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Alterations of Hypoxia-Induced Factor Signaling Pathway Due to Mammalian Target of Rapamycin (mTOR) Suppression in Ovarian Clear Cell Adenocarcinoma: In Vivo and in Vitro Explorations for Clinical Trial

Hirasawa, Takeshi MD, PhD*; Miyazawa, Masaki PhD*; Yasuda, Masanori MD, PhD; Shida, Masako MD*; Ikeda, Masae MD, PhD*; Kajiwara, Hiroshi MD, PhD; Matsui, Naruaki PhD; Fujita, Mariko PhD§; Muramatsu, Toshinari MD, PhD*; Mikami, Mikio MD, PhD*

International Journal of Gynecological Cancer: September 2013 - Volume 23 - Issue 7 - p 1210–1218
doi: 10.1097/IGC.0b013e31829d2d51
Ovarian Cancer

Objectives Before setting into the clinical trial using a combination of mammalian target of rapamycin (mTOR) inhibitors (rapamycin and everolimus) and other anticancer drugs, this study was conducted to confirm the efficacy of the new therapeutic strategy for ovarian clear cell adenocarcinoma (CCA), which targeted mTOR–hypoxia-induced factor (HIF) signal transduction system.

Materials and Methods Using the cultured cells of CCA and animal models, alteration of mTOR-HIF cofactors and cell proliferation under the mTOR inhibitor–treated condition were analyzed.

Results Mammalian target of rapamycin–HIF cofactors were inhibited dependent on concentration by mTOR inhibitor, resulting in suppression of the cultured CCA proliferation. However, von Hippel-Lindau was up-regulated at the messenger RNA level. In the nude mice with subcutaneously implanted CCA cells, apoptosis and necrosis were detected especially around the center of the tumors in the mTOR inhibitor–treated group more conspicuously than in the nontreated group. In the assessment of combination therapy with other antitumor agents, a combined treatment with mTOR inhibitor and chemotherapeutic agents caused a significant decrease in tumor size compared to the chemotherapeutic agents–only group.

Conclusions Treatment by mTOR inhibitor is expected to down-regulate the cell proliferation of the CCA as a new therapeutic strategy.

*Department of Obstetrics and Gynecology, Tokai University School of Medicine, Isehara, Kanagawa, Japan; †Department of Pathology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan; ‡Department of Pathology, and §Department of Breast and Endocrine Surgery, Tokai University School of Medicine, Isehara, Kanagawa, Japan.

Address correspondence and reprint requests to Masanori Yasuda, MD, PhD, Department of Pathology, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan. E-mail:

This study was supported by grants from the Ministry of Education in Japan (No. 23592466), 2011-2013 (Ministry of Education, Culture, Sports, Science and Technology).

The authors declare no conflicts of interest.

Received February 6, 2013

Accepted May 22, 2013

© 2013 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.