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发展。许多研究已经证明，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来促进上皮癌，并且通过合成细胞外蛋白酶来促进组织重塑和血管生成;因此，肿瘤发展所必需的生理过程（增强的细胞存活、组织重塑和血管生成）部分地由白细胞和它们递送的可溶性介质来调节。然而，介导浸润性免疫细胞与起始上皮细胞之间对话的分子机制的特征很差。此外，这些相互作用在肿瘤环境中改变干细胞生态位的程度尚未探讨。我们假设浸润的免疫细胞通过激活启动的肺上皮中的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，该项目的目标是确定增强肺癌发展的功能重要的免疫细胞的谱系，确定这些免疫细胞中哪些调节肺上皮中的Wnt和Shh信号传导，并确定在这样做时，它们赋予干细胞小生境自主性以起始的上皮细胞，并因此增强致瘤潜力。为了评估我们的假设，我们提出，1）定义与人和小鼠肺癌发生相关的免疫细胞的概况，并确定这些免疫细胞如何与CD 133+细胞的存在以及Wnt和Shh信号级联的激活相关，2）定义招募的免疫细胞作为肺癌发生期间Wnt和Shh信号的调节剂的功能意义，和3）定义免疫细胞作为Wnt和Shh信号调节剂的功能意义及其对推定肺癌干细胞的综合影响。

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.