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Linking Obesity and Pancreatic Cancer

Written By

Kelly McCall, Anthony L Schwartz and Frank L Schwartz

Submitted: 19 September 2013 Published: 14 May 2014

DOI: 10.5772/58546

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1. Introduction

Cancer of the pancreas is the tenth most common form of cancer in the United States and the fourth leading cause of cancer-related death with a stunningly low 5-year survival rate of less that 6% [1-4]. Although there are genetic links with pancreatic cancer (10-15% of patients diagnosed will have a family history) [5], chronic pancreatitis [6], cigarette smoking and smokeless tobacco [7, 8], obesity [9-11], and type 2 diabetes mellitus (T2DM) [12-14] are the strongest environmental risk factors linked to this malignancy. Recently high fructose corn syrup (HFCS) consumption which also contributes to obesity, T2DM, and non-alcoholic fatty liver disease (NAFLD), has also been directly linked to pancreatic cancer [15]. The development of the industrial age and subsequent loss of the “hunter-gatherer” life-style has resulted in a world-wide epidemic of obesity and its associated chronic diseases including: atherosclerotic heart disease, stroke, diabetes, and multiple obesity-associated malignancies including cancer of the pancreas. Epidemiologic studies have demonstrated that as underdeveloped countries progress into industrialized economies and life-styles change (especially consumption of high density fat/carbohydrate diets coupled with decreased physical activity), the prevalence of obesity and obesity-related chronic diseases increases. The direct link between obesity, chronic inflammation, and oncogenesis is becoming increasingly more appreciated and the underlying cellular mechanisms involved this process are currently intensively being investigated and reviewed [16, 17]. In addition to the direct role of obesity in oncogenesis, obese individuals also demonstrate worse outcomes and shorter cancer survival compared to persons with normal body mass indexes (BMIs) [16]. These observations suggest that the abnormal hormonal and inflammatory milieu of obesity is directly involved in oncogenesis, promotes tumor growth, spread, and metastasis while possibly also increasing resistance to therapeutic intervention [16]. This chapter is meant to review the links between obesity, abnormal adipose tissue function, induction of abnormal hormonal and chronic inflammatory signaling pathways involved pancreatic cancer origin, growth, spread, and resistance to treatment. Our research efforts have been focused on the role of pathologic expression of toll like receptors (TLRs) in this process which links increasing visceral obesity to these processes.


2. Genetic linkage to pancreatic cancer

Family aggregation of pancreatic cancers suggests a genetic linkage and several important pancreatic cancer susceptibility genes have been identified including high-penetrance genes: BRCA2, PALB2, PRSS1, SPINK1, STK11 have recently been reviewed [5], and DNA miss-match repair genes. Genome-wide association studies (GWAS) are also finding single-gene polymorphisms (snps) that are also associated with increased risk for pancreatic cancer including: ABO, 1q32.1, 13q22.1, CLPTM1/TERT, CFTR [18, 19].

Chronic pancreatitis is the strongest independent risk factor for cancer of the pancreas and there are environmentally induced forms as well as rare inherited forms. Autosomal dominant mutations of the cationic trypsinogen gene PRSS1 causes a hereditary form of chronic pancreatitis [20] while an autosomal recessive defect in the serine protease inhibitor gene SPINK1 also causes hereditary pancreatitis [21]. These familial forms of chronic pancreatitis exhibit the greatest risk for pancreatic cancer (50-fold increase compared to the general population) and these individuals also experience the longest duration of chronic pancreatitis as well. As life expectancy from cystic fibrosis (CF) has increased from childhood into adulthood, individuals with the cystic fibrosis transmembrane conductance regulator (CFTR) gene now exhibit a 5-fold increased risk for pancreatic cancer from their early onset exocrine pancreatic disease and chronic pancreatitis [22, 23]. These are the major genes associated with risk for pancreatic cancer to date and most investigators anticipate that gene-gene and gene-environmental interactions coupled with the chronic inflammation are cooperatively involved in the pathogenesis of such complex cancers.


3. Environmental causes of chronic pancreatitis

Patients with chronic pancreatitis from any cause are at increased risk for pancreatic cancer with severity and duration of chronic pancreatitis (>20 years), age of the patient, and concomitant tobacco use being the major associated co-factors. Although alcohol abuse is causally linked to the development of chronic pancreatitis, interestingly it does not appear to be an independent risk factor for pancreatic cancer which has been confirmed by multiple recent epidemiologic met-analysis studies [24, 25]. Cigarette smoke contains numerous carcinogenic compounds including nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) [26]. One of the most well-known features of NNK is the ability of its metabolites to bind to DNA and induce activating point mutations in the RAS gene [26]. Nicotine itself has also been shown to stimulate Src kinase activity which facilitates the induction of the inhibitor of differentiation-1 (Id1) transcription factor which promotes pancreatic tumor growth, metastasis, and resistance to chemotherapeutics. Cigarette smoking also increases the risk for T2DM by inducing insulin resistance as well. Finally, as will be reviewed below, increasing BMI and obesity are also clearly risk factors for the development of hyperlipidemia, T2DM, chronic pancreatitis, and a 2-fold higher prevalence of pancreatic cancer.


4. Epidemiology of obesity, T2DM, and pancreatic cancer

There are multiple epidemiologic studies in the US and world-wide linking the epidemic of obesity and higher BMI to increa`sed risk for multiple malignancies including carcinoma of the pancreas [10, 27]. The American Cancer Society calculates that of the 1.5 million new cancer cases diagnosed each year, at least 20% are due to obesity [2]. The risk of pancreatic cancer in both men and women is increased in those who have a BMI > 25 but is most pronounced in those with a BMI of 35 or greater [11, 28]. The risk has been shown to increase by 10 per cent for every five-point increase in BMI. The strongest environmental risk factors related to pancreatic cancer as