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Published on: September 7, 2016
Altered expression of transforming growth factor-beta ligands and receptors in primary and recurrent ovarian
R E Bristow1, R L Baldwin, S D Yamada
1Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center and the University of California, Los Angeles 90048, USA.
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.
Insights
Transforming growth factor-beta (TGF-beta) signaling is altered in ovarian cancer, with increased TGF-beta1 and TGF-beta3 ligands and decreased TGF-beta receptors (TbetaR-I, TbetaR-III) observed. These changes are more pronounced in recurrent tumors, suggesting a role in ovarian carcinogenesis and chemoresistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Resistance to transforming growth factor-beta (TGF-beta) growth inhibition is common in malignancies.
- TGF-beta insensitivity involves altered TGF-beta receptors and downstream signaling.
- Elevated TGF-beta ligand levels are found in various tumors; its role in ovarian cancer is under investigation.
Purpose of the Study:
- To investigate the role of TGF-beta-mediated autocrine and paracrine signaling in epithelial ovarian carcinoma.
- To examine mRNA expression of TGF-beta ligand isoforms (TGF-beta1, TGF-beta2, TGF-beta3) and receptors (TbetaR-I, TbetaR-II, TbetaR-III) in ovarian tumors.
Main Methods:
- Northern blot analysis to quantify mRNA expression of TGF-beta ligands and receptors in primary and recurrent ovarian carcinomas.
- Immunohistochemical analysis to localize TbetaR-I and TbetaR-II expression.
- Southern blot analysis to detect genetic alterations in TbetaR-I.
Main Results:
- Significant overexpression of TGF-beta1 and TGF-beta3 mRNA was observed in both primary and recurrent ovarian carcinomas compared to normal tissue.
- TbetaR-III mRNA levels were significantly reduced in both primary and recurrent tumors.
- Expression of TbetaR-I and TbetaR-III mRNA was notably reduced in recurrent tumors; no major genetic alterations in TbetaR-I were found.
Conclusions:
- Alterations in TGF-beta ligand and receptor expression were more pronounced in recurrent ovarian carcinomas, potentially promoting tumor recurrence and chemoresistance.
- Enhanced TGF-beta1 and TGF-beta3 expression, coupled with loss of TbetaR-I and TbetaR-III expression, likely contributes to ovarian carcinogenesis and tumor progression.
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