Journal of Cancer Therapy, 2013, 4, 34-40
Published Online November 2013 (http://www.scirp.org/journal/jct)
http://dx.doi.org/10.4236/jct.2013.410A005
Open Access JCT
Smoking and Pancreatic Disease
Mouad Edderkaoui1*, Edwin Thrower2
1Cedars-Sinai Medical Center & University of California, Los Angeles, USA; 2Yale University & VA CT Healthcare, New Haven,
USA.
Received October 4th, 2013; revised November 1st, 2013; accepted November 8th, 2013
Copyright © 2013 Mouad Edderkaoui, Edwin Thrower. This is an open access article distributed under the Creative Commons At-
tribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is prop-
erly cited.
ABSTRACT
Smoking is a major risk factor for chronic pancreatitis and pancreatic cancer. However, the mechanisms through which
it causes the diseases remain unknown. In the present manuscript we reviewed the latest knowledge gained on the effect
of cigarette smoke and smoking compounds on cell signaling pathways mediating both diseases. We also reviewed the
effect of smoking on the pancreatic cell microenvironment including inflammatory cells and stellate cells.
Keywords: Smoking; Pancreatitis; Pancreatic Cancer
1. Introduction
Numerous studies have shown that cigarette smoking
increases the risk of developing pancreatic cancer, al-
though its contribution to pancreatitis has only been ap-
preciated in recent years [1-3]. Clinical advances have
identified a role for cigarette smoke in pancreatitis, but
experimental data regarding its disease mechanism are
scarce. In this review, advances in basic science research
are summarized, regarding the role of cigarette smoke,
and it’s most potent constituents, in pancreatitis and pan-
creatic cancer.
Factors Involved in Smoking-Related
Pancreatic Disease
Of the 4000 chemicals in cigarette smoke, greater than 60
have been identified as prospective carcinogens. Tobacco
smoke and its various components, including nicotine,
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK),
and other tobacco specific nitrosamines have been stud-
ied in cells and in vivo [4-11]. In laboratory animals, the
most potent nicotine metabolite is NNK [12]. Other ni-
trosamines formed from nicotine include N’-nitrosonor-
nicotine (NNN) and Diethylnitrosamine [13]. These nico-
tine metabolites are potentially formed via nitrosation
during processing of the tobacco plant [14]. It has been
reported that roughly 46% of NNN and 26% - 37% of
NNK in tobacco are preformed and the remainder is py-
rosynthesized from nicotine during smoking [15]. Of
these constituents, nicotine and NNK are the most stud-
ied constituents with respect to pancreatic disease. Other
potentially harmful components of tobacco smoke in-
clude polycyclic aromatic hydrocarbons, although their
role in pancreatic disease is undetermined [15,16].
Few reliable animal models of smoking and pancreatic
disease have been developed, and little is known about
underlying cellular mechanisms. Those that have been
established involve exposure of rodents to cigarette
smoke in specialized smoke-delivery chambers, or inges-
tion/injection of a tobacco toxin over a period of time.
The subsequent sections will focus on some of these
models and underscore the latest developments in our
understanding of smoking-related pancreatitis and pan-
creatic cancer.
2. Smoking and Pancreatitis
2.1. Cigarette Smoke Exposure and Pancreatitis
In models of cigarette smoke exposure over a period of
weeks rats developed pancreatic damage, elevated pan-
creatic levels of the digestive zymogens, trypsinogen and
chymotrypsinogen, [5] and altered gene expression, af-
fecting the ratio of trypsinogen to its endogenous inhibi-
tor (pancreas-specific trypsin inhibitor; PSTI). Smoke-
exposed animals had increased susceptibility to pan-
creatitis as a result of these changes [7]. Given that smo-
king exacerbates the clinical effects of alcohol in pan-
*Corresponding author.

Smoking and Pancreatic Disease 35
creatitis, one model combined smoke treatment with
ethanol consumption; pancreatic ischemia worsened and
increased leukocyte infiltration was seen [9].
While these studies are informative, they only describe
effects of smoke; they do not identify relevant toxins or
how they initiate these cellular effects. The studies de-
tailed in subsequent sections focus on nicotine and its
potent metabolite NNK, revealing a role for these ni-
trosamines and potential pathways underlying disease
initiation.
