The pathobiological impact of cigarette smoke on pancreatic cancer development (Review)

Abstract

Despite extensive efforts, pancreatic cancer remains incurable. Most risk factors, such as genetic disposition, metabolic diseases or chronic pancreatitis cannot be influenced. By contrast, cigarette smoking, an important risk factor for pancreatic cancer, can be controlled. Despite the epidemiological evidence of the detrimental effects of cigarette smoking with regard to pancreatic cancer development and its unique property of being influenceable, our understanding of cigarette smoke-induced pancreatic carcinogenesis is limited. Current data on cigarette smoke-induced pancreatic carcinogenesis indicate multifactorial events that are triggered by nicotine, which is the major pharmacologically active constituent of tobacco smoke. In addition to nicotine, a vast number of carcinogens have the potential to reach the pancreatic gland, where they are metabolized, in some instances to even more toxic compounds. These metabolic events are not restricted to pancreatic ductal cells. Several studies show that acinar cells are also greatly affected. Furthermore, pancreatic cancer progenitor cells do not only derive from the ductal epithelial lineage, but also from acinar cells. This sheds new light on cigarette smoke-induced acinar cell damage. On this background, our objective is to outline a multifactorial model of tobacco smoke-induced pancreatic carcinogenesis.

How does cigarette smoking cause acute pancreatitis?

“…The association between smoking and AP was initially overlooked possibly due to the general perception that alcohol was a more likely risk factor for AP [20,21]. However, over the last 2 decades [22e25] there has been a steady increase in our appreciation of the effect of cigarette smoking on pancreatic function and the causation of pancreatic diseases, especially pancreatic cancer [26] and pancreatitis [27]. Within the last year itself, there have been 4 published metaanalyses [28e31] highlighting the clinical/epidemiological association between smoking and the development of AP.…”

(−)-Epigallocatechin-3-gallate blocks nicotine-induced matrix metalloproteinase-9 expression and invasiveness via suppression of NF-κB and AP-1 in endothelial cells

“…Nicotine alone or in combination with other substances present in the cigarette smoking is recognized as an agent for the modulation of key cellular processes involved in the pathobiological effects of tobacco (34). Nicotine has been shown to enhance cell migration, invasion and subsequent metastasis in many cancer cells (35).…”

Phosphatidylinositol 3-Kinase

“…As an alternative mechanism, nicotine metabolites can bind to receptors on the exocrine pancreas, thereby promoting pancreatitis and pancreatic cancer 25 . Importantly, cigarette smoking increases the risk of pancreatic cancer by 1.5 to 3 fold, depending on the duration and number of cigarette smoked 26 . Recently, Jang and colleagues showed that the effect of tobacco smoking on increasing the risk of pancreatic cancer may depend on certain genetic variations 27 .…”