Inflammation and Lung Carcinogenesis

描述(由申请人提供)：众所周知，慢性炎症有助于癌症的发展。许多研究表明，炎性白细胞通过向启动的细胞提供可溶性生长和存活因子促进上皮性癌症，并通过合成细胞外蛋白水解酶促进组织重塑和血管生成；因此，肿瘤发生所需的生理过程(增强细胞存活、组织重塑和血管生成)部分受白细胞及其递送的可溶性介质的调节。然而，介导浸润性免疫细胞与启动的上皮细胞之间对话的分子机制尚不清楚。此外，这些相互作用在多大程度上改变了肿瘤环境中的干细胞生态位还没有得到探索。我们假设，浸润性免疫细胞通过激活Wnt和Sonic Hedgehog(Shh)信号级联调节假定的肺癌干细胞的生态位自主性；因此，该项目的目标是定义促进肺癌发展的功能重要免疫细胞的谱系，确定其中哪些调节肺上皮细胞中的Wnt和Shh信号，并确定是否通过这样做，它们赋予启动的上皮细胞干细胞生态位自主性，从而增强肿瘤发生的潜力。为了验证我们的假设，我们建议，1)定义与人和小鼠肺癌发生相关的免疫细胞的特征，并确定这些细胞如何与CD133+细胞的存在以及Wnt和Shh信号级联的激活相关联；2)定义招募的免疫细胞作为肺癌发生过程中Wnt和Shh信号的调节者的功能意义；以及3)定义免疫细胞作为Wnt和Shh信号的调节者的功能意义及其对可能的肺癌干细胞的联合作用。

DESCRIPTION (provided by applicant): It is well established that chronic inflammation contributes to cancer development. Many studies have demonstrated that inflammatory leukocytes promote epithelial cancer by providing soluble growth and survival factors to initiated cells and contribute to tissue remodeling and angiogenesis via synthesis of extracellular proteases; thus, physiological processes necessary for tumor development (enhanced cell survival, tissue remodeling and angiogenesis) are regulated, in part, by leukocytes and the soluble mediators they deliver. However, molecular mechanisms mediating the dialogue between infiltrating immune cells with initiated epithelia are poorly characterized. Moreover, the degree to which these interactions alter stem cell niches in neoplastic environments have not been explored. We hypothesize that infiltrating immune cells regulate niche autonomy of putative lung cancer stem cells through activation of Wnt and Sonic hedgehog (Shh) signaling cascades in initiated lung epithelia; thus, the goals of this project are to define the lineages of functionally significant immune cells that potentiate cancer development in lung, determine which of these regulate Wnt and Shh signaling in lung epithelia, and determine if in so doing, they confer stem cell niche autonomy to initiated epithelial cells and therefore enhance tumorigenic potential. To assess our hypothesis, we propose to, 1) define the profile of immune cells associated with human and mouse lung carcinogenesis and determine how these correlate with presence of CD133+ cells and activation of Wnt and Shh signaling cascades, 2) define functional significance of recruited immune cells as regulators of Wnt and Shh signaling during lung carcinogenesis, and 3) Define the functional significance of immune cells as regulators of Wnt and Shh signaling and their combined effects on putative lung cancer stem cells.