AKT and mTOR expression in human pancreatic ductal adenocarcinoma. Relevance for tumor biology.

Abstract

Background and study aimsSeveral signaling pathways interfere with pancreatic ductal adenocarcinoma (PDAC) carcinogenesis processes, among which the AKT-pathway. The relevance of proteins in this pathway for the malignant phenotype or prognosis of PDAC is incompletely understood. We aimed to study AKT-pathway proteins in PDAC. MethodsWe examined immunohistochemical expression of two main AKT pathway proteins, AKT and mTOR, in 99 PDAC. Protein expression patterns were analysed with regard to tumor features, to MAPK and TGFbeta pathway protein expression and, to cell proliferation. ResultsTumor AKT was more frequent in PDAC with an abundant stromal inflammatory infiltrate (p = 0.03). When considering intra-pancreatic PDACs, mTOR correlated to T2 as compared to T1-TNM stage tumors. When considering the entire series, mTOR correlated to intra-pancreatic tumors (T1- and T2-TNM stage) as compared to T3-TNM PDAC (Fisher p < 0.01 for both comparisons). mTOR expression was more frequent in PDAC with an abundant intratumor stromal component and tumors with a high Ki67-positive tumor cell component (Fisher p = 0.05 and p < 0.01, respectively). mTOR, related to SMAD4 (Fisher p < 0.01) as well as to nuclear ERK (Fisher p = 0.02). ConclusionThe results of this study indicate an intricated role, mainly for mTOR in PDAC cell proliferation and tumor components development. The relationships we have found between AKT and mTOR and, MAPK and SMAD-pathway proteins suggest interactions at several levels of the protein framework resulting in varied impact on cell proliferation and tumor behavior/development.