Abstract
Smoking is highly associated with pancreatic cancer. Nicotine, the addictive component of tobacco, is involved in pancreatic cancer tumorigenesis, metastasis, and chemoresistance. This work aimed to describe the role of nicotine within the pancreatic cancer tumor microenvironment. Nicotine treatment was used in vitro to assess its effect on tumor-associated stromal cells and pancreatic cancer cells. Nicotine treatment was then used in a pancreatic cancer patient-derived xenograft model to study the effects in vivo. Nicotine induced secretion of interleukin 8 (IL-8) by tumor-associated stroma cells in an extracellular signal-regulated kinase (ERK)-dependent fashion. The secreted IL-8 and nicotine acted on the pancreatic cancer cell, resulting in upregulation of IL-8 receptor. Nicotine treatment of mice bearing pancreatic cancer patient-derived xenografts had significantly increased tumor mass, increased tumor-free weight loss, and decreased muscle mass. These represent important pathways through which nicotine acts within the tumor microenvironment and worsens pancreatic cancer-induced cachexia, potentially representing future therapeutic targets.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with a 5 year overall survival rate of 9% [1]
Tumorigenesis, progression, and metastasis.and importance of importance of this observation is amplified by the growing use of e-cigarettes and vaping products, this observation is amplified by the growing use of e-cigarettes and vaping products, which can which contain higher levels of nicotine than traditional tobacco[16]
Nicotine acts on stromal cells in the tumor microenvironment to secrete interleukin 8 (IL-8), which subsequently acts on the pancreatic cancer cells
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with a 5 year overall survival rate of 9% [1]. PDAC has the highest prevalence of cancer-induced cachexia and the highest average weight loss of all malignancies at diagnosis [2]. This contributes to the dismal progress of PDAC. Diabetes mellitus, obesity, alcohol use, and pancreatitis are acquired risk factors for the development of PDAC [3]. Tobacco use is one of the most important modifiable risk factors and is attributable to nearly 25% of PDAC cases [4]. The risk of PDAC carcinogenesis decreases upon tobacco cessation and returns to the level of non-smokers after about 20 years [5,6,7]
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