Abstract 3182: Tobacco smoke induces pulmonary neuroendocrine alterations in vivo

Abstract Tobacco smoke is the leading cause of lung cancer. High-grade malignant pulmonary neuroendocrine tumors, including small cell lung cancers (SCLCs) and large cell neuroendocrine carcinomas (LCNECs), are almost exclusively associated with tobacco smoking. Unanalogous to most of other lung tumors such as squamous cell carcinomas, adenocarcinoma, adenosquamous carcinoma or carcinoid, no precursor lesions for high-grade lung neuroendocrine tumors have so far been identified. The purpose of the present study was to investigate the effects of tobacco smoke on pulmonary neuroendocrine alterations in phenotypically normal cells in vivo. Male BALB/c mice were exposed to tobacco smoke for 6h/day, 7days/week for 12 weeks. Pulmonary histology, neuroendocrine differentiation as well as MAPK/AP-1 activation were examined in lung tissues. Exposure to tobacco smoke significantly induced expression of neuroendocrine differentiation markers such as chromogranin A, neural cell adhesion molecule/(CD56), synaptophysin, and neuron specific enolase, as demonstrated by immunohistochemistry, Western blotting and real-time PCR. The expression levels of epithelial markers, including E-cadherin, zona ocludens-1, cytokeratin 5 and involucrin, were downregulated by tobacco smoke. Moreover, tobacco smoke significantly increased levels of p-ERK1/2, p-JNK and p-p38, while it suppressed p-ERK5 level. Expression of Jun and Fos proteins were differentially regulated by tobacco smoke. Taken together, the present study provides experimental evidence for the first time that tobacco smoke induces pulmonary neuroendocrine differentiation, shedding new light on the carcinogenic process of pulmonary neuroendocrine tumors. Citation Format: Wei Xie, Zhaofeng Liang, Ying Yin, Chunfeng Xie, Hao Geng, Li Zhao, Rui Wu, Xiaoting Li, Feifei Deng, Jieshu Wu, Shanshan Geng, Mingming Zhu, Jianyun Zhu, Weiwei Zhu, Cong Huang, Caiyun Zhong. Tobacco smoke induces pulmonary neuroendocrine alterations in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3182. doi:10.1158/1538-7445.AM2014-3182