Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Cancer Chemother Pharmacol. 2010 Apr;65(5):889-93. doi: 10.1007/s00280-009-1094-6. Epub 2009 Aug 6.
Gastroenteropancreatic neuroendocrine tumors are rare, and the current WHO classification divides this tumor entity into well-differentiated (neuro)endocrine tumors, well-differentiated (neuro)endocrine carcinomas, and poorly differentiated (neuro)endocrine carcinomas. Poorly differentiated (neuro)endocrine carcinoma is extremely aggressive, and no appropriate therapeutic approach has been established. The mammalian target of rapamycin (mTOR), an important regulator of cell proliferation and protein translation, is activated in various malignancies. Recent phase II trial has revealed the efficacy of mTOR inhibitor (RAD001; everolimus) against low-to-intermediate grade neuroendocrine tumors. However, the beneficial role of mTOR inhibitor against poorly neuroendocrine carcinoma remains uncertain. The purpose of the present study was to determine the activation of mTOR in gastropancreatic neuroendocrine tumors, especially in poorly differentiated neuroendocrine carcinomas.
Expression of p-mTOR(Ser2448) was assessed by immunohistochemistry in 20 gastropancreatic neuroendocrine tumors (seven well-differentiated neuroendocrine tumors, four well-differentiated neuroendocrine carcinomas, and nine poorly differentiated neuroendocrine carcinomas). Double immunohistochemistry was performed with p-Akt for patients with high p-mTOR expression.
Expression of mTOR was seen in 9 (45%) of 20 gastroenteropancreatic neuroendocrine tumors. High expression of p-mTOR was seen in 6 (67%) of 9 poorly differentiated neuroendocrine carcinomas which was higher than the expression rate of well-differentiated neuroendocrine tumors and carcinomas, 3 (27%) of 11. All large cell neuroendocrine carcinomas showed high p-mTOR expression. Some tumor cells showed positive staining for p-mTOR co-expressed p-Akt.
High expression rate of p-mTOR in poorly differentiated neuroendocrine carcinomas (large-cell type) may suggest the potential role of mTOR inhibitors as effective therapeutic agents for this highly malignant disease.
胃肠胰神经内分泌肿瘤较为罕见，目前的世界卫生组织分类将该肿瘤实体分为分化良好的（神经）内分泌肿瘤、分化良好的（神经）内分泌癌和低分化（神经）内分泌癌。低分化（神经）内分泌癌侵袭性极强，目前尚无合适的治疗方法。雷帕霉素哺乳动物靶标（mTOR）是细胞增殖和蛋白质翻译的重要调节剂，在各种恶性肿瘤中被激活。最近的 II 期临床试验表明，mTOR 抑制剂（RAD001；依维莫司）对低至中级别神经内分泌肿瘤有效。然而，mTOR 抑制剂对低分化神经内分泌癌的有益作用尚不确定。本研究旨在确定 mTOR 在胃胰神经内分泌肿瘤中的激活情况，特别是在低分化神经内分泌癌中。
通过免疫组化检测 20 例胃胰神经内分泌肿瘤（7 例分化良好的神经内分泌肿瘤、4 例分化良好的神经内分泌癌和 9 例低分化神经内分泌癌）中 p-mTOR（Ser2448）的表达。对 mTOR 高表达的患者进行 p-Akt 的双免疫组化染色。
20 例胃肠胰神经内分泌肿瘤中有 9 例（45%）表达 mTOR。9 例低分化神经内分泌癌中有 6 例（67%）高表达 p-mTOR，高于分化良好的神经内分泌肿瘤和癌的表达率（11 例中的 3 例，27%）。所有大细胞神经内分泌癌均表现出高 p-mTOR 表达。一些肿瘤细胞表现出 p-mTOR 与 p-Akt 的共表达阳性染色。
低分化神经内分泌癌（大细胞型）中 p-mTOR 的高表达率可能提示 mTOR 抑制剂作为这种高度恶性疾病的有效治疗药物的潜在作用。
