The
mammalian target of rapamycin (mTOR) has become an interesting target for
cancer therapy through its influence on oncogenic signals, which involve phosphatidylinositol-3-kinase and
hypoxia-inducible factor-1alpha (HIF-1alpha). Since mTOR is an upstream regulator of HIF-1alpha, a key mediator of
gastric cancer growth and angiogenesis, we investigated mTOR activation in human gastric
adenocarcinoma specimens and determined whether
rapamycin could inhibit
gastric cancer growth in mice. Expression of phospho-mTOR was assessed by immunohistochemical analyses of human tissues. For in vitro studies, human
gastric cancer cell lines were used to determine S6K1, 4E-BP-1 and HIF-1alpha activation and
cancer cell motility upon
rapamycin treatment. Effects of
rapamycin on
tumor growth and angiogenesis in vivo were assessed in both a subcutaneous
tumor model and in an experimental model with orthotopically grown
tumors. Mice received either
rapamycin (0.5 mg/kg/day or 1.5 mg/kg/day) or diluent per intra-peritoneal
injections. In addition, antiangiogenic effects were monitored in vivo using a dorsal-skin-fold chamber model. Immunohistochemical analyses showed strong expression of phospho-mTOR in 60% of intestinal- and 64% of diffuse-type human gastric
adenocarcinomas. In vitro,
rapamycin-treatment effectively blocked S6K1, 4E-BP-1 and HIF-1alpha activation, and significantly impaired
tumor cell migration. In vivo,
rapamycin-treatment led to significant inhibition of subcutaneous
tumor growth, decreased CD31-positive vessel area and reduced
tumor cell proliferation. Similar significant results were obtained in an orthotopic model of
gastric cancer. In the dorsal-skin-fold chamber model,
rapamycin-treatment significantly inhibited
tumor vascularization in vivo. In conclusion, mTOR is frequently activated in human
gastric cancer and represents a promising new molecular target for
therapy.