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

• Published in: Cancer research (Chicago, Ill.) Vol. 59; no. 3; pp. 720 - 727
• Main Authors: BAGNATO, A, SALANI, D, DI CASTRO, V, WU-WONG, J. R, TECCE, R, NICOTRA, M. R, VENUTI, A, NATALI, P. G
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.02.1999
• Subjects: Adult; Aged; Biological and medical sciences; Blotting, Northern; Cell Division - drug effects; Cell Division - physiology; Endothelin Receptor Antagonists; Endothelin-1 - biosynthesis; Endothelin-1 - pharmacology; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Medical sciences; Middle Aged; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Peptides, Cyclic - pharmacology; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin - biosynthesis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; RNA, Messenger - metabolism; Tumor Cells, Cultured; Tumors; Human; Carcinoma; Gene product; Tumoral tissue; Endothelin 1; Malignant tumor; Gene expression; In vitro; Female genital diseases; Ovarian diseases; Ovary; Autocrine secretion; Established cell line; Tumor progression; Advanced stage; Tumor cell; Biological receptor
• ISSN: 0008-5472; 1538-7445

In the present study, we have investigated the expression of endothelin 1 (ET-1) and the ET(A) receptor (ET(A)R) and ET(B) receptor (ET(B)R) 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). ET(A)R mRNA was also detected in 84% of the carcinomas examined, whereas ET(B)R mRNA was expressed in 50% of the tumors. The in vivo presence of mature ET-1 and ET(A)R 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 ET(A)R mRNA, whereas only 40% expressed ET(B)R mRNA. Radioligand binding studies showed that ET-1-producing cells also expressed functional ET(A)R, whereas no specific ET(B)R could be demonstrated. ET-1 stimulated dose-dependent [3H]thymidine incorporation and enhanced the mitogenic effect of epidermal growth factor. The ET(A)R-selective antagonist BQ 123 strongly inhibited ET-1-stimulated growth and substantially reduced the basal growth rate of unstimulated cells, whereas the ET(B)R-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 ET(A)R.