Diet and Pancreatic Cancer Prevention

Abstract

Pancreatic cancer is without any doubt the malignancy with the poorest prognosis and the lowest survival rate. This highly aggressive disease is rarely diagnosed at an early stage and difficult to treat due to its resistance to radiotherapy and chemotherapy. Therefore, there is an urgent need to clarify the causes responsible for pancreatic cancer and to identify preventive strategies to reduce its incidence in the population. Some circumstances, such as smoking habits, being overweight and diabetes, have been identified as potentially predisposing factors to pancreatic cancer, suggesting that diet might play a role. A diet low in fat and sugars, together with a healthy lifestyle, regular exercise, weight reduction and not smoking, may contribute to prevent pancreatic cancer and many other cancer types. In addition, increasing evidence suggests that some food may have chemo preventive properties. Indeed, a high dietary intake of fresh fruit and vegetables has been shown to reduce the risk of developing pancreatic cancer, and recent epidemiological studies have associated nut consumption with a protective effect against it. Therefore, diet could have an impact on the development of pancreatic cancer and further investigations are needed to assess the potential chemo preventive role of specific foods against this disease. This review summarizes the key evidence for the role of dietary habits and their effect on pancreatic cancer and focuses on possible mechanisms for the association between diet and risk of pancreatic cancer.

Full text

Review
Diet and Pancreatic Cancer Prevention
Ilaria Casari and Marco Falasca *
Received: 12 August 2015; Accepted: 10 November 2015; Published: 23 November 2015
Academic Editor: Hildegard M. Schuller
Metabolic Signalling Group, School of Biomedical Sciences, CHIRI Biosciences, Curtin University,
Perth 6102, Australia; ilaria.casari@curtin.edu.au
*Correspondence: marco.falasca@curtin.edu.au; Tel.: +61-8-9266-9712
Abstract: Pancreatic cancer is without any doubt the malignancy with the poorest prognosis and
the lowest survival rate. This highly aggressive disease is rarely diagnosed at an early stage and
difficult to treat due to its resistance to radiotherapy and chemotherapy. Therefore, there is an urgent
need to clarify the causes responsible for pancreatic cancer and to identify preventive strategies
to reduce its incidence in the population. Some circumstances, such as smoking habits, being
overweight and diabetes, have been identified as potentially predisposing factors to pancreatic
cancer, suggesting that diet might play a role. A diet low in fat and sugars, together with a healthy
lifestyle, regular exercise, weight reduction and not smoking, may contribute to prevent pancreatic
cancer and many other cancer types. In addition, increasing evidence suggests that some food may
have chemo preventive properties. Indeed, a high dietary intake of fresh fruit and vegetables has
been shown to reduce the risk of developing pancreatic cancer, and recent epidemiological studies
have associated nut consumption with a protective effect against it. Therefore, diet could have an
impact on the development of pancreatic cancer and further investigations are needed to assess
the potential chemo preventive role of specific foods against this disease. This review summarizes
the key evidence for the role of dietary habits and their effect on pancreatic cancer and focuses on
possible mechanisms for the association between diet and risk of pancreatic cancer.
Keywords: pancreatic cancer; cancer prevention; diet; obesity
1. Introduction
Pancreatic cancer is an aggressive disease which holds the gloomy record of having become one
of the most deadly malignancies in the USA, being the fourth leading cause of cancer-related death
in the USA, despite holding the 10th place in the incident rate scale [1,2]. Due to the difficulty in
obtaining an early diagnosis and to its resistance to treatment, pancreatic cancer has a very poor
prognosis, with a five-year survival rate of 7%, according to the American Cancer Society. Although
recent studies have pointed out the diversity and complexity of pancreatic cancer genetics, some
predisposing factors have been identified for this disease. Genetic factors are the main overt factors
responsible, followed by other DNA damage-inducing causes such as age, smoking (implicated in
20%–25% of cases), type 2 diabetes and chronic pancreatitis [3,4]. However, dietary components are
also thought to play a part in the development of this disease, as obesity, and high consumption of
red meat and fried foods are all risk factors. Conversely and according to some studies, a diet rich in
vegetables, fresh fruit, nuts and whole grain is useful in the prevention of pancreatic cancer [1,5–7].
