Functional Expression of the Angiotensin II Type1 Receptor in Human Ovarian Carcinoma Cells and Its Blockade Therapy Resulting in Suppression of Tumor Invasion, Angiogenesis, and Peritoneal Dissemination

Abstract

Purpose: Angiotensin II is a bioactive peptide of the renin-angiotensin system, acting not only as a vasoconstrictor but also as a growth promoter via angiotensin II type 1 receptors (AT 1 R). The present study examined AT 1 R expression in human ovarian carcinoma and attempted to determine whether AT 1 R blocker could suppress the tumor progression. Experimental Design: Expression of AT 1 R, vascular endothelial growth factor (VEGF), and CD34 was immunohistochemically analyzed in ovarian tumor tissues (n = 99). Effects of AT 1 R blocker on invasive potential and VEGF secretion in ovarian cancer cells were examined in vitro. Effects of AT 1 R blocker in vivo were evaluated in a mouse model of peritoneal carcinomatosis. Results: AT 1 R was expressed in 57 of 67 (85%) invasive ovarian adenocarcinomas and 12 of 18 (66%) borderline malignant tumors but in only 2 of 14 (14%) benign cystadenomas. In invasive carcinomas,VEGF expression intensity and intratumor microvessel density were significantly higher in cases that were strongly positive for AT 1 R (n = 37) compared with those in cases weakly positive (n = 20) or negative (n = 10) for AT 1 R. Angiotensin II significantly enhanced the invasive potential and VEGF secretion in AT 1 R-positive SKOV-3 ovarian cancer cells, both of which were completely inhibited by the AT 1 R blocker candesartan. Administration of candesartan into SKOV-3-transplanted athymic mice resulted in the reduction of peritoneal dissemination, decreased ascitic VEGF concentration, and suppression of tumor angiogenesis. Conclusions: AT 1 R is functionally expressed in ovarian carcinoma and involved in tumor progression and angiogenesis. AT 1 R blockade therapy may become a novel and promising strategy for ovarian cancer treatment.

Angiotensin II type 1 receptor expression in ovarian cancer and its correlation with tumour angiogenesis and patient survival

“…Recently, we were the first to show that AT 1 R is expressed in human ovarian cancer cells and angiotensin II enhanced tumour cell invasion and VEGF expression/secretion via AT 1 R (Suganuma et al, 2005). Furthermore, we demonstrated that AT 1 R blocker suppresses angiogenesis and the peritoneal dissemination of ovarian cancer in a mouse model (Suganuma et al, 2005).…”

The renin-angiotensin system meets the hallmarks of cancer

“…32 AT1R expression is also strongly associated with ovarian tumour invasiveness and with the histological classification: AT1R is expressed in a high proportion of invasive ovarian adenocarcinomas and borderline malignant tumours, but it is expressed in few benign cystadenomas. 33 Recently, Krishnan and colleagues studied the capacity of Ang(1-7) to reduce prostate cancer metastasis in mice. They found in pre-treated mice with Ang(1-7) a prevention in metastatic tumour formation while the untreated mice developed tumours in metastatic sites.…”

Specific single chain variable fragment (ScFv) antibodies to angiotensin II AT2 receptor: evaluation of the angiotensin II receptor expression in normal and tumor-bearing mouse lung

“…Increasing evidence suggests that angiotensin II signaling plays an important role in carcinogenesis (Fujita et al 2005;Ino et al 2006;Kanehira et al 2005;Suganuma et al 2005;Takagi et al 2002:Egami 2003. However, the specific role of AT 2 in carcinogenesis has not been rigorously elucidated.…”