2.2. Nicotine and NNK-Mediated Pathways
in Pancreatitis
Nicotine is a key toxin in tobacco and cigarettes and may
contribute to the development of pancreatitis and pancre-
atic cancer. Nicotine is swiftly absorbed in the lungs and
is eliminated from the body within 120 - 180 minutes
[17]. Metabolism of nicotine primarily occurs via the
cytochrome P450 (CYP) 2A6 pathway along with other
enzymes including aldehyde oxidase 1, UDP-glucuro-
nosyltranferases, flavin-containing monooxygenase 3 and
other CYPs e.g. 2A13, 2B6. Polymorphisms in CYP2A6
have been related to racial and genetic variations in nico-
tine metabolism, but it is unknown if these contribute to
smoking-related pancreatic disease [18]. Moreover, ele-
vated P450 enzyme levels have been reported in patients
with chronic pancreatitis and pancreatic cancer as com-
pared to healthy controls [19]. Rats exposed to 3H-nico-
tine saw a noticeable buildup of it in the pancreas and
intestine [19,20]. Further, metabolites of nicotine were
detected in samples of human pancreatic juice from
smokers. Cotinine, the primary nicotine metabolite, was
present at levels of 129 +/− 156 ng/ml followed by NNK
at 1.37 ng/ml to 600 ng/ml (0.7µM and 6.6 nM - 3 µM
respectively) [21]. These levels of nicotine metabolites
may be sufficient to activate cell surface receptors on the
exocrine pancreas that could mediate pancreatitis and
pancreatic cancer responses.
Studies have been undertaken to ascertain the patho-
logical and functional effects of nicotine on the pancreas.
In several studies, nicotine exposure resulted in cyto-
plasmic swelling, vacuolization, pyknotic nuclei and
karyorrhexis, which were localized to the exocrine pan-
creas. Furthermore, a decreased secretory response was
observed. along with increased retention of pancreatic
pro-enzymes [4,22-29]. A recent study has shown that
secretory effects induced by nicotine in isolated rat acini
were abrogated following treatment with a nicotinic re-
ceptor antagonist and calcium channel antagonists [28].
These findings indicate that nicotine effects are mediated
via a nicotinic acetylcholine receptor (nAChR) and cal-
cium is the resultant signaling pathway. Nicotine also has
been shown to alter basal levels of GI hormones (gastrin;
CCK) and serum enzymes such as amylase and lipase in
blood circulation in rats [24]. Such changes have been
linked to morphological changes observed during pan-
creatitis [19,27]. Nicotine has also been shown to modu-
late oxidative stress and lipid peroxidation although it is
unclear if these processes participate in the pathophysi-
ology of acute and chronic pancreatitis [29].
The nicotine metabolite, NNK, is one of the most
abundant and injurious tobacco-specific carcinogens. It is
a high-affinity agonist of nicotinic acetylcholine recep-
tors (nAChR) and may affect the development of pancre-
atic cancer through receptor-mediated pathways [10,13].
These receptors were first characterized within the nerv-
ous system, but have since been shown to be present in
non-neuronal cells [13]. Cancer cell lines as well as hu-
man keratinocytes and epithelial cells has been shown to
have α7 nAChR and respond to NNK (EC50 for NNK =
0.03 µM). Although nicotine is 5000 - 10000 times more
concentrated in tobacco smoke than NNK and 2000 -
3000 times more concentrated than NNN, NNK shows
1000-fold higher affinity for α7 nAChR compared to
nicotine. Additionally, α7 nAchRs are up-regulated in the
organs of smokers, and experimentally in the pancreas
and lungs of rodents following chronic nicotine/NNK
exposure [8,13].
The role of NNK as an initiator of acute pancreatitis in
rats was described recently by Alexandre et al., [30].
Using isolated acinar cells and in vivo models of pan-
creatitis, they demonstrated that NNK induced premature
activation of digestive zymogens (trypsinogen and chy-
motrypsinogen), a pivotal event in initiating pancreatitis.
Cerulein (an orthologue of the hormone cholecystokinin;
CCK) is commonly used in isolated pancreatic acinar
cells or animals in supraphysiologic concentrations (10 -
100 x that required to induce physiological responses), to
cause experimental pancreatitis. NNK treatment in a ce-
rulein model of the disease elevated zymogen activation
above that seen with NNK or cerulein treatment alone.
Furthermore, NNK triggered cellular damage in the pan-
creas (vacuolization, pyknotic nuclei, and edema) con-
sistent with that observed during acute pancreatitis. The
NNK receptor target, α-7 nAChR, was detected in rat
acini by PCR analysis. In addition, NNK mediated zy-
mogen activation was completely abrogated when iso-
lated acini were pre-treated with mecamylamine (a
nAChR blocker), validating a key role for α-7 nAChR in
triggering smoking-related pancreatitis. These findings
are the first to identify direct effects of cigarette toxins
on the acinar cell through a receptor-mediated mecha-
nism.