In this review, we will discuss the possible links between diet and pancreatic cancer, analysing the
potential role of diet in promoting or preventing the onset of this disease.
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2. Pancreatic Cancer Progression Model
The pancreas is an elongated organ situated behind the stomach that holds digestive and
hormonal functions. Digestive enzymes are secreted by its exocrine gland, while the islets of
Langerhans, which constitute the endocrine gland, are devolved to hormones secretion. The vast
majority of tumours originate in the exocrine gland and, amongst them, 90% are pancreatic ductal
adenocarcinoma (PDAC), which is also the most aggressive form of pancreatic cancer. Due to the fact
that, especially in its early stages, pancreatic cancer can be asymptomatic or associated to non-specific
symptoms (they may include nausea, indigestion, weight loss, back pain, abdominal pain, jaundice,
steatorrhea and depression), it is rarely possible to obtain an early diagnosis and this therefore
implies an even greater difficulty of treatment [8]. The development of PDAC is very complex
and it is characterized by a sequence of precursor lesions, which occur at different stages of time
and ultimately evolve into invasive cancer. These lesions are known as pancreatic intraepithelial
neoplasia (PanIN), intraductal papillary mucinous neoplasms and mucinous cystic neoplasm. The
majority of PDACs develop from PanINs, and have been classified according to their morphological,
cytological, and genetic transformations, each of which leads to significant alterations of the signalling
pathway. Three stages, characterized by increasingly atypical cells, have been identified and called
PanIN1 (sub classified into PanIN1a and PanIN1B), PanIN2 and PanIN3 [9]. One of the early events
in the progression of the disease is the occurrence of Kras gene mutations at codon 12 in the normal
pancreatic epithelial cells, which are a characteristic of 90% of all PDAC. These mutations induce
cellular proliferation, invasion and survival. In the intermediate stage of the disease, the inhibition
of the p16 tumour suppressor gene occurs, promoting further cytological and architectural atypia in
the duct cells. In a later stage, the inactivation of the p53 tumour suppressor gene (TP53), which is
normally responsible for DNA repairing, cell division blocking and apoptosis activation, takes place
in 70% of all PDAC. In the late stage of the disease, inactivation of the SMAD4 gene involved in the
cell signalling pathway also occurs in 55% of all PDAC [10].
PDAC Defining Features
PDAC defining features can be summarized in: altered metabolism, desmoplasia, and hypo
vascularization. In order to survive and proliferate in the new micro-environment, pancreatic
cancer cells are forced to be subjected to a metabolic reprogramming and they rely on anabolic
reactions to synthetized de novo proteins, nucleic acids and lipids. Oncogenic Kras has been found
to play a key part in PDAC metabolism rearrangement. One of the most important constituents of
pancreatic cancer cells metabolism is autophagy. Autophagy is a very important catabolic process,
regulated by several protein complexes, whose function is to recycle unneeded or damaged cellular
particles, protein or molecular complexes, in order to maintain cells homeostasis. This function is
also anti-tumorigenic as it contributes to control pro-tumorigenic elements such as tissue damage,
oxidative stress and genomic imbalance. On the contrary, when increased above the baseline in
established tumours, autophagy becomes a pro-tumorigenic factor by furnishing cancer cells with
nutrients and energy [11]. Desmoplasia, which is another key feature of PDAC, is a complex reaction
of pancreatic stroma that involves stroma components such as stellate cells, leukocytes, endothelial
cells, fibroblasts, and extracellular matrix, as well as invading tumour cells and growth factors, and
results in fibrotic tissue formation. The characteristic hypo vascularization of the pancreatic tissue is
likely to be the cause of the presence of hypoxic areas within PDAC, which stimulate cancer cell to
adapt their metabolism to the new microenvironment and have also been demonstrated to affect the
efficacy of chemotherapy treatments [11–13].
