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[Cancer Research 59, 720-727, February 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 720-727, February 1, 1999]
© 1999 American Association for Cancer Research

Tumor Biology

Expression of Endothelin 1 and Endothelin A Receptor in Ovarian Carcinoma

Evidence for an Autocrine Role in Tumor Growth1

Anna Bagnato2, Debora Salani, Valeriana Di Castro, Jinshyun R. Wu-Wong, Raffaele Tecce, Maria Rita Nicotra, Aldo Venuti and Pier Giorgio Natali

Laboratories of Molecular Pathology and Ultrastructure [A. B., D. S., V. D. C., R. T.], Virology [A. V.], and Immunology [P. G. N.], Regina Elena Cancer Institute, 00158 Rome, Italy; Biotechnology Institute, Consiglio Nazionale delle Ricerche, 00161 Rome, Italy [M. R. N.]; and Pharmaceutical Product Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500 [J. R. W-W.]

In the present study, we have investigated the expression of endothelin 1 (ET-1) and the ETA receptor (ETAR) and ETB receptor (ETBR) in primary (n = 30) and metastatic (n = 8) ovarian carcinomas and their involvement in tumor growth. By reverse transcription-PCR and Northern blot analysis, we detected ET-1 mRNA in 90% of primary and 100% of metastatic ovarian carcinomas. ET-1 mRNA expression was significantly higher in tumors than in normal ovarian tissues (n = 12; P < 0.01). ETAR mRNA was also detected in 84% of the carcinomas examined, whereas ETBR mRNA was expressed in 50% of the tumors. The in vivo presence of mature ET-1 and ETAR was confirmed by immunohistochemistry, demonstrating a higher expression in primary and metastatic cells. Ten primary cultures of ovarian tumors secreted ET-1 and were positive for ET-1 and ETAR mRNA, whereas only 40% expressed ETBR mRNA. Radioligand binding studies showed that ET-1-producing cells also expressed functional ETAR, whereas no specific ETBR could be demonstrated. ET-1 stimulated dose-dependent [3H]thymidine incorporation and enhanced the mitogenic effect of epidermal growth factor. The ETAR-selective antagonist BQ 123 strongly inhibited ET-1-stimulated growth and substantially reduced the basal growth rate of unstimulated cells, whereas the ETBR-selective antagonist BQ 788 had no effect. In conclusion, the present data demonstrate a novel mechanism in the growth control of ovarian carcinoma in vivo mediated by the ET-1 autocrine loop that selectively occurs via the ETAR.




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