = 33) revealed preope rative activin A levels > 3 SD above the mean for pre-and postmenopaus al women in 13/33 (39%) subjects. We conclude that in epithelial ovari an cancer: 1) beta A subunit mRNA is expressed, 2) activin protein is secreted more frequently than inhibin and in greater quantities than F S, 3) beta A subunit mRNA expression is greater in neoplastic and norm al epithelium in culture than in the primary tissue, 4) the majority o f tumors in culture do not respond to activin or FS treatment with pro liferation, and 5) serum activin levels may reflect tumor secretion in some patients. Thus, activin A appears to be available as an autocrin e/paracrine factor in epithelial ovarian tumors and may contribute to circulating levels, but its role in tumorigenesis has yet to be define d.