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Expression and Secretion of Inhibin and Activin in Normal and Neoplastic Uterine Tissues. High Levels of Serum Activin A in Women with Endometrial and Cervical Carcinoma¹

Department of Surgical Sciences (F.P.), Chair of Obstetrics and Gynecology, University of Udine, Udine, Italy; Institute of Obstetrics and Gynecology (P.F., S.L., R.G., A.G., A.R.G.), University of Pisa, Pisa, Italy; Auxologic Institute (P.V., A.M.D.B), University of Milano, Milano, Italy; and The Clayton Foundation Laboratories for Peptide Biology (W.V.), Salk Institute, La Jolla, California

Address all correspondence and requests for reprints to: Felice Petraglia, M.D., Department of Surgical Sciences, Chair of Obstetrics and Gynecology, University of Udine, piazzale S. Maria della Misericordia, 33100 Udine, Italy.

Abstract

Inhibins and activins are growth factors belonging to the transforming growth factor-ß) family and are known to influence cell proliferation and differentiation. Because transforming growth factor-ß is involved in physiological and tumoral changes of uterine tissues, the present study aimed to evaluate whether human normal and neoplastic endometrial and cervical epithelial cells express and secrete inhibin A, inhibin B, and activin A.

To test this hypothesis, different approaches were used. By RT-PCR, the expression of specific messenger RNAs (mRNAs) for the inhibin , activin ßA and ßB subunits, and activin receptor type II and type IIB was investigated: 1) in primary cultures of endometrial (stroma and epithelium) or cervical (epithelium) cells from healthy women; and 2) in specimens of endometrial or cervical carcinoma. To demonstrate a possible secretion of the proteins, dimeric inhibin A, inhibin B, and activin A were measured in culture medium of normal epithelial or stromal endometrial cells and in uterine washing fluid of healthy women or patients with endometrial adenocarcinoma. Levels of the proteins were also measured in serum of women with endometrial or cervical carcinoma.

Cultured endometrial stromal or epithelial cells and epithelial cervical cells expressed inhibin , activin ßA and ßB, and activin receptor type II and type IIB mRNAs. The same finding was obtained in specimens of endometrial or cervical carcinomas.

Dimeric inhibin A, inhibin B, and activin A were measured in culture medium of both endometrial and cervical cells. In particular, resulting activin A levels were significantly higher in epithelial than in stromal cultured endometrial cells (P < 0.01). Dimeric proteins were also detected in the washing fluid of the uterine cavities of healthy women (controls) and with endometrial adenocarcinoma, in which higher activin A levels were found (P < 0.01 vs. controls). Women with endometrial carcinoma showed serum activin A levels significantly higher than healthy controls (P < 0.01), which significantly decreased after surgical removal of endometrial or cervical tumors (P < 0.01).

The present study, for the first time, showed that inhibin A, inhibin B, and activin A, as well as activin receptors, are expressed in normal and neoplastic human uterine tissues. A secretion of activin A from tumoral cells into systemic circulation is suggested by the observation that the high levels in serum of patients with endometrial or cervical carcinoma decreased after the surgical removal of the tumor.

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