3. Obesity and Pancreatic Cancer
The link between obesity (body mass index > 30.0 Kg/m2), type 2 diabetes, cardiovascular
diseases and cancer has long been established, even though the mechanisms by which extra fat
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deposits increase cancer risk have yet to be fully elucidated. This is a dreary perspective considering
that, according to the 2010 Health and Nutrition Examination Survey (NHANES), 35.5% of the USA
adult population and 17% of children and teenagers are obese [14,15]. Pancreatic cancer is currently
within the list of obesity-related cancers, together with colon, oesophageal, kidney, endometrial and
postmenopausal breast cancer [15]. Obesity or a high-fat diet, is one of the factors that can increase
the risk of developing acute pancreatitis [16,17], by changing the balance of digesting enzymes
within acinar cells and lowering pancreatic enzyme secretion. Acute pancreatitis is characterized
by an inflammatory state of the pancreas and by dysfunctional autophagy in pancreatic cells. In
addition, by increasing the levels of the pro-inflammatory hormone leptin and decreasing the levels
of the anti-inflammatory hormone adiponectin, obesity promotes inflammation. While normally
inflammation is a natural response of the body, which activates immune cells using cytokines,
chemokines and other mediators [18], persistent inflammation can lead to several cell damages
caused by metabolic changes and oxidative stress. Similarly, obesity, promoting the activation of
Akt and mTOR signalling pathways and down-regulating autophagy genes, such as Ulk1/Atg1
and Atg5, Atg6/Beclin1, inhibits autophagy, a cell defence mechanism which involves degradation
and recycling of damaged cellular components and that controls inflammation [19]. Autophagy
can also mediate mechanisms of chemoresitance of cancer cells to anticancer drugs. In response
to metabolic and therapeutic stresses, autophagy induces cell death, increases inflammation and
promotes tumorigenesis [20–22]. Moreover, the breakdown of excessive pancreatic fat caused by
obesity produces a surplus of unsaturated fatty acids that can increase inflammation, parenchymal
necrosis and lead to multi-organ damage and death [17]. Furthermore, unresolved or recurrent
acute pancreatitis that shows a persistent low-grade inflammation can activate pancreatic stellate
cells. These cells, which normally have the function of storing Vitamin-A lipid droplets in the
cytoplasm, upon activation during pancreatic injuries, promote fibrogenesis, leading to chronic
pancreatitis with an increased risk (around 5% of patients) of developing pancreatic cancer. In
addition, the exceeding production of cytokines induced by the excessive number of immune
cells stimulated by inflammation, can lead to the activation of oncogenic Kras, representing the
initial switch for Kras activation followed by mutations to an oncogenic form, a typical feature of
almost 90% of all pancreatic adenocarcinoma [19]. As well as many other cancer cells, one of the
characteristic features of pancreatic cancer cells is the substantial alteration of cellular metabolism,
which, together with genetic and epigenetic alteration, promotes tumour growth. In the early stages
of cancer development, lipid biosynthesis, de novo lipogenesis, provides extra lipids necessary for
the generation of biological membranes, energy store, and signalling functions [23]. It has been
demonstrated that lipoprotein catabolism and cholesterol synthesis are very stimulated in PDAC,
as tumour cells require high level of cholesterol [24]. Recent findings indicate that cancer cells can
utilize diet-derived fats present in blood, together with de novo lipogenesis, to satisfy lipid necessities,
strengthening the link between obesity, high fat diet, and cancer risk [25–28].
3.1. Epidemiological Studies
Recent epidemiological studies have also collected evidence supporting the connection between
obesity and risk of pancreatic cancer. In the Metabolic Syndrome and Cancer Project, a study
population of 577,315 individuals was observed for about 12 years follow-up and 315 women and
547 men were diagnosed with pancreatic cancer. As a result, a positive correlation between body
mass index and risk of pancreatic cancer emerged, although only for women [29]. Results from a
study conducted between 2008 and 2015 on 110 patients, where half of them were overweight or
obese, showed a direct link between precancerous lesions of the pancreas, pancreatic fatty infiltration,
intralobular fibrosis, subcutaneous and intravisceral fat and a high BMI. The authors also found the
number of PanIN lesions to be correlated with the percentage of intravisceral fat, which was not
found to be localized around the lesions. For this reason, they hypothesised fatty infiltrations to be the
cause of PanIN lesions and not vice versa [30]. A large case-control study conducted in USA associated
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obesity to a 50%–60% elevated risk of developing pancreatic cancer, particularly amongst women and
black subjects [31]. A positive association between pancreatic cancer risk and obesity and an increased
risk, especially for women in the presence of waist localized fat, was also underlined by a pooled
analysis from the National Cancer Institute Pancreatic Cancer Cohort Consortium (PanScan) [32]. A
case-control study, conducted in the USA on 841 patients with pancreatic adenocarcinoma and 754
healthy individuals, found that obesity and overweight in early adulthood determined an increased
risk of developing pancreatic cancer and led to precocity in the onset of this disease. Moreover, this
study showed that survival rates of patients with pancreatic cancer were affected by the presence of
obesity at an older age [33]. High BMI was also associated to poor survival in a retrospective study
conducted on advanced or metastatic pancreatic cancer patients between 1994 and 2004 [34]. A pooled
analysis of 14 cohort studies involving 846,340 persons found a 54% higher risk of pancreatic cancer
for people obese at baseline and those who were overweight in their early adulthood. In addition,
a 40% increased risk for individuals who had gained weight, compared to individuals who had a
constant weight, and also an increase for persons with a high waist-to hip ratio was observed [35].
