Overexpression of Phosphorylated Mammalian Target of Rapamycin Predicts Lymph Node Metastasis and Prognosis of Chinese Patients with Gastric Cancer

• Published in: Clinical cancer research 2009-03, Vol.15 (5), p.1821-1829
• Main Authors: Yu, Guanzhen, Wang, Jiejun, Chen, Ying, Wang, Xi, Pan, Jun, Li, Gang, Jia, Zhiliang, Li, Qiang, Yao, James C, Xie, Keping
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - metabolism; Adenocarcinoma - secondary; Adenocarcinoma, Mucinous - metabolism; Adenocarcinoma, Mucinous - secondary; angiogenesis; Animals; Antineoplastic agents; Asian Continental Ancestry Group; Biological and medical sciences; Blotting, Western; Carcinoma, Papillary - metabolism; Carcinoma, Papillary - secondary; Carcinoma, Signet Ring Cell - metabolism; Carcinoma, Signet Ring Cell - secondary; Cells, Cultured; Endothelium, Vascular; Female; gastric cancer; Gastroenterology. Liver. Pancreas. Abdomen; Hematologic and hematopoietic diseases; Humans; Immunoenzyme Techniques; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Lymphatic Metastasis; Male; Medical sciences; Mice; Mice, Nude; Middle Aged; mTOR; Neoplasm Staging; Neovascularization, Pathologic; Pharmacology. Drug treatments; Phosphorylation; Prognosis; Protein Kinases - metabolism; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Survival Rate; Tissue Array Analysis; tissue microarray; TOR Serine-Threonine Kinases; Tumors; Vascular Endothelial Growth Factor A - metabolism; VEGF; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-2138

Purpose: 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. Experimental Design: 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. Results: 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, T 1 /T 2 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. Conclusions: 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.