Mammalian target of rapamycin is activated in human gastric cancer and serves as a target for therapy in an experimental model

Abstract

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-1a (HIF-1a). Since mTOR is an upstream regulator of HIF-1a, 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 HIF1a 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-1a activation, and significantly impaired tumor cell migration. In vivo, rapamycintreatment 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. ' 2007 Wiley-Liss, Inc.

Relation between outcomes and localisation of p-mTOR expression in gastric cancer

“…The rate of negative p-mTOR in gastric cancer was similar to that in another study (Lang et al, 2007). That study also showed that negative expression of p-mTOR was observed in normal gastric mucosa, whereas its positive expression was more frequent in advanced disease.…”

Targeting the PI3K/mTOR Pathway in Murine Endocrine Cell Lines

“…Indeed, even when the treatment was started after the formation of liver metastases, rapamycin was able to slow tumor growth, likely as a result of a combination of a direct antiproliferative action and of possible indirect effects, such as antiangiogenic properties. 13,14 The inhibitory effects of rapamycin on tumor growth in vivo resulted in prolonged survival and improved clinical status.…”

“…Rapamycin and LY294002 were administered intraperitoneally at the dose of 1.5 mg/kg daily and 25 mg/kg three times a week, respectively, in accordance with previous studies. [13][14][15][16][17] Three protocols of administration were tested in STC-1 tumor-bearing mice. In the first protocol, 8 days after intrasplenic STC-1 injection to allow liver engraftment and early growth of tumor cells, mice were randomized into two groups.…”

Angiogenesis inhibitors in gastric and gastroesophageal junction cancer

“…The PI3K/AKT pathway is an intracellular signaling pathway that is important in angiogenesis [67]. Everolimus (RAD001) is an oral inhibitor of the mammalian target of rapamycin serine-threonine kinase (mTOR), inhibiting the PI3K/Akt/mTOR pathway.…”