3.2. Experimental Studies
Experimental studies on animals also provided data to corroborate the connection between
obesity and pancreatic cancer risk. Hamsters fed with a high fat diet and treated with
N-nitrosobis(2-oxopropyl)amine (BOP) developed hyperlipidaemia and intrapancreatic fatty
infiltration which led to pancreatic ductal adenocarcinoma in 67% of the animals, compared to 0%
in the control group fed with a standard diet [36]. A study conducted on a genetically engineered
mouse model revealed that mice fed with a HFD had an increased activation of oncogenic Kras via
pro-inflammatory factor COX-2, compared to the control group. This resulted in an enhancement
of the number of precancerous lesions of the pancreas and pancreatic ductal adenocarcinoma in the
HFD group [37]. Taken together these data strongly support the theory that obesity and a high fat
diet, by causing intrapancreatic fatty infiltration and promoting inflammation in the pancreas, trigger
a chain reaction leading to the activation of oncogenic Kras signalling and to the developing of chronic
pancreatitis and PanIn lesions, all well-known prerequisites of pancreatic cancer [38].
4. Diet and Pancreatic Cancer
Epidemiological and experimental studies have consistently shown the direct link between
obesity, high BMI, weight gain and elevated risk of developing pancreatic cancer. As a consequence, it
is logical to affirm that a high-calorie diet, and/or high consumptions of fats and sugars, predisposing
over time to overweight or obesity, has a negative impact on pancreatic cancer risk. In addition, a
high consumption of red meat has been found to elevate the risk of several types of cancer, including
pancreatic cancer [39]. On the other hand, there is also evidence that a healthy diet can have a role
in protecting against pancreatic cancer. In the 2010 Dietary guidelines for Americans (DGA), the
recommendation focuses on maintaining a healthy weight through consuming the right amount of
calories and nutrient-dense foods, together with the suggestion of eating a diet rich in fruit, vegetables
and whole grains [5].
4.1. Phytochemicals and Dietary Fibre
It is well known that fruit, vegetables, whole grains and nuts contain elevated amounts
of phytochemicals, bioactive compounds that can provide protection against several chronic
diseases and cancer and that are classified as carotenoids, phenolics, alkaloids, nitrogen-containing
compounds and organosulfur compounds [40–43]. Although their mechanisms of action are yet
to be fully elucidated, phytochemicals have been discovered to possess an additive and synergistic
action, which would account for their anticancer properties [44]. Some of the mechanisms proposed
to explain phytochemicals anticancer properties include: antioxidant and anti-inflammatory action;
inhibition of cell proliferation, differentiation, adhesion and invasion; anti-bacterial and anti-viral
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effects and stimulation of immune functions; DNA damage repair; regulation of steroid hormone and
oestrogen metabolism; regulation of signal transduction pathways; enzyme regulation; inhibition of
oncogene suppression and induction of tumour suppress gene expression; activation of cell cycle G
arrest; induction of cell differentiation and apoptosis [44]. In addition to the role of phytochemicals,
dietary fibre, one of the main components of fruit, vegetables, whole grains and nuts, has been
found to have an inverse correlation with cancer risk. A case control study on 326 pancreatic cancer
patients in Italy found soluble and insoluble fibre and fibre from fruit to be inversely associated to
pancreatic cancer, even though no association between grain fibre and risk of pancreatic cancer was
established [6]. On the contrary, whole grains were found to have a protective effect against several
types of cancers, including pancreatic cancer, in a study on Mediterranean diet and cancer risk [39].
