Abstract
49 Background: The phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B, PKB) signaling pathway plays a critical role in cell growth and survival. Dysregulation of this pathway has been found in a variety of cancer cells. Recently, constitutively active PI3K/Akt signaling has been firmly established as a major determinant for cell growth and survival in an array of cancers. Blocking the constitutively active PI3K/AKT signaling pathway provides a new strategy for targeted cancer therapy. The purpose of our present study was to investigate the expression of activated mTOR (p-mTOR), PTEN, and pAKT in non-neoplastic gastric tissue and in gastric cancer patients to determine their pattern of expression in gastric tumors and their prognostic significance. Methods: The expression of p-mTOR, pAKT, and PTEN was detected in specimens of 239 gastric cancers who underwent radical resection (R0) and in 200 non-neoplastic gastric tissues by immunohistochemistry. Slides were scanned and analyzed with an automated cellular imaging system (ACIS III, Dako). The correlation of p-mTOR, pAKT, and PTEN expression to clinicopathologic features and survival of gastric cancer was studied. Results: Overexpression of pMTOR in the cytoplasmic pattern, nuclear pAKT, and nuclear PTEN was observed in the non-neoplastic tissues when compared with gastric tumor tissues (all, p<0.001). Overexpression of pmTOR, pAKT, and PTEN in gastric tumors was closely correlated with pTNM stage (p<0.001, p=0.008, p=0,036, respectively). Patients with p-AKT positive showed significantly longer disease-free survival (DFS) and overall survival (OS) rates than those with pAKT-negative tumors in univariable analyses. In multivariable analyses, higher expression rates of pMTOR and losses of PTEN were significantly associated with worse overall survival. Conclusions: Taken together, the observations indicate the PI3K/Akt pathway plays an important role in the gastric carcinogenesis. A new strategy for combined chemotherapy of gastric cancer should be designed to more specifically block PI3K/Akt pathway for selected patients.
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