Abstract
We determined the expression of mammalian target of rapamycin (mTOR) and its activated form, p-mTOR, in Chinese patients with gastric cancer and its clinical effects and underlying mechanisms. Tissue microarray blocks containing gastric cancer tissue and matched noncancer gastric tissue specimens obtained from 1,072 patients were constructed. Expression of total mTOR and p-mTOR in these specimens was analyzed using immunohistochemical studies and confirmed by Western blotting. The overall rates of total mTOR and p-mTOR overexpression were 50.8% (545 of 1,072) and 46.5% (499 of 1,072), respectively. The p-mTOR overexpression was significantly correlated with total mTOR overexpression. Overexpression of total mTOR protein was significantly correlated with tumor differentiation, T1/T2 tumors, and stage I/II/III disease, whereas p-mTOR overexpression was significantly correlated with lymph node metastasis and all stage disease. The Cox proportional hazards model revealed that the overexpression of p-mTOR, but not total mTOR, was an independent prognostic factor for gastric cancer. The overexpression of p-mTOR also predicted the angiogenic phenotype of human gastric cancer and regulated angiogenesis of gastric cancer cells. Increased activation of mTOR is frequent in human gastric cancer and overexpression of p-mTOR is an independent prognostic factor, suggesting that mTOR pathway could be a potential target for therapy of this malignancy.
Highlights
Gastric cancer is the second leading cause of cancer-related deaths worldwide
We reported a construction of gastric cancer tissue microarray containing 1,072 tumor tissues and matched noncancerous tissues and used both microarray and standard molecular biology and animal models to evaluate the activation and function of mammalian target of rapamycin pathway in human gastric cancer.We showed that mTOR was frequently activated in gastric cancer
Both mTOR and p-mTOR overexpression was associated with tumor progression, only p-mTOR overexpression was an independent predictor of survival after resection of primary gastric cancer
Summary
Gastric cancer is the second leading cause of cancer-related deaths worldwide. More than one-third of all gastric cancer cases occur in China [1, 2]. We reported a construction of gastric cancer tissue microarray containing 1,072 tumor tissues and matched noncancerous tissues and used both microarray and standard molecular biology and animal models to evaluate the activation and function of mammalian target of rapamycin (mTOR) pathway in human gastric cancer.We showed that mTOR was frequently activated in gastric cancer. Both mTOR and p-mTOR overexpression was associated with tumor progression, only p-mTOR overexpression was an independent predictor of survival after resection of primary gastric cancer. Given the critical role of VEGF in cancer angiogenesis in general, those recent findings suggest a critical link between mTOR activation and VEGF-mediated angiogenesis in gastric cancer
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