Role of Endothelin-1 in Neovascularization of Ovarian Carcinoma

Abstract

Endothelin-1 (ET-1) is overexpressed in ovarian carcinomas and acts, via ET(A) receptors (ET(A)R), 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 ET(A)R and ET(A)R mRNA expression, as detected by autoradiography and in situ hybridization, was evident in tumors and in intratumoral vessels, whereas ET(B)R 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 ET(A)R, 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.

Inhibitory effect of endothelin A receptor blockade on tumor growth and liver metastasis of a human gastric cancer cell line

“…Elevated plasma levels of ET-1 have also been detected in patients with various solid tumors, including hepatocellular [8] and colorectal [9] cancers. Furthermore, increased ET-A expression in malignant tissue has been demonstrated in several cancer types, including breast [10], ovarian [11], and advanced prostate [12] cancer. The engagement of ET-A by ET-1 is known to trigger activation of tumor growth [13], VEGF-induced angiogenesis [11], cancer cell invasiveness [14], and inhibition of apoptosis [15].…”

ZD4054, a specific antagonist of the endothelin A receptor, inhibits tumor growth and enhances paclitaxel activity in human ovarian carcinoma in vitro and in vivo

“…Interestingly, in gene expression profiles of latestage ovarian cancer, ET A R was identified as a metastasisassociated gene that activates cell signaling involved in the control of cell migration, spread, and invasion (8,9). Levels of ET-1 are markedly elevated in the ascites of patients with epithelial ovarian cancer (10) and, together with the ET A R, are overexpressed and activated in 85% of ovarian tumors, correlating with advanced stages (7,11,12). In ovarian cancer cells, the autocrine loop mediated by the ET-1/ET A R receptor-ligand interaction has been implicated in the parallel activation of several signal transduction pathways, including Ras/Raf/mitogenactivated protein kinase (MAPK), phosphoinositide-3-kinase (PI3K) -dependent integrin-linked kinase and AKT activation, Src-mediated epidermal growth factor receptor transactivation, and p125 focal adhesion kinase and paxillin modulation (8, 13 -15).…”

Expression of Endothelin-A-Receptor predicts unfavourable response to neoadjuvant chemotherapy in locally advanced breast cancer

“…Of the three ET isoforms, ET-1 has been the most extensively studied, and appears to be the most important isoform in cancer pathophysiology (Grant et al, 2003;Nelson et al, 2003). ET-1 expression is increased in several human malignancies including ovarian, prostate and colorectal cancer (Nelson et al, 1996(Nelson et al, , 2003Salani et al, 2000;Asham et al 2001). Upregulation of ET-1 occurs in response to cell activation and is induced by various stimuli such as hypoxia, growth factors, and cytokines (Kourembanas et al, 1991).…”

“…With respect to ET receptors, predominantly ET A R mediates tumour-associated functions, whereas there is less evidence for ET B R-dependent tumour-related functions (Grant et al, 2003;Nelson et al, 2003). Engagement of ET A -receptor by ET-1 triggers tumorigenesis and tumour progression by activation of tumour proliferation, invasion, angiogenesis, and inhibition of apoptosis (Pedram et al, 1997;Bagnato and Catt, 1998;Bagnato et al, 1999;Eberl et al, 2000b;Salani et al, 2000;Rosano et al, 2001;Del Bufalo et al, 2002). There is also evidence for an autocrine and/or paracrine mechanism of action of ET-1 including angiogenesis-promoting effects in malignant tissues.…”

“…There is also evidence for an autocrine and/or paracrine mechanism of action of ET-1 including angiogenesis-promoting effects in malignant tissues. It has been shown that ET-1 induces endothelial cell growth through ET B R and exerts mitogenic effects on vascular smooth muscle cells and pericytes through ET A R (Bek and McMillen, 2000;Salani et al, 2000). Moreover, activation of ET A R by ET-1 stimulates the production of VEGF, which in turn induces endothelial cell proliferation and vascular permeability by increasing the levels of HIF-1a .…”