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Altered expression of transforming growth factor‐β ligands and receptors in primary and recurrent ovarian carcinoma
Author(s) -
Bristow Robert E.,
Baldwin Rae Lynn,
Yamada S. Diane,
Korc Murray,
Karlan Beth Y.
Publication year - 1999
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/(sici)1097-0142(19990201)85:3<658::aid-cncr16>3.0.co;2-m
Subject(s) - autocrine signalling , ovarian carcinoma , paracrine signalling , biology , cancer research , transforming growth factor , transforming growth factor beta , ovarian cancer , immunohistochemistry , receptor , carcinogenesis , medicine , endocrinology , cancer , immunology , genetics
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.