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

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Abstract
BACKGROUND Resistance to the potent growth inhibitory effects of transforming growth factor-β (TGF-β) is a characteristic of many malignancies. TGF-β insensitivity has been attributed to alterations in the number and function of the TGF-β receptors as well as disturbances of downstream signal transduction. Paradoxically, increased levels of TGF-β ligand have been demonstrated in several types of malignant tumors. TGF-β also may play a role in ovarian carcinogenesis; however, the nature of this interaction has yet to be defined completely. METHODS To explore the potential role of TGF-β-mediated autocrine and paracrine influences in epithelial ovarian carcinoma, mRNA expression levels of the three TGF-β ligand isoforms (TGF-β1, TGF-β2, and TGF-β3) and the three TGF-β receptors (TβR-I, TβR-II, and TβR-III) were examined by Northern blot analysis in both primary and recurrent ovarian carcinoma specimens. Immunohistochemical analysis was performed to localize expression of TβR-I and TβR-II, whereas the presence of genetic alterations in TβR-I was examined through Southern blot analysis. RESULTS Compared with normal ovarian tissue, both primary and recurrent ovarian carcinomas demonstrated significant overexpression of the TGF-β1 and TGF-β3 mRNA transcripts. TGF-β2 expression was detectable in 75% of primary and only 53% of recurrent tumor specimens. Alterations also were detected in TβR mRNA expression. Expression levels of TβR-III were significantly reduced in both primary and recurrent ovarian carcinomas. Furthermore, detectable levels of TβR-I and TβR-III mRNA transcripts were present in only 47% and 50% of recurrent ovarian tumors, respectively. Immunohistochemical staining demonstrated that TβR-I and TβR-II expression localized to tumor cells; however, receptor staining in stromal tissue also was detected. Southern blot analysis of TβR-I did not reveal any major genetic changes to account for the absence of TβR-I expression. CONCLUSIONS Alterations in expression of TGF-β 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-β1 and TGF-β3, as well as the loss of expression of TβR-I and TβR-III, contribute to ovarian carcinogenesis and/or tumor progression. Cancer 1999;85:658–68. © 1999 American Cancer Society.