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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

Authors' Affiliations: Departments of ¹ Obstetrics and Gynecology and ² Division of Pathology/Clinical Laboratory, Nagoya University Graduate School of Medicine, Nagoya, Japan

Requests for reprints: Kazuhiko Ino, Departments of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Phone: 81-52-744-2261; Fax: 81-52-744-2268; E-mail: kazuino{at}med.nagoya-u.ac.jp.

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 (AT₁R). The present study examined AT₁R expression in human ovarian carcinoma and attempted to determine whether AT₁R blocker could suppress the tumor progression.

Experimental Design: Expression of AT₁R, vascular endothelial growth factor (VEGF), and CD34 was immunohistochemically analyzed in ovarian tumor tissues (n = 99). Effects of AT₁R blocker on invasive potential and VEGF secretion in ovarian cancer cells were examined in vitro. Effects of AT₁R blocker in vivo were evaluated in a mouse model of peritoneal carcinomatosis.

Results: AT₁R 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 AT₁R (n = 37) compared with those in cases weakly positive (n = 20) or negative (n = 10) for AT₁R. Angiotensin II significantly enhanced the invasive potential and VEGF secretion in AT₁R-positive SKOV-3 ovarian cancer cells, both of which were completely inhibited by the AT₁R 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: AT₁R is functionally expressed in ovarian carcinoma and involved in tumor progression and angiogenesis. AT₁R blockade therapy may become a novel and promising strategy for ovarian cancer treatment.

Key Words: AT₁ receptor • Microvessel density • Ovarian cancer • VEGF

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