Phospho-mTOR is not upregulated in metastatic SDHB paragangliomas.
Phospho-mTOR is not upregulated in metastatic SDHB paragangliomas.
复制标题
Phospho-mTOR 在转移性 SDHB 副神经节瘤中并未上调。
DOI：
10.1111/eci.12127
复制
发表时间：
2013
影响因子：
5.5
通讯作者：
Pacak,Karel
中科院分区：
文献类型：
--
作者：
Ghayee,HansK;Giubellino,Alessio;Click,Arielle;Kapur,Payal;Christie,Alana;Xie,Xian-Jin;Martucci,Victoria;Shay,JerryW;Souza,RhondaF;Pacak,Karel
背景嗜铬细胞瘤（PCCs）/副神经节瘤（PGL）是神经内分泌肿瘤，如果不治疗，可能导致心律失常和死亡。缺乏对转移性肿瘤患者的治疗。随着与mTOR通路相关的新PCC/PGL易感基因的发现，针对该通路的治疗靶点正在被深入探索。设计分析了来自两个三级医疗中心的21例人类PCC/PGL。对6例转移性SDHBPCC/PGL、15例非转移性PCC/PGL（包括1例TMEM 127 PCC和1例非转移性SDHBPGL）和6例正常肾上腺髓质中的磷酸化mTOR（pmTOR）、磷酸化S6 K（pS 6 K）、磷酸化肌醇3激酶（PI 3 K）、磷酸化4 EBP 1（p4 EBP 1）、HIF 1 α和MIB-1进行免疫组织化学（IHC）分析。染色强度和染色细胞百分比的乘积计算为H score.ResultsUsing双样本检验和配对t检验，pmTOR和pS 6 K在非转移性PCC/PGL中的H评分显著高于在转移性SDHBPCC/PGL中的H评分。HIF 1 α在转移性SDHBPCC/PGL中的H评分显著高于非转移性PCC/PGL和正常肾上腺髓质。当比较转移性SDHBPCC/PGL和非转移性PCC/PGL时，p4 EBP 1、PI 3 K和MIB-1的H评分无差异。pS 6 K在正常肾上腺髓质中的差异显著高于非转移性PCC/PGLs和metastaticSDHBPCC/PGLs.ConclusionThe目前的结果表明，单独使用mTOR抑制剂对metastaticSDHBPCC/PGLs可能不会达到良好的治疗效果的患者。
BackgroundPheochromocytomas (PCCs)/paragangliomas (PGLs) are neuroendocrine tumours that may cause arrhythmia and death if untreated. Treatment for patients with metastatic tumours is lacking. As new PCC/PGL susceptibility genes are discovered that are associated with the mTOR pathway, treatment targets focusing on this pathway are being intensively explored.DesignTwenty‐one human PCC/PGLs were analysed from two tertiary care centres. Immunohistochemistry (IHC) analysis was performed for phospho‐mTOR (pmTOR), phospho‐S6K (pS6K), phosphoinositide 3‐kinase (PI3K), phospho‐4EBP1 (p4EBP1), HIF1α and MIB‐1 in 6 metastaticSDHBPCC/PGLs, 15 nonmetastatic PCC/PGLs, (including 1TMEM127PCC and 1 nonmetastaticSDHBPGL) and 6 normal adrenal medullas. The product of the intensity of stain and percentage of cells stained was calculated as an H score.ResultsUsing a two‐samplet‐test and pairedt‐test, pmTOR and pS6K had significantly higher H scores in nonmetastatic PCC/PGLs than in metastaticSDHBPCC/PGLs. HIF1α had significantly higher H scores in metastaticSDHBPCC/PGLs compared with nonmetastatic PCC/PGLs and normal adrenal medulla. No difference in H scores was seen with p4EBP1, PI3K and MIB‐1 when comparing metastaticSDHBPCC/PGLs and nonmetastatic PCC/PGLs. Significantly higher difference in pS6K was seen in normal adrenal medullas compared to nonmetastatic PCC/PGLs and metastaticSDHBPCC/PGLs.ConclusionThe present results suggest that the use of mTOR inhibitors alone for metastaticSDHBPCC/PGLs may not achieve good therapeutic efficacy in patients.