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，炎性白细胞通过为启动细胞提供可溶性生长和存活因子，并通过合成细胞外蛋白酶促进组织重塑和血管生成，从而促进上皮癌的发生；因此，肿瘤发展所必需的生理过程（增强细胞存活、组织重塑和血管生成）在一定程度上是由白细胞及其传递的可溶性介质调节的。然而，介导浸润性免疫细胞与初始上皮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肿瘤环境中的干细胞生态位还没有被探索。我们假设浸润性免疫细胞通过激活启动肺上皮中的Wnt和Sonic hedgehog （Shh）信号级联来调节假定的肺癌干细胞的生态位自主性；因此，本项目的目标是确定促进肺癌发展的功能重要免疫细胞的谱系，确定哪些免疫细胞调节肺上皮细胞中的Wnt和Shh信号，并确定它们是否在这样做时赋予启动上皮细胞干细胞生态位自主性，从而增强致瘤潜力。为了评估我们的假设，我们建议：1)确定与人和小鼠肺癌发生相关的免疫细胞的特征，并确定它们如何与CD133+细胞的存在和Wnt和Shh信号级联的激活相关；2)确定募集的免疫细胞在肺癌发生过程中作为Wnt和Shh信号的调节因子的功能意义。3)明确免疫细胞作为Wnt和Shh信号调节因子的功能意义及其在肺癌干细胞中的联合作用。

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.