Altered expression of transforming growth factor-beta ligands and receptors in primary and recurrent ovarian carcinoma.

Abstract

Resistance to the potent growth inhibitory effects of transforming growth factor-beta (TGF-beta) is a characteristic of many malignancies. TGF-beta insensitivity has been attributed to alterations in the number and function of the TGF-beta receptors as well as disturbances of downstream signal transduction. Paradoxically, increased levels of TGF-beta ligand have been demonstrated in several types of malignant tumors. TGF-beta also may play a role in ovarian carcinogenesis; however, the nature of this interaction has yet to be defined completely. To explore the potential role of TGF-beta-mediated autocrine and paracrine influences in epithelial ovarian carcinoma, mRNA expression levels of the three TGF-beta ligand isoforms (TGF-beta1, TGF-beta2, and TGF-beta3) and the three TGF-beta receptors (TbetaR-I, T/betaR-II, and TbetaR-III) were examined by Northern blot analysis in both primary and recurrent ovarian carcinoma specimens. Immunohistochemical analysis was performed to localize expression of TbetaR-I and TbetaR-II, whereas the presence of genetic alterations in TbetaR-1 was examined through Southern blot analysis. Compared with normal ovarian tissue, both primary and recurrent ovarian carcinomas demonstrated significant overexpression of the TGF-beta1 and TGF-beta3 mRNA transcripts. TGF-beta2 expression was detectable in 75% of primary and only 53% of recurrent tumor specimens. Alterations also were detected in TbetaR mRNA expression. Expression levels of TbetaR-III were significantly reduced in both primary and recurrent ovarian carcinomas. Furthermore, detectable levels of TbetaR-I and TbetaR-III mRNA transcripts were present in only 47% and 50% of recurrent ovarian tumors, respectively. Immunohistochemical staining demonstrated that TbetaR-I and TbetaR-II expression localized to tumor cells; however, receptor staining in stromal tissue also was detected. Southern blot analysis of TbetaR-I did not reveal any major genetic changes to account for the absence of TbetaR-I expression. Alterations in expression of TGF-beta ligands and receptors consistently were greater in recurrent ovarian carcinomas compared with primary tumors, and may reflect a phenotype that promotes tumor recurrence or chemoresistance. Together, these data suggest that enhanced expression of TGF-betaI and TGF-beta3, as well as the loss of expression of TbetaR-I and TbetaR-III, contribute to ovarian carcinogenesis and/or tumor progression.