NNK may also stimulate pancreatitis responses via
β-adrenergic receptors. NNK is structurally similar to
classic β-adrenergic agonists and has high affinity for
human β-1 and β-2 receptors, with a preference for β-1
(EC50 for β1 = 5.8 nM; EC50 for β2 = 128 nM) [31]. Ac-
tivation of β-adrenergic receptors results in activation of
Open Access JCT

Smoking and Pancreatic Disease 36
adenylate cyclase, generation of cAMP, or release of
arachidonic acid. Elevations in cAMP have been impli-
cated in pancreatitis responses [32]. The enzyme phos-
pholipase A2 (PLA2) mediates arachidonic acid release
which is an important facilitator of inflammation; iso-
forms of phospholipase A2-II and A2-IV are elevated
during human acute pancreatitis and may contribute to
inflammatory effects through this pathway [33]. One
study identified β-1 and β-2 adrenergic receptors in rat
acini by PCR analysis, however the β-adrenergic receptor
blocker propranolol did not prevent NNK-mediated zy-
mogen activation in isolated acini [30].
Whether NNK potentiates additional pancreatitis re-
sponses through nicotinic, β-adrenergic, or other recep-
tors remains a focus for future research.
2.3. Regulation of Inflammation by Smoke
Compounds in Pancreatitis
NNK and nicotine may exert influence over inflamma-
tory cells during pancreatitis by binding to α7 nAChR
expressed on macrophages, thereby modulating immune
responses. Nicotine blocks production of pro-inflamma-
tory cytokines from macrophages by inhibiting the NF
 B
pathway, which is involved in macrophage activation
[24,35]. Furthermore, treatment of mice with meca-
mylamine (α7 nAChR blocker) decreased neutrophil and
macrophage migration to pancreatic tissue and intensi-
fied severity of experimental pancreatitis [36]. Prolonged
exposure to cigarette smoke, however, results in chronic
inflammation in the pancreas, indicating that an anti-
inflammatory effect may be a short term response that
gives way to a chronic inflammatory phase [37]. Pro-
inflammatory effects of NNK may be a result of its up-
take and metabolism by macrophages. In U937 human
macrophages NNK was metabolized and subsequently it
activated NF
 B, causing TNFα release which promotes
inflammation [10]. Therefore, NNK and other tobacco
derived nitrosamines likely mediate early pancreatitis
events through interaction with α7 nAChR on acini and
macrophages; chronic-inflammatory responses occur
much later, perhaps through uptake and metabolism of
such compounds.
3. Smoking and Pancreatic Cancer
Tobacco smoking is a major established risk factor for
pancreatic cancer [21,38]. It increases the risk of pancre-
atic cancer up to 6-fold depending on the duration and
intensity of smoking [39-41]. Nearly one quarter of all
pancreatic cancer deaths are linked to tobacco use [42].
Two different studies published recently showed that
smokers are diagnosed with pancreatic cancer at ages 8
to 15 years younger than non-smokers [43,44]. Therefore,
understanding the mechanisms through which smoking
predisposes to pancreatic cancer is urgently needed. This
will help target patients at high risk for the disease with
preventive strategies, and permit development of treat-
ment approaches directed at cell signaling pathways in-
volved in smoking-induced pancreatic cancer.
3.1. Cigarette Smoke-Mediated Pathways in
Pancreatic Cancer
As in chronic pancreatitis, slight progress has been
achieved in understanding the signaling pathways regu-
lated by cigarette smoke compounds in pancreatic cancer
in recent years.
A major mechanism through which smoking com-
pounds predispose to cancer in general is through induc-
ing DNA adducts leading to genetic mutations. However,
analysis of the pancreatic tissue did not show any asso-
ciation between increased level of mutations of pancre-
atic cancer-associated genes such as K-ras and p53 and
smoking [45,46]. However, the same study found asso-
ciation between increases in less common mutations in
pancreatic cancer patients and smoking status suggesting
possible role of these mutations in mediating the smok-
ing pro-cancer effect in the pancreas [46].
As discussed earlier, major cigarette smoke carcinogen
NNK interacts with pancreatic cells through β-adrenergic
receptor and nAChR [6,47-49]. These receptors mediate
NNK activation of Cox2, EGFR and Erk in pancreatic
cancer cells and ductal cells [47,48]. These pathways
regulate proliferation and cell death in pancreatic cells.
We showed that NNK and cigarette smoke extract
stimulate proliferation and inhibit apoptosis of normal
pancreatic ductal cells through a mechanism that in-
volves Akt and AMP kinases [50]. In pancreatic cancer
cells nicotine stimulates proliferation and invasion of the
AsPC1 pancreatic cancer cell line. Furthermore, nicotine
stimulates epithelial to mesenchymal transition (EMT)
by down-regulating E-cadherin and β-catenin and up-
regulating vimentin and fibronectin in several cancer
cells [51]. EMT has been associated with acquiring can-
cer stem cells characteristics suggesting regulation of
pancreatic cancer stemness and resistance to treatment by
smoking compounds.
