Tumor stroma as the main source of inhibin production in ovarian epithelial tumors

Elevated serum inhibin levels have been found in ovarian cancer patients; however, the source of the elevated inhibin is uncertain. Previous studies of activin in human ovarian cancer suggest that activin may promote the growth of the tumor. The aims of this study were to examine the source of elevated inhibin from ovarian epithelial tumors (OETs) and to preliminarily investigate the role of the gonadotropin-inhibin/activin relationship in the development of OET.

The protein and mRNA expression of alpha and betaA subunits of inhibin/activin were examined by immunohistochemistry (IHC) and reverse transcription polymerase chain reaction (RT-PCR) in 120 OETs, including 30 benign cystadenomas, 30 borderline tumors, and 60 carcinomas. Stromal and epithelial cells were microdissected from 23 OETs to further examine the expression of alpha and betaA subunits by RT-PCR. Dimeric inhibin A and activin A production were measured by using the two-site ELISA from three OET cell lines in culture under treatment of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

betaA subunit was expressed in the epithelial component of 100% of the cystadenomas, in 80% of borderline tumors, and in 75% of the carcinomas, but not in tumor stroma. Inhibin alpha expression was not found in the epithelium of all OETs studied, but focal inhibin alpha immunoreactivity was seen in the tumor stroma (mainly luteinized stromal cells) in the majority of cases. Dimeric activin A was produced by all of the three OET cell lines with a 1.5-1.9-fold increment after FSH stimulation. However, activin A production was not augmented by LH treatment. No inhibin A was produced by the three OET cell lines with or without gonadotropin stimulation.

The stroma of OET is the major source in the production of inhibin alpha (monomer). Dimeric inhibin A production may be the result of combined efforts of the tumor stroma (alpha subunit) and epithelium (betaA subunit). Cellular, compartmental expression of inhibin and activin subunits may play a role in the development of OET, although the mechanism remains undefined. The unopposed activin A production stimulated by FSH in OET cell lines suggests that activin production may represent one of the cellular mechanisms of growth promotion by FSH.