Departments of Pathology and Surgical and Gastroenterological Sciences, University of Verona, Verona, Italy.
J Clin Oncol. 2010 Jan 10;28(2):245-55. doi: 10.1200/JCO.2008.21.5988. Epub 2009 Nov 16.
We investigated the global gene expression in a large panel of pancreatic endocrine tumors (PETs) aimed at identifying new potential targets for therapy and biomarkers to predict patient outcome.
Using a custom microarray, we analyzed 72 primary PETs, seven matched metastases, and 10 normal pancreatic samples. Relevant differentially expressed genes were validated by either quantitative real-time polymerase chain reaction or immunohistochemistry on tissue microarrays.
Our data showed that: tuberous sclerosis 2 (TSC2) and phosphatase and tensin homolog (PTEN) were downregulated in most of the primary tumors, and their low expression was significantly associated with shorter disease-free and overall survival; somatostatin receptor 2 (SSTR2) was absent or very low in insulinomas compared with nonfunctioning tumors; and expression of fibroblast growth factor 13 (FGF13) gene was significantly associated with the occurrence of liver metastasis and shorter disease-free survival. TSC2 and PTEN are two key inhibitors of the Akt/mammalian target of rapamycin (mTOR) pathway and the specific inhibition of mTOR with rapamycin or RAD001 inhibited cell proliferation of PET cell lines.
Our results strongly support a role for PI3K/Akt/mTOR pathway in PET, which ties in with the fact that mTOR inhibitors have reached phase III trials in neuroendocrine tumors. The finding of differential SSTR expression raises the potential for SSTR expression to be evaluated as a marker of response to somatostatin analogs. Finally, we identified FGF13 as a new prognostic marker that predicted poorer outcome in patients who were clinically considered free from disease.
我们研究了一大组胰腺内分泌肿瘤（PET）的全基因表达，旨在鉴定新的潜在治疗靶点和预测患者预后的生物标志物。
使用定制的微阵列，我们分析了 72 例原发 PET、7 例匹配的转移灶和 10 例正常胰腺样本。通过定量实时聚合酶链反应或组织微阵列免疫组织化学验证相关差异表达基因。
我们的数据表明：结节性硬化症 2 型（TSC2）和磷酸酶和张力蛋白同源物（PTEN）在大多数原发肿瘤中下调，其低表达与无病生存期和总生存期缩短显著相关；与无功能肿瘤相比，胰岛素瘤中生长抑素受体 2（SSTR2）缺失或非常低；成纤维细胞生长因子 13（FGF13）基因的表达与肝转移的发生和无病生存期缩短显著相关。TSC2 和 PTEN 是 Akt/哺乳动物雷帕霉素靶蛋白（mTOR）通路的两个关键抑制剂，雷帕霉素或 RAD001 对 mTOR 的特异性抑制抑制了 PET 细胞系的细胞增殖。
我们的结果强烈支持 PI3K/Akt/mTOR 通路在 PET 中的作用，这与 mTOR 抑制剂已在神经内分泌肿瘤中达到 III 期试验的事实相符。SSTR 表达差异的发现提出了评估 SSTR 表达作为对生长抑素类似物反应的标志物的潜力。最后，我们确定了 FGF13 作为一种新的预后标志物，可预测临床认为无疾病患者的预后较差。