In fact, recent data indicate that nicotine stimulates
growth, invasion, and resistance of pancreatic cancer
cells to chemotherapy through a mechanism that involves
Src pathways and the inhibitor of differentiation-1 (Id1)
transcription factor [52]. These effects were mediated by
the α7 nAChR receptor.
Regulation of EMT/invasion/metastasis pathways and
resistance to chemotherapeutic agents is extremely im-
portant to understand as these are the major contributors
to the aggressiveness of pancreatic cancer. The data pub-
lished in the last few years suggest that smoking com-
pounds do not only contribute to the initiation of cancer,
but also to the progression and the transformation of the
Open Access JCT

Smoking and Pancreatic Disease 37
cancer cells making them more metastatic and resistant
to drugs. EMT and stemness pathways regulated by smo-
king compounds need to be further investigated.
3.2. Cigarette Smoke and Regulation of the
Microenvironment of the Pancreatic Tumors
Pancreatic cancer is characterized by a strong desmo-
plastic reaction that includes inflammatory cells infiltra-
tion and fibrosis. There is increasing awareness of the
role of the tumor microenvironment in progression of the
disease.
Smoking compounds can worsen chronic pancreatitis
leading to pancreatic cancer [53]. Fibrosis and inflamma-
tion are major characteristics of chronic pancreatitis.
Exposure to cigarette smoke stimulates both fibrosis and
inflammation in the pancreas of rats [54].
Extracellular matrix proteins (ECM) secretion leading
to fibrosis is mainly mediated by activated pancreatic
stellate cells. These cells have been shown to express
nicotinic acetylcholine receptors and respond to nicotine
exposure by increased proliferation and ECM production
[55]. ECM production contributes to pancreatic cancer
cell survival and resistance to apoptosis [56].
Differently from the effect of smoking on inflamma-
tion in chronic pancreatitis [30,33], very little is known
about how inflammatory response would mediate smok-
ing-induced pancreatic cancer.
NNK treatment has been shown to significantly in-
crease macrophage infiltration and expression of pro-
inflammatory mediators such as macrophage inflamma-
tory protein 1 alpha (MIP-1α), interleukin 1 beta (IL-1β),
and transforming growth factor-beta (TGF-β) in mice
neoplastic lesions [5]. Macrophage and mast cell infiltra-
tion is observed in human pancreatic cancer as well [57].
Recent data showed that cigarette smoke extract sig-
nificantly stimulated pancreatic ductal epithelial flatten-
ing and induced severe acini atrophy in Elastase-IL-1β
transgenic mice. Cigarette smoke extract stimulated pro-
liferation and inhibited apoptosis in pancreatic ductal
epithelial cells in this model. Furthermore, analysis of the
cell signaling pathways showed induction of COX-2 in
the setting of chronic inflammation. A very recent paper
showed that high fat diet activates oncogenic Kras via
COX2 leading to pancreatic inflammation and fibrosis,
and development of pancreatic intraepithelial neoplasia
lesions and pancreatic ductal adenocarcinoma [58].
3.3. Future Directions
The lack of good animal models to study pancreatic can-
cer contributed to the slow progress in understanding
how smoking causes the disease. Previous studies using
hamsters and rats showed pro-cancer effect of the smok-
ing compounds but only after very long time (1 to 2 years)
[12,59]. More recent animal models combining cigarette
smoke compounds with carcinogenic chemicals such as
7,12-dimethylbenzanthracene (DMBA) or using or-
thotopic model of pancreatic cancer showed faster pro-
gression of the disease [59,60]. Developing mouse mod-
els of pancreatic cancer based on K-ras mice is greatly
required and will serve as a useful tool in understanding
the disease. These models will provide a good base to
study the interaction between immune cells, stellate cells
and pancreatic cancer cells in early and late stage of the
disease.
4. Conclusion
The last few years have seen slow progress in under-
standing the effect of cigarette smoking on pancreatic
disease. Smoking is a risk factor for acute and chronic
pancreatitis, and pancreatic cancer. It also increases the
risk of pancreatic cancer in patients with pancreatitis.
Identification of cellular targets, such as nAChR, will
help in development of potential therapies. Furthermore,
the use of reliable animal models such as the Pdx1-Cre,
LSL-Kras mice will help dissect relevant cellular changes
in the pancreas induced by smoking.
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