Targeting Mammalian Target of Rapamycin by Rapamycin Prevents Tumor Progression in an Oral-Specific Chemical Carcinogenesis Model
Targeting Mammalian Target of Rapamycin by Rapamycin Prevents Tumor Progression in an Oral-Specific Chemical Carcinogenesis Model
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DOI：
10.1158/1940-6207.capr-08-0147
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发表时间：
2009-01-01
影响因子：
3.3
通讯作者：
Gutkind, J. Silvio
中科院分区：
文献类型：
--
作者：
Czeminski, Rakefet;Amornphimoltham, Panomwat;Gutkind, J. Silvio
对癌症生长的分子理解的增加，现在可能为开发针对促进每种癌症进展的特定失调分子机制的新疗法提供了机会。因此，Akt/哺乳动物雷帕霉素靶蛋白（mTOR）通路的异常激活是头颈部鳞状细胞癌（HNSCC）中常见的事件，因此代表了治疗HNSCC患者的潜在分子靶点。然而，将这一新兴信息转化为有效治疗策略的能力受到口腔恶性肿瘤动物模型可用性有限的阻碍。在这里，我们展示了在饮用水中给予小鼠4-硝基喹啉-1氧化物，一种DNA加合物形成剂，作为烟草暴露的替代品，导致舌头和口腔粘膜的癌前病变和肿瘤病变的进行性出现，仅在致癌物质暴露16周后发病率为100%。值得注意的是，许多这些病变在停用4-硝基喹啉-1氧化物后几周内自发发展为高度恶性的SCCs。在这个模型中，我们观察到Akt-mTOR生化途径的激活代表了一个早期事件，这在发育不良病变中已经可以检测到。此外，我们发现慢性雷帕霉素对mTOR的抑制可以阻止癌前病变的恶性转化，并促进晚期致癌物质诱导的SCCs的消退。总之，这些发现支持mTOR信号通路对HNSCC进展的贡献，并为mTOR抑制剂作为HNSCC化学预防和治疗的分子靶向策略的早期评估提供了强有力的理论依据。
The increased molecular understanding of cancerous growth may now afford the opportunity to develop novel therapies targeting specific dysregulated molecular mechanisms contributing to the progression of each cancer type. In this regard, the aberrant activation of Akt/mammalian target of rapamycin ( mTOR) pathway is a frequent event in head and neck squamous cell carcinomas (HNSCC), thus representing a potential molecular target for the treatment of HNSCC patients. The ability to translate this emerging body of information into effective therapeutic strategies, however, has been hampered by the limited availability of animal models for oral malignancies. Here, we show that the administration in the drinking water to mice of 4-nitroquinoline-1 oxide, a DNA adduct-forming agent that serves as a surrogate of tobacco exposure, leads to the progressive appearance of preneoplastic and tumoral lesions in the tongue and oral mucosa, with 100% incidence after only 16 weeks of carcinogen exposure. Remarkably, many of these lesions evolve spontaneously into highly malignant SCCs few weeks after 4-nitroquinoline-1 oxide withdrawal. In this model, we have observed that the activation of the Akt-mTOR biochemical route represents an early event, which is already detectable in dysplastic lesions. Furthermore, we show that the inhibition of mTOR by the chronic administration of rapamycin halts the malignant conversion of precancerous lesions and promotes the regression of advanced carcinogen-induced SCCs. Together, these findings support the contribution of the mTOR signaling pathway to HNSCC progression and provide a strong rationale for the early evaluation of mTOR inhibitors as a molecular-targeted strategy for HNSCC chemoprevention and treatment.