Nicotine promotes pancreatic carcinogenesis by disrupting signaling and transcriptional pathways to cause dedifferentiation of acinar cells, researchers report in the November issue of Gastroenterology.
One fourth of all deaths from pancreatic ductal adenocarcinoma (PDAC) are associated with tobacco use, and heavy smoking increases risk for PDAC 6-fold.
Although smokers develop PDAC more frequently and about 15 years earlier than non-smokers, their tumors contain the same mutations. So, smoking might promote pancreatic carcinogenesis by mechanisms beyond mutagenesis.
Patrick C. Hermann et al. studied the effects of nicotine on carcinogenesis in mice that are prone to pancreatic tumors. Ela-KRAS and KPC mice, which express oncogenic forms of KRAS in pancreatic cells, were given nicotine for up to 86 weeks to produce blood levels comparable with those of intermediate smokers.
Although there were no significant changes in body weights of mice that were vs were not exposed to nicotine, mice given nicotine had severe morphologic changes in the pancreata. Areas of pancreatic intraepithelial neoplasia (PanIN), acinar-to-ductal metaplasia, and atrophy were significantly increased in mice exposed to nicotine compared with controls, and ductal cells of PanINs had increased proliferative activity.
The authors found no neoplastic lesions in mice without KRAS mutations exposed to nicotine, supporting the concept that nicotine itself is not carcinogenic.
However, levels of the transcription factors GATA6 and MIST1 were down-regulated after 86 weeks exposure to nicotine. There was also a strong decrease in expression of acinar genes, acinar granularity, and enzyme production, indicating a loss of acinar differentiation.
Hermann et al. conclude that nicotine suppresses the acinar fate regulator GATA6, and subsequently other transcription factors such as MIST1, resulting in loss of pancreatic acinar cells and increased cellular plasticity and progenitor activity.
They propose that this nicotine-induced de-differentiation of the acinar compartment renders the cells more susceptible to oncogenic transformation by oncogenic KRAS, or in combination with loss of TP53 activity (see figure).
Hermann et al. state that it is important to note that nicotine can also increase the activity of oncogenic KRAS, but only when levels of GATA6 are low.
Metformin has been reported to reduce risk for pancreatic cancer and to inhibit several of the mechanisms necessary for the effects of nicotine. Hermann et al. also showed that the nicotine-induced effects could be offset by metformin. They concluded that by promoting acinar cell differentiation, metformin counteracts the effects of environmental noxious substances by promoting acinar commitment and differentiation.
Nicotine contributed not only to the early stages of pancreatic carcinogenesis, but also to progression of late-stage tumors. It increased the aggressiveness of established tumors, induced the epithelial–mesenchymal transition, and increased numbers of circulating cancer cells and their dissemination to the liver. Nicotine induced pancreatic cells to acquire gene expression patterns and functional characteristics of cancer stem cells.
In an editorial, Moorthy P. Ponnusamy and Surinder K. Batra add that nicotine alters the functions of cancer cells, increasing proliferation and their angiogenic activities. Nicotine and cotinine, the metabolic derivative of nicotine, can be detected in pancreata of animals exposed to tobacco smoke. A previous study showed that nicotine upregulated the mucin MUC4 in pancreatic cancer cells by activating the α-7 nicotinic receptor (α7nAChR), signaling via JAK2−STAT3 to promote metastasis.
Hermann et al. state that their latest findings provide strong rationale for eliminating nicotine intake, as it is the main risk factor for PDAC, and for designing metformin-based treatment regimens for patients at high risk for PDAC.