Molecular Pathways: Targeting Mechanisms of Asbestos and Erionite Carcinogenesis in Mesothelioma
Molecular Pathways: Targeting Mechanisms of Asbestos and Erionite Carcinogenesis in Mesothelioma
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DOI：
10.1158/1078-0432.ccr-11-2259
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发表时间：
2012-02-01
影响因子：
11.5
通讯作者：
Yang, Haining
中科院分区：
文献类型：
--
作者：
Carbone, Michele;Yang, Haining
恶性间皮瘤是一种侵略性的恶性肿瘤有关石棉和毛沸石暴露。AP-1转录活性和NF-κ B信号通路与间皮细胞转化和肿瘤进展有关。HQ和c-Met在间皮瘤中高度表达。磷酸肌醇3-激酶，AKT，和下游的mTOR参与细胞的生长和存活，它们经常被发现在间皮瘤中被激活。p16（INK 4a）和p14（ARF）在人类间皮瘤中经常失活，并且类似于50%的间皮瘤含有NF 2突变。旨在干扰这些途径的分子疗法并没有改善间皮瘤的预后，除了可能对一小部分受益于某些疗法的患者。最近的研究表明，石棉诱导的炎症在间皮瘤的发生和生长中的重要性，HMGB 1和Nalp 3炎性体已被确定为该过程的关键启动子。石棉诱导细胞坏死，引起HMGB 1的释放，这反过来又可能激活Nalp 3炎性体，这是一个由石棉诱导的活性氧产生增强的过程。HMGB 1和Nalp 3诱导促炎反应并导致白细胞介素-1 β和TNF-α分泌以及NF-κ B活性，从而促进细胞存活和肿瘤生长。干扰石棉和毛蕊石介导的炎症的新策略可能会预防或延迟高危人群（包括遗传易感个体）间皮瘤的发作，和/或抑制肿瘤生长。最近发现，生殖系BAP 1突变导致一种新的癌症综合征，其特征是间皮瘤，葡萄膜黑色素瘤和黑色素细胞肿瘤，为研究人员提供了预防和早期检测的新靶点。临床癌症研究; 18（3）; 598-604。（C）2011年《非洲标准化评论》。
Malignant mesothelioma is an aggressive malignancy related to asbestos and erionite exposure. AP-1 transcriptional activity and the NF-kappa B signaling pathway have been linked to mesothelial cell transformation and tumor progression. HQ, and c-Met are highly expressed in mesotheliomas. Phosphoinositide 3-kinase, AKT, and the downstream mTOR are involved in cell growth and survival, and they are often found to be activated in mesothelioma. p16(INK4a) and p14(ARF) are frequently inactivated in human mesothelioma, and similar to 50% of mesotheliomas contain the NF2 mutation. Molecular therapies aimed at interfering with these pathways have not improved the dismal prognosis of mesothelioma, except possibly for a small subset of patients who benefit from certain therapies. Recent studies have shown the importance of asbestos-induced inflammation in the initiation and growth of mesothelioma, and HMGB1 and Nalp3 inflammasome have been identified as key initiators of this process. Asbestos induces cell necrosis, causing the release of HMGB1, which in turn may activate Nalp3 inflammasome, a process that is enhanced by asbestos-induced production of reactive oxygen species. HMGB1 and Nalp3 induce proinflammatory responses and lead to interleukin-1 beta and TNF-alpha secretion and NF-kappa B activity, thereby promoting cell survival and tumor growth. Novel strategies that interfere with asbestos- and erionite-mediated inflammation might prevent or delay the onset of mesothelioma in high-risk cohorts, including genetically predisposed individuals, and/or inhibit tumor growth. The very recent discovery that germline BAP1 mutations cause a new cancer syndrome characterized by mesothelioma, uveal melanoma, and melanocytic tumors provides researchers with a novel target for prevention and early detection. Clin Cancer Res; 18(3); 598-604. (C)2011 AACR.