Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.