Abstract
Abstract Smoking is an established risk factor for the development of pancreatic adenocarcinoma (PC). However, the relationship between smoking and PC tumor biology is incompletely defined. We report reduced overall survival (OS) in PC patients who continued smoking after surgical resection with curative intention (HR 1.93; P = .040). We further demonstrate augmented paracrine signaling via the hepatocyte growth factor (HGF)/c-Met pathway as a result of nicotine exposure in the PC microenvironment. Specifically, HGF, secreted by patient-derived PC tumor associated stroma (TAS), activates the c-Met receptor in PC cells. This paracrine activation subsequently leads to downstream induction of inhibitor of differentiation-1 (Id1) in PC cells, previously established as a mediator of chemoresistance. Further delineation of the signaling pathway demonstrates HGF-induced Id1 expression is abrogated by silencing of c-Met or pharmacologic inhibition. In patient-derived PC xenografts, nicotine treatment augmented tumor growth and metastasis; tumor lysates from nicotine-treated mice demonstrated elevated HGF expression and phospho-Met levels. Additionally, patients with high intratumoral phospho-Met levels exhibited reduced overall survival compared to those with low phospho-Met levels (Median OS 6.1 vs. 15.2 months, respectively; P = .028). Taken together, our data reveal that nicotine promotes the progression of PC via a microenvironment-dependent, paracrine signaling mechanism. Citation Format: Daniel Delitto, Dongyu Zhang, Song Han, Brian S. Black, Andrea E. Knowlton, Adrian C. Vlada, George A. Sarosi, Kevin E. Behrns, Ryan M. Thomas, Xiaomin Lu, Chen Liu, Thomas J. George, Steven J. Hughes, Shannon M. Wallet, Jose G. Trevino. Nicotine reduces survival via augmentation of paracrine HGF-MET signaling in the pancreatic cancer microenvironment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 470. doi:10.1158/1538-7445.AM2015-470
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