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Research Articles: Therapeutics, Targets, and Development

Overexpression of PTEN in ovarian cancer cells suppresses i.p. dissemination and extends survival in mice

¹ Department of Obstetrics and Gynecology and ² Division of Genetic Therapeutics, Center for Molecular Medicine, School of Medicine, Jichi Medical University, Tochigi, Japan

Requests for reprints: Yuji Takei, Department of Obstetrics and Gynecology, School of Medicine, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. Phone: 81-285-58-7376; Fax: 81-285-44-8505. E-mail: ytakei{at}jichi.ac.jp

Abstract

The main mode of progression of ovarian cancer is peritoneal dissemination, and its inhibition may lead to improved outcome. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) reportedly inhibits the proliferation, migration, and invasion of cancer cells. The purpose of this study is to explore the possibility of PTEN gene therapy for ovarian cancer. We transfected the ovarian cancer cell line SHIN-3 [vascular endothelial growth factor (VEGF)–hypersecretory cell line] with PTEN or luciferase (LUC)–expressing plasmid. After selection, PTEN-overexpressing cells (SHIN-3/PTEN) and control cells (SHIN-3/LUC) were obtained. SHIN-3/PTEN implanted s.c. into nude mice was examined for the change in tumor diameter and the number of new blood vessels. Mice with peritoneally disseminated tumors created by i.p. inoculation of the same cells were examined for changes in body weight and abdominal circumference and for survival time. The growth of s.c. SHIN-3/PTEN was significantly lower than that of control (P < 0.001). Compared with controls, mice with i.p. inoculated SHIN-3/PTEN showed significantly smaller increases in the body weight and abdominal circumference (P < 0.01) and a significantly longer survival time (P < 0.05). VEGF concentration in the supernatant of SHIN-3/PTEN was about half that of controls (P < 0.05). The number of new blood vessels in SHIN-3/PTEN was significantly smaller than that in controls (P < 0.001). Overexpression of PTEN suppressed tumor growth and peritoneal dissemination of VEGF-hypersecretory ovarian cancer cells and prolonged the survival time of the mice with peritoneal disseminated tumor. PTEN gene therapy could have therapeutic potential for ovarian cancer and exerts some of this effect by inhibiting angiogenesis. [Mol Cancer Ther 2008;7(3):704–11]

Grant support: Ministry of Health, Labor and Welfare of Japan; Ministry of Education, Culture, Sports, Science and Technology, Japan grants-in-aid for scientific research; and Japan Medical Association grant-in-aid.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

³ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 11/22/06; revised 12/21/07; accepted 2/ 1/08.