Presence of activin, inhibin, and follistatin in epithelial ovarian carcinoma

Activin induces proliferation in epithelial ovarian carcinoma cell lines, whereas follistatin (FS), an activin binding protein, inhibits this action. To test the hypothesis that activin production, in excess of inhibin and FS, results in cell proliferation in epithelial ovarian tumors, messenger RNA (mRNA) expression of the activin family of proteins, FS, and activin type I and II receptors was examined in 25 primary epithelial ovarian tumors and tumor epithelium in culture (n = 7) using RT-PCR. Activin A was measured in the serum of ovarian cancer patients, and activin A, total inhibin, and FS protein secretion was measured from primary epithelial tumors in vitro. The effect of activin and FS on cell proliferation was assessed by measuring [³H]thymidine incorporation. All results were compared with normal ovarian epithelium. All epithelial ovarian tumors expressed mRNA for the α, βA, and βB subunits; FS 288 and 315; and the activin type IA, IB, II, and IIB receptors. βA mRNA expression, as assessed using semiquantitative RT-PCR, was 3-fold greater in cultured tumor epithelium than in primary tumors (band density 0.86 ± 0.17 vs. 0.28 ± 0.09; P < 0.01). In addition, βA mRNA was abundantly expressed in normal epithelium in culture (n = 2), whereas only trace amounts were seen in 2/9 primary 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 free FS was not detectable in the medium of any tumor (<0.5 ng/mL). Treatment with activin or FS did not consistently affect cell growth. Measurement of serum activin A in a subset of subjects and in 27 additional subjects with epithelial ovarian carcinoma (n = 33) revealed preoperative activin A levels >3 SD above the mean for pro- and postmenopausal women in 13/33 (39%) subjects. We conclude that in epithelial ovarian cancer: 1) βA subunit mRNA is expressed, 2) activin protein is secreted more frequently than inhibin and in greater quantities than FS, 3) βA subunit mRNA expression is greater in neoplastic and normal epithelium in culture than in the primary tissue, 4) the majority of tumors in culture do not respond to activin or FS treatment with proliferation, and 5) serum activin levels may reflect tumor secretion in some patients. Thus, activin A appears to be available as an autocrine/paracrine factor in epithelial ovarian tumors and may contribute to circulating levels, but its role in tumorigenesis has yet to be defined.