Krencz Ildikó, Sebestyén Anna, Fábián Katalin, Márk Ágnes, Moldvay Judit, Khoor András, Kopper László, Pápay Judit
1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary.
1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary; Tumor Progression Research Group Joint Research Organization of Hungarian Academy of Sciences and Semmelweis University, 1117 Budapest, Hungary.
Hum Pathol. 2017 Apr;62:66-73. doi: 10.1016/j.humpath.2016.12.012. Epub 2016 Dec 24.
Brain metastases (BMs) are common complications of adenocarcinomas (ADCs) of the lung and are associated with a poor prognosis. Although an increasing amount of data indicates that dysregulated activity of mammalian target of rapamycin (mTOR) can influence the metastatic potential of various tumors, the role of mTOR complexes in the development of BMs from ADCs of the lung is largely unknown. To estimate mTOR activity, we studied the expression of mTOR-related proteins (mTORC1: p-mTOR, p-S6; mTORC2: p-mTOR, Rictor) in primary (n=67) and brain metastatic (n=67) lung ADCs, including 15 paired tissue samples, using immunohistochemistry and tissue microarrays. Correlation with clinicopathological parameters was also analyzed. Increased p-mTOR, p-S6, and Rictor expressions were observed in 34%, 33%, and 37% of primary ADCs and in 79%, 70%, and 66% of BMs, respectively. Expression of these markers was significantly higher in BMs as compared with primary carcinomas (P<.0001, P<.0001, P<.001). Rictor expression was significantly higher in primary ADCs of the paired cases with BMs as compared with primary ADCs without BMs (67% versus 28%; P<.01). No other statistically significant correlations were found between mTOR activity and clinicopathological parameters. The increased mTORC1/C2 activity in a subset of pulmonary ADCs and the higher incidence of increased mTORC1/C2 activity in BMs suggest that the immunohistochemistry panel for characterizing mTOR activity and its potential predictive and prognostic role warrants further investigations.
脑转移瘤（BMs）是肺腺癌（ADCs）常见的并发症，且与预后不良相关。尽管越来越多的数据表明，雷帕霉素哺乳动物靶蛋白（mTOR）活性失调可影响各种肿瘤的转移潜能，但mTOR复合物在肺腺癌脑转移瘤发生发展中的作用仍不清楚。为评估mTOR活性，我们采用免疫组织化学和组织芯片技术，研究了原发性肺腺癌（n = 67）和脑转移瘤（n = 67）中mTOR相关蛋白（mTORC1：p - mTOR、p - S6；mTORC2：p - mTOR、Rictor）的表达，其中包括15对配对组织样本。还分析了其与临床病理参数的相关性。原发性肺腺癌中p - mTOR、p - S6和Rictor表达增加的分别占34%、33%和37%，脑转移瘤中分别占79%、70%和66%。与原发性癌相比，这些标志物在脑转移瘤中的表达显著更高（P <.0001，P <.0001，P <.001）。与无脑转移瘤的原发性肺腺癌相比，有脑转移瘤的配对病例中原发性肺腺癌中Rictor表达显著更高（67%对28%；P <.01）。未发现mTOR活性与临床病理参数之间存在其他具有统计学意义的相关性。肺腺癌亚组中mTORC1/C2活性增加以及脑转移瘤中mTORC1/C2活性增加的发生率更高，提示用于表征mTOR活性及其潜在预测和预后作用的免疫组织化学检测值得进一步研究。
