Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Ann Surg Oncol. 2010 Sep;17(9):2486-93. doi: 10.1245/s10434-010-1040-1. Epub 2010 Mar 26.
The mammalian target of rapamycin (mTOR) plays central roles in the regulation of cell growth and proliferation by monitoring nutrient availability, cellular energy level, oxygen level, and mitogenic signals. The aberrant activation of mTOR in relation to clinical outcome has been reported in several types of cancers. mTOR is increasingly important as a potential target for anticancer therapy. Nonetheless, a prognostic feature of mTOR activation in esophageal squamous cell carcinoma (ESCC) remains uncertain.
First, in order to validate phospho-specific mTOR antibody (Ser2448), phosphorylated mTOR (p-mTOR) expression levels in five ESCC cell lines under cultural conditions with or without everolimus (mTOR inhibitor, also known as RAD001) were evaluated by in vitro immunohistochemistry and immunoblotting. Second, we examined p-mTOR expression by immunohistochemistry using 143 resected ESCC specimens. Prognostic significance of p-mTOR expression was examined by Cox regression and Kaplan-Meier analyses.
Among 143 patients, 71 (49.7%) were classified into p-mTOR-positive and 72 (50.3%) were classified into p-mTOR-negative. Compared with p-mTOR-negative patients, p-mTOR-positive patients experienced high overall mortality [hazard ratio (HR) 2.44; 95% confidence interval (CI), 1.24-4.83; P = 0.008], which persisted in multivariate analysis (multivariate HR 2.92; 95% CI, 1.48-5.78; P = 0.002). A similar finding was observed for esophageal cancer-specific mortality. p-mTOR expression was not related with any clinical or pathologic variables including age, sex, tumor location, histological grading, operative procedure, T classification (tumor invasion), or lymph-node metastasis.
p-mTOR overexpression was independently associated with poor prognosis in ESCC, supporting the potential for mTOR as a therapeutic target for ESCC.
哺乳动物雷帕霉素靶蛋白（mTOR）通过监测营养物质可用性、细胞能量水平、氧水平和有丝分裂信号等途径，在细胞生长和增殖的调控中发挥核心作用。在几种类型的癌症中，与临床结果相关的 mTOR 异常激活已有报道。mTOR 作为一种潜在的抗癌治疗靶点变得越来越重要。然而，mTOR 激活在食管鳞状细胞癌（ESCC）中的预后特征仍不确定。
首先，为了验证磷酸化特异性 mTOR 抗体（Ser2448），我们通过体外免疫组织化学和免疫印迹法评估了在文化条件下（有无依维莫司[ mTOR 抑制剂，也称为 RAD001]）五种 ESCC 细胞系中磷酸化 mTOR（p-mTOR）的表达水平。其次，我们使用 143 例切除的 ESCC 标本通过免疫组织化学检测 p-mTOR 表达。通过 Cox 回归和 Kaplan-Meier 分析检查 p-mTOR 表达的预后意义。
在 143 例患者中，71 例（49.7%）被归类为 p-mTOR 阳性，72 例（50.3%）被归类为 p-mTOR 阴性。与 p-mTOR 阴性患者相比，p-mTOR 阳性患者的总死亡率较高[风险比（HR）2.44；95%置信区间（CI），1.24-4.83；P = 0.008]，这在多变量分析中仍然存在（多变量 HR 2.92；95% CI，1.48-5.78；P = 0.002）。在食管癌特异性死亡率方面也观察到了类似的发现。p-mTOR 表达与包括年龄、性别、肿瘤位置、组织学分级、手术程序、T 分类（肿瘤侵袭）或淋巴结转移在内的任何临床或病理变量均无关。
p-mTOR 过表达与 ESCC 的不良预后独立相关，支持 mTOR 作为 ESCC 的治疗靶点的潜力。
