Expression of endothelin 1 and endothelin A receptor in ovarian carcinoma:Evidence for an autocrine role in tumor growth

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 = 3 0) and metastatic (n = 8) ovarian carcinomas and their involvement in tumor growth. By reverse transcription-PCR and Northern blot analysis, we detect ed ET-1 mRNA in 90% of primary and 100% of metastatic ovarian carcinomas. E T-1 mRNA expression was significantly higher in tumors than in normal ovari an tissues (n = 12; P < 0.01). ETAR mRNA was also detected in 84% of the ca rcinomas examined, whereas ETAR mRNA was expressed in 50% of the tumors. Th e in vivo presence of mature ET-1 and ETAR was confirmed by immunohistochem istry, demonstrating a higher expression in primary and metastatic cells. T en primary cultures of ovarian tumors secreted ET-1 and were positive for E T-1 and ETAR mRNA, whereas only 40% expressed ETBR mRNA. Radioligand bindin g studies showed that ET-1-producing cells also expressed functional ETAR, whereas no specific ETBR could be demonstrated, ET-1 stimulated dose-depend ent [H-3]thymidine incorporation and enhanced the mitogenic effect of epide rmal 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 eff ect, In conclusion, the present data demonstrate a novel mechanism in the g rowth control of ovarian carcinoma in vivo mediated by the ET-1 autocrine l oop that selectively occurs via the ETAR.