CHARACTERIZATION OF INDUCED NEUROENDOCRINE LUNG CANCER

神经内分泌型肺癌是人类最常见的癌症之一。 并表明吸烟与吸烟有很强的联系。我们有 建立了第一个也是唯一一个体内神经内分泌癌模型 通过将仓鼠同时施加到与高氧和烟草相关的 亚硝胺。这一新的系统允许研究 这种致命疾病的发生和发展 预防和治疗的策略。 在NIH资助的过去三年的研究中，我们有 其病理、发病机制和神经内分泌学特征 仓鼠神经内分泌肺肿瘤的详细信息，我们已经开发出 从两个这样的肿瘤中获得连续的细胞系。我们提供了令人信服的 有证据表明，在肿瘤起始阶段，刺激 烟碱型胆碱能受体在分子水平上起着至关重要的作用。 导致细胞持续增殖的机制。此外，我们有 研究表明，ras家族癌基因在肿瘤中过表达。 和细胞系。 利用仓鼠模型和这些肿瘤细胞系，我们将在 详细说明烟碱型胆碱能受体在该阶段的分子作用 肿瘤的启动和该受体的调节 进步。此外，我们还将对仓鼠肿瘤和细胞系进行筛选 用于相关癌基因的表达和突变 人类和啮齿动物肺癌。随后，我们将在 这些基因表达的变化发生在什么肿瘤的发展阶段 以及这与已有文献记载的发病阶段有何关系？ 神经内分泌标志物的调节。在今年的第三年 继续项目，然后我们将开始探索关联 在基因表达的改变和细胞周期蛋白的功能调节之间 烟碱胆碱能受体。 我们的数据与人类神经内分泌肺癌和 将为这一疾病的防治提供有意义的依据。 常见的肺癌类型。

Neuroendocrine lung cancer is among the most common cancers of mankind and demonstrates a strong association with cigarette smoking. We have developed the first and only in vivo model of neuroendocrine ling cancer by imposing hamsters simultaneously to hyperoxia and tobacco-related nitrosamines. This novel system allows to study the mechanisms of initiation and progression of this deadly disease and to develop strategies for its prevention and therapy. During the past three years of NIH-funded research, we have characterized the pathology, pathogenesis, and neuroendocrinology of the hamster neuroendocrine lung tumors in detail, and we have developed continuous cell lines from two such tumors. We have provided convincing evidence that during the stage of tumor initiation, stimulation of nicotinic cholinergic receptors play a crucial role in the molecular mechanisms which cause continuous cell proliferation. Moreover, we have shown that overexpression of ras-family oncogenes is found in the tumors and cell lines. Using the hamster model and these tumor cell lines, we will study in detail the molecular role f nicotinic cholinergic receptors at the stage of tumor initiation and the modulation of this receptor during progression. Moreover, we will screen the hamster tumors and cell lines derived from them for the expression and mutation of oncogenes pertinent to human and rodent lung cancers. Subsequently, we will determine at what stag of tumor development these changes in gene expression occur and how this relates to the already documented stages of pathogenesis and modulations in neuroendocrine markers. During the third year of this continuation project, we will then begin to explore the association between alterations in gene expression and functional modulations of the nicotinic cholinergic receptor . Our data are highly relevant to human neuroendocrine lung cancer and will provide a meaningful basis for the prevention and therapy of this common lung cancer type.