ACETYLCHOLINE AND NICOTINIC RECEPTORS IN LUNG CANCER

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 为子项目列出的总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 我们实验室最近的研究表明，在气道上皮细胞、肺神经内分泌细胞（PNEC）和肺II型细胞中存在高水平的烟碱受体（nAChR）和毒蕈碱受体（mAChR）。由于这些细胞类型分别与鳞状细胞癌（SCC）、小细胞肺癌（SCLC）、支气管肺泡癌（BAC）的起源相关，因此这些癌也很可能表达nAChR和mAChR。由于这些受体的激活导致细胞内细胞钙增加，它们的激活通常刺激细胞生长。更重要的是，我们实验室最近观察到，这些细胞类型也会产生乙酰胆碱，乙酰胆碱是nAChR和mAChR的配体。这表明了一个自分泌循环，在这个循环中，肺癌分泌乙酰胆碱来刺激自身的生长。虽然先前已经研究了SCLC中烟碱受体的表达，并且已经清楚地显示尼古丁刺激SCLC的生长，但我们观察到SCLC可以产生乙酰胆碱并因此调节其自身的生长是一个新的和令人兴奋的观察结果。因此，外源配体（即，吸烟产生的尼古丁）与内源性配体（乙酰胆碱）的生长促进作用相互作用，这就成为一个非常重要的问题。因此，本研究的目的是确定SCLC，SCC和BAC是否表达乙酰胆碱，nAChR和mAChR，然后确定胆碱能信号的拮抗剂的潜力，以提供新的方法来阻断肺癌的生长和发展。 今年的进展已证明M3毒蕈碱拮抗剂在抑制肺癌生长方面具有潜在用途。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Recent studies from our laboratory have demonstrated high levels of nicotinic receptors (nAChR) and muscarinic receptors (mAChR) in airway epithelial cells, pulmonary neuroendocrine cells (PNEC) and pulmonary type II cells. Since these cell types are related to the origin of squamous cell carcinomas (SCC), small cell lung carcinomas (SCLC), bronchoalveolar carcinomas (BAC), respectively, it is highly likely that these carcinomas will also express nAChR and mAChR. Since activation of these receptors leads to increased intracellular cellular calcium, their activation typically stimulates cellular growth. Adding further significance is the recent observation from our laboratory that these cell types also make acetylcholine, the ligand for both nAChR and mAChR. This suggests an autocrine loop in which lung cancers secrete acetylcholine to stimulate their own growth. While the expression of nicotinic receptors in SCLC has been previously studied and nicotine has been clearly shown to stimulate growth of SCLC, our observation that SCLC may make acetylcholine and hence modulate their own growth is a new and exciting observation. Hence, how exogenous ligand (i.e., nicotine from smoking) then interacts with the growth promoting effects of endogenous ligand (acetylcholine) becomes a very important question. Thus the purpose of this study is to determine if SCLC, SCC and BAC express acetylcholine, nAChR and mAChR and to then determine the potential for antagonists of cholinergic signaling to provide new approaches to blocking the growth and development of lung cancer. Progress in the current year has demonstrated potential utility for M3 muscarinic antagonists to inhibit lung cancer growth.