In the Nurses’ health study, a prospective study on 75,680 women, individuals who consumed a
28 g portion of nuts, two or more times per week were associated with a significant diminished
risk of developing pancreatic cancer [45]. A case control study within EPIC cohort study (European
Prospective Investigation into Cancer and Nutrition) recently reported an inverse correlation between
plasma levels of beta-carotene (contained in orange fruit and vegetables and dark green leafy
vegetables), zeaxantin (contained in paprika, corn and wolfberries) and alpha-tocopherol (contained
in green and orange vegetables and tomatoes) and pancreatic cancer risk [46]. Moreover, some
isothiocyanates, compounds contained in cruciferous vegetables (i.e., broccoli, cauliflower, cabbage,
and Brussels sprouts), such as sulforaphane, benzyl isothiocyanate and phenethyl isothiocyanate,
have been shown to have an inhibitory effect on pancreatic cancer cells in in vitro and in animal
studies [47–51].
4.2. Dietary Compounds and Autophagy
Autophagy can have different roles in cancer depending on tumour types and context [20].
Indeed, during the first stages of tumour progression autophagy prevents genomic instability
and blocks tumour initiation, whereas in advanced states of the disease, autophagy, through
the degradation and recycling of cellular components, contributes to the increased demand for
rapid growth of cancer cells. PDAC are characterized by high levels of basal autophagy, and
pharmacological or genetic suppression of autophagy have been shown to inhibit pancreatic cancer
growth in vivo and in vitro [11]. Therefore, autophagy is required for tumour growth of PDAC,
and drugs that inhibit this process have been proposed for clinical testing in PDAC patients, as
well as in other tumour showing a similar dependence on autophagy. As a consequence of this
increasing interest in targeting this process, there are currently several clinical trials involving
autophagy inhibitors, such as chloroquine and its derivatives, worldwide. Among the different
mechanisms through which dietary compounds can affect the risk of cancer, autophagy is emerging as
an important process affected by diet [52]. This is not surprising considering that nutrient availability
is the major regular of autophagy. Several dietary compounds have been shown to affect autophagy
such as quercetin, genistein, curcumin, sulforaphane and resveratrol [53]. In addition, Vitamin D has
been shown to influence autophagy and increasing evidence supports a potential role of vitamin D
and its analogues in preventing or treating pancreatic cancer [54,55]. Nevertheless, several questions
remain to be addressed, such as the dose and duration of exposures and tissue specificity in response
to bioactive compounds as well as the implications of changes in autophagy during the early stages
of tumour initiation.
4.3. Calorie Restriction
In addition to a diet rich in fruit, vegetables, nuts, and whole grains, calorie restriction is
another promising strategy that seems to be effective in protecting against cancer risk [56]. In
fact, by chronically controlling the amount of calories consumed (in animal model a 20% to 40%
reduction is usually implemented), a reduction in the level of insulin, insulin-like growth factor,
leptin, adiponectin, plasminogen activator inhibitor, cytokines and vascular endothelial growth factor
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is obtained. These changes contribute to lower inflammation and growth factor signalling, and to
diminish vascular disorders, causing a reduction in cancer risk and cancer progression [56]. These
findings clearly show a link between a high-calorie diet and the probability of developing pancreatic
cancer and suggest a plan of action from a preventive perspective.
5. Conclusions
Given the extreme aggressiveness of pancreatic cancer and the difficulties in achieving an early
diagnosis and an efficacious cure, it is mandatory to concentrate not only on finding new adequate
treatments, but also on effective preventive strategies. As overweightness, high BMI and obesity are
increasingly common in our society and can play a role in increasing the risk of pancreatic cancer,
targeting these conditions and implementing a healthier lifestyle in the global population could be a
method for having an impact in the prevention of pancreatic cancer, and also on other types of cancer
and chronic diseases. A diet rich in fruit and vegetables, nuts and whole grain foods, together with a
balanced calorie control, could be a valuable tool in future pancreatic cancer prevention strategies.
Acknowledgments: M.F. is supported by Pancreatic Cancer Research Fund.
Author Contributions: Ilaria Casari: idea, concept, collection of data, review, paper writing, and paper revision.
Marco Falasca: Idea, Collection of data, paper revision, and editing, concept, and review of paper.
Conflicts of Interest: The authors declare no conflict of interest.
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