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(American Journal of Pathology. 2000;157:1537-1547.)
© 2000 American Society for Investigative Pathology

Regular Articles

Role of Endothelin-1 in Neovascularization of Ovarian Carcinoma

Debora Salani*, Valeriana Di Castro*, Maria Rita Nicotra§, Laura Rosanò*, Raffaele Tecce*, Aldo Venuti{ddagger}, Pier Giorgio Natali{dagger} and Anna Bagnato*

From the Laboratories of Molecular Pathology and Ultrastructure,*
Immunology,{dagger}
and Virology,{ddagger}
Regina Elena Cancer Institute; and the Biotechnology Institute,§
Consiglio Nazionale delle Ricerche, Rome, Italy

Endothelin-1 (ET-1) is overexpressed in ovarian carcinomas and acts, via ETA receptors (ETAR), as an autocrine growth factor. In this study we investigate the role of ET-1 in the neovascularization of ovarian carcinoma. Archival specimens of primary (n = 40) and metastatic (n = 8) ovarian tumors were examined by immunohistochemistry for angiogenic factor and receptor expression and for microvessel density using antibodies against CD31, ET-1, vascular endothelial growth factor (VEGF), and their receptors. ET-1 expression correlated with neovascularization and with VEGF expression. The localization of functional ETAR and ETAR mRNA expression, as detected by autoradiography and in situ hybridization, was evident in tumors and in intratumoral vessels, whereas ETBR were expressed mainly in endothelial cells. High levels of ET-1 were detected in the majority of ascitic fluids of patients with ovarian carcinoma and significantly correlated with VEGF ascitic concentration. Furthermore ET-1, through ETAR, stimulated VEGF production in an ovarian carcinoma cell line, OVCA 433, by an extent comparable to hypoxia. Finally, conditioned media from OVCA 433 as well as ascitic fluids caused an increase in endothelial cell migration and the ET-1 receptor blockade significantly inhibited this angiogenic response. These findings indicate that ET-1 could modulate tumor angiogenesis, acting directly and in part through VEGF.




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