Activated Status of mTOR-HIF-1-VEGF Pathway in Ovarian Clear Cell Adenocarcinoma
M Yasuda, S Hori, M Miyazawa, H Kajiwara, N Ogane, M Shimizu. Saitama Medical University International Medical Center, Saitama, Japan; Tokai University School of Medicine, Kanagawa, Japan; Kanagawa Cancer Center, Kanagawa, Japan
Background: Malignant tumors are usually involved in a relatively hypoxic state, which induces overexpression of hypoxia-inducible factor-1 (HIF-1) to satisfactorily enable the tumor to survive. Recently, the mechanism of HIF-1 activation through the phosphoinositide-3 kinase (PI3K) signaling pathway was explored in detail. Inhibition of the mammalian target of rapamycin (mTOR) pathway including HIF-1 is expected to play a major role in suppression of tumor cell growth, having recently drawn much attention as an anti-cancer therapeutic strategy for malignant tumors. Clinical trials with treatment of mTOR inhibitors, represented by the analogues of rapamycin, have been performed in some malignant tumors as well as in vitro studies.
Design: Focusing on clear cell adenocarcinoma (CLA) of the ovary in comparison with serous adenocarcinoma (SEA), immunohistochemical expressions of mTOR, phosphorylated-mTOR (p-mTOR), HIF-1, and vascular endothelial growth factor (VEGF) were examined in the surgically resected specimens of 29 SEAs and 49 CLAs. Using the cell lines of CLA (RMG-1 and W3uF), an experimental study was designed to clarify whether tumor suppression due to down-regulation of mTOR activity could represent a promising therapeutic strategy for CLA. After treatment of an analogue of rapamycin (everolimus), expressions of mTOR, p-mTOR, HIF-1 and VEGF were examined by western blotting. Then, a transplant xenograft model of RMG-1 was used to confirm the results of in vitro analysis.
Results: There were no significant differences in expressions of mTOR, HIF-1 and VEGF between SEA and CLA, but p-mTOR expression was more prominent in CLA than SEA. Although mTOR expression remained unchangeable in everolimus-treated cell lines, expressions of p-mTOR, HIF-1 and VEGF were shown to be sharply depressed. The same alterations were demonstrated in the xenograft model treated with everolimus. Many tumor cells were involved in necrosis with an inflammatory cell reaction. Irrespective of tumor degradation, no apparent decline of mTOR expression was observed, but p-mTOR reaction was shown to be nearly negative. HIF-1 and VEGF expressions fairly attenuated.
Conclusions: In comparison with SEA, CLA is characterized by activated mTOR status represented by marked expression of p-mTOR. This evidence is considered to support the mTOR-targeted therapeutic strategy for CLA.
Wednesday, March 11, 2009 9:30 AM
Poster Session V # 152, Wednesday Morning