Immunohistochemical Expression of Phospho-mTOR Is Associated With Poor Prognosis in Patients With Gallbladder Adenocarcinoma

Abstract

Context.-Advanced gallbladder carcinoma (GBC) is a highly fatal disease with poor prognosis and few therapeutic alternatives. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays a central role in cell growth and homeostasis. Its regulation is frequently altered in various tumors and is an attractive target for cancer therapy; however, its status in GBC remains unclear.Objective.-To characterize immunohistochemical expression and prognostic significance of phospho-mTOR in advanced gallbladder carcinoma.Design.-Phospho-mTOR expression was examined by immunohistochemistry in tissue microarrays containing 128 advanced GBCs and 99 cases of chronic cholecystitis, which were divided into 2 groups according to the presence or absence of metaplasia. To evaluate the association of the level of phospho-mTOR expression with clinical variables and patient survival, the advanced GBCs were classified as having low or high expression. Statistical analysis was performed by using a significance level of P , .05, and Kaplan-Meier curves were constructed for survival analysis.Results.-Immunostaining for phospho-mTOR was positive in 82 of 128 tumors (64.1%) and in 24% of chronic cholecystitis cases (16% nonmetaplasia and 32% with metaplasia) (P , .001). Survival analysis indicated that a high phospho-mTOR immunohistochemical expression was associated with poorer prognosis in patients with advanced GBC (P ¼ .02).Conclusions.-Metaplasia is a common finding in chronic cholecystitis and is considered a precursor lesion of dysplasia. Our results suggest that the activation of mTOR occurs very early during the development of GBC, contributing to the carcinogenesis process. PhosphomTOR expression is correlated with poor survival, supporting the potential of mTOR for targeted therapy.

Fibronectin promotes cell proliferation and invasion through mTOR signaling pathway activation in gallbladder cancer

“…4A). As one of the primary kinases downstream of PI3K/Akt, mTOR has recently been reported to be substantially activated in GBC [18,19], which prompted our interest in exploring the potential activation of Akt-mTOR signaling cascades by FN. We first assessed the activation status of mTOR and its major downstream effectors (4E-BP1 and p70S6K) in FN-treated GBC-SD and NOZ cells.…”

“…Recent studies have demonstrated that mTOR and p70S6K are substantially activated in GBC, especially in advanced tumors. Notably, highly expression of p-mTOR has been associated with worse prognosis in GBC patients [18,19]. Furthermore, the therapeutic targeting of mTOR was found to potently attenuate the migration and invasion of GBC cells via epithelial-mesenchymal transition inhibition [20].…”

Adenocarcinoma of the Gallbladder: Biology of Disease, Prognosticators, and Staging

“…Expression of this protein in CG is an independent prognostic marker for CG progression (Sun et al 2011). Expression of connective tissue growth factor/CTGF in CG was correlated with better survival in two studies (Alvarez et al 2008;Garcia et al 2013), while in another investigation a role of CTGF expression in CG progression was found (Garcia et al 2013). Part of CGs produce several classes of mucins (see below).…”

“…The mammalian target of rapamycin (mTOR), a serine/threonine kinase, plays an essential role in the regulation of cell growth and is frequently deregulated in cancers. In CG, phospho-mTOR is an overexpression in early phases of cancer evolution, associated with poor prognosis (Leal et al 2013). The sphingosine-1-phosphate receptor 1 (S1P1) is overexpressed in CG, and higher levels of S1P1 were significantly correlated with tumor differentiation, tumor mass, lymph node metastasis, invasion, and decreased survival time ).…”

Expression of insulin-like growth factor I receptor as a biomarker for predicting prognosis in biliary tract cancer patients

“…Activation of the Akt/mTOR signaling pathway may also result from enhanced HER2, activation since a significant percentage of human GB tumors have been shown to have positive expression of HER2 and/or EGFR (23-26). Leal et al (27,28) reported that phospho-mTOR was associated with poor prognosis and the Akt/mTOR substrate P70S6K is frequently phosphorylated in patients with GBCa. Our results revealed that ~70% of BTC samples expressed mTOR, which did not deviate from the IGF-IR expression rate.…”