Critical and Diverse Involvement of Akt/Mammalian Target of Rapamycin Signaling in Human Lung Carcinomas
Critical and Diverse Involvement of Akt/Mammalian Target of Rapamycin Signaling in Human Lung Carcinomas
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DOI：
10.1002/cncr.23996
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发表时间：
2009-01-01
期刊：
影响因子：
6.2
通讯作者：
Ooi, Akishi
中科院分区：
文献类型：
--
作者：
Dobashi, Yoh;Suzuki, Shioto;Ooi, Akishi
背景技术背景：表皮生长因子受体（EGFR）的异常信号级联参与了肺癌中复杂的致癌信号网络。一种代表性级联是磷脂酰肌醇3-激酶/Akt/哺乳动物雷帕霉素靶（mTOR）途径。方法：作者通过免疫组织化学和免疫印迹技术分别与上游和下游蛋白Akt和p70 S6-激酶（S6 K）相关，研究了mTOR在150例肺癌标本中的病理生物学特征。研究结果：免疫组化显示44%的肿瘤中Akt活化，68.7%的肿瘤中mTOR表达，并且在腺癌（AC）中观察到活化的优势（100%）。在53.3%的肿瘤中观察到磷酸化mTOR（p-mTOR），在AC中的频率最高（89.7%）。在AC中，p-mTOR染色的频率在分化良好的亚型中较高，特别是在腺泡结构中。然而，除了5例携带EGFR基因突变的AC标本（其表现出Akt和mTOR的组成性激活）外，在mTOR和Akt的激活之间几乎没有观察到相关性。相反，在鳞状细胞癌中，mTOR激活与淋巴结转移的频率显著较高相关。结论：本研究结果提示mTOR具有双重功能。首先，mTOR不仅作为EGFR下游的效应分子参与肿瘤细胞的增殖，还可能参与AC的形态发生。其次，mTOR的激活可能在鳞状细胞癌的转移中起关键作用。总的来说，目前的结果证明了雷帕霉素（一种mTOR抑制剂）作为一种额外的新的化疗成分用于肺癌患者的潜在应用。Cancer 2009;115：107-18. (C)2008美国癌症协会
BACKGROUND: Aberrant signaling cascades emanating from epidermal growth factor receptor (EGFR) are involved in the complex network of oncogenic signaling in lung carcinomas. One representative cascade is the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway. METHODS: The authors investigated the involvement of mTOR in the pathobiologic profiles of 150 specimens of lung carcinoma by immunohistochemistry and immunoblotting in correlation with the upstream and downstream proteins Akt and p70S6-kinase (S6K), respectively. RESULTS: Immunohistochemistry revealed Akt activation in 44% of tumors and mTOR expression in 68.7% of tumors, and the preponderance of activation was observed in adenocarcinoma (AC) (100%). Phosphorylated mTOR (p-mTOR) was observed in 53.3% of tumors and had the highest frequency in AC (89.7%). In AC, the frequency of p-mTOR staining was higher in the well differentiated subtype, in particular, in the acinar structure. However, little correlation was observed between the activation of mTOR and Akt, except in the 5 AC specimens that harbored an EGFR gene mutation, which exhibited constitutive activation of both Akt and mTOR. Conversely, in squamous cell carcinomas, mTOR activation was associated with a significantly higher frequency of lymph node metastasis. CONCLUSIONS: The results of this study suggested the dual functions of mTOR. First, mTOR may function not only in the proliferation of tumor cells as an effector molecule downstream of EGFR but also possibly in the morphogenesis of AC, Second, the activation of mTOR may play a key role in metastasis in squamous cell carcinoma. Overall, the current results demonstrated the potential for the application of rapamycin, an mTOR inhibitor, as an additional novel component of chemotherapy for a defined subset of patients with lung carcinoma. Cancer 2009;115:107-18. (C) 2008 American Cancer Society.