Han Xu, Ji Yuan, Zhao Jing, Xu Xuefeng, Lou Wenhui
Department of Pancreatic Surgery, Zhong Shan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
Tumour Biol. 2013 Oct;34(5):2871-9. doi: 10.1007/s13277-013-0849-1. Epub 2013 May 19.
The purposes of this study were to clarify the expression patterns of phosphorylated mammalian target of rapamycin (p-mTOR), mTOR, and phosphatase and tensin homolog (PTEN) in primary pancreatic neuroendocrine tumors (pNETs) and their significance in predicting clinical behaviors and postoperative outcomes. The expressions of p-mTOR, mTOR, and PTEN were assessed in 20 normal pancreatic islets and in 90 resectable pNETs using immunohistochemistry. The associations of the biomarker expressions with clinicopathologic variables and survival duration were analyzed. The percentages of G1, G2, and G3 tumors were 54.4, 43.3, and 2.2 %, respectively. A strongly positive staining was observed for both mTOR and PTEN in normal pancreatic islets, whereas negative staining was observed for p-mTOR. In primary pNETs, the mTOR and p-mTOR positive rates were 70.8 % (63/89) and 44.4 % (40/90), respectively. p-mTOR expressions strongly correlate with mTOR expressions. No significant correlation between p-mTOR and clinicopathological features was found. The high expression rate of PTEN was 56.7 % (51/90), whereas the low expression rate was 43.4 % (39/90). PTEN loss (low expression) was significantly more frequent in patients with advanced WHO grades (p = 0.004) and in patients with higher Ki-67 index (p = 0.002). In our immunohistochemical classification system, the Ki-67 index was significantly higher in the PTEN low expression/p-mTOR-positive subgroup (2.7 ± 2.5) than in the PTEN high expression/p-mTOR-negative subgroup (1.0 ± 1.7, p = 0.006). Patients in the PTEN low expression/p-mTOR-positive subgroup presented a significantly lower 5-year overall survival (OS) than those in the PTEN high expression/p-mTOR-negative subgroup (p = 0.049; 5-year OS = 79 vs. 100 %, HR = 7.0). ENETS TNM staging and major vascular invasion were independently associated factors for predicting the overall survival rate of patients (p = 0.019 and 0.011, respectively). In conclusion, positive p-mTOR expression and PTEN loss may have a synergic effect on tumorigenesis and proliferation; targeted therapy based on mTOR/PTEN signal pathway and its associated molecular mechanism may play a role in the treatment of pancreatic neuroendocrine tumors.
本研究的目的是阐明磷酸化雷帕霉素哺乳动物靶蛋白（p-mTOR）、mTOR和磷酸酶及张力蛋白同源物（PTEN）在原发性胰腺神经内分泌肿瘤（pNETs）中的表达模式及其在预测临床行为和术后结局中的意义。采用免疫组织化学方法评估20个正常胰岛和90个可切除pNETs中p-mTOR、mTOR及PTEN的表达情况。分析生物标志物表达与临床病理变量及生存时间的相关性。G1、G2和G3肿瘤的比例分别为54.4%、43.3%和2.2%。在正常胰岛中mTOR和PTEN均呈强阳性染色，但p-mTOR呈阴性染色。在原发性pNETs中，mTOR和p-mTOR的阳性率分别为70.8%（63/89）和44.4%（40/90）。p-mTOR表达与mTOR表达密切相关。未发现p-mTOR与临床病理特征之间存在显著相关性。PTEN高表达率为56.7%（51/90），低表达率为43.4%（39/90）。PTEN缺失（低表达）在WHO分级较高的患者（p = 0.004）和Ki-67指数较高的患者（p = 0.002）中更为常见。在我们的免疫组织化学分类系统中，PTEN低表达/p-mTOR阳性亚组的Ki-67指数（2.7±2.5）显著高于PTEN高表达/p-mTOR阴性亚组（1.0±1.7，p = 0.006）。PTEN低表达/p-mTOR阳性亚组患者的5年总生存率（OS）明显低于PTEN高表达/p-mTOR阴性亚组（p = 0.049；5年OS = 79%对100%，HR = 7.0）。ENETS TNM分期和主要血管侵犯是预测患者总生存率的独立相关因素（分别为p = 0.019和0.011）。总之，p-mTOR阳性表达和PTEN缺失可能对肿瘤发生和增殖具有协同作用；基于mTOR/PTEN信号通路及其相关分子机制的靶向治疗可能在胰腺神经内分泌肿瘤治疗中发挥作用。
