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

Robert E. Bristow, Rae Lynn Baldwin, S. Diane Yamada, Murray Korc, Beth Y. Karlan

Research output: Contribution to journalArticle

55 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)658-668
Number of pages11
JournalCancer
Volume85
Issue number3
DOIs
StatePublished - Feb 1 1999

Keywords

  • Iigand
  • Ovarian carcinoma
  • Receptor
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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