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-CARCINOMA

Inhibins and activins are growth factors belonging to the trans formin g growth factor-beta) family and are known to influence cell prolifera tion and differentiation. Because transforming growth factor-beta is i nvolved in physiological and tumoral changes of uterine tissues. the p resent study aimed to evaluate whether human normal and neoplastic end ometrial and cervical epithelial cells express and secrete inhibin A, inhibin B, and activin A. To test this hypothesis, different approache s were used. Ey RT-PCR, the expression of specific messenger RNAs (mRN As) for the inhibin alpha, activin beta A and beta B subunits, and act ivin receptor type II and type IIB was investigated: 1) in primary cul tures of endometrial (stroma and epithelium) or cervical (epithelium) cells from healthy women; and 2) in specimens of endometrial or cervic al carcinoma. To demonstrate a possible secretion of the proteins, dim eric inhibin A, inhibin B, and activin A were measured in culture medi um of normal epithelial or stromal endometrial cells and in uterine wa shing fluid of healthy women or patients with endometrial adenocarcino ma. Levels of the proteins were also measured in serum of women with e ndometrial or cervical carcinoma. Cultured endometrial stromal or epit helial cells and epithelial cervical cells expressed inhibin alpha, ac tivin beta A and beta B, and activin receptor type II and type IIB mRN As. The same finding was obtained in specimens of endometrial or cervi cal carcinomas. Dimeric inhibin A, inhibin BI and activin A were measu red in culture medium of both endometrial and cervical cells. In parti cular, resulting activin A levels were significantly higher in epithel ial than in stromal cultured endometrial cells (P < 0.01). Dimeric pro teins were also detected in the washing fluid of the uterine cavities of healthy women (controls) and with endometrial adenocarcinoma, in wh ich higher activin A levels mere found (P < 0.01 us. controls). Women with endometrial carcinoma showed serum activin A levels significantly higher than healthy controls (P < 0.01), which significantly decrease d 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 norm al and neoplastic human uterine tissues. A secretion of activin A from tumoral cells into systemic circulation is suggested by the observati on that the high levels in serum of patients with endometrial or cervi cal carcinoma decreased after the surgical removal of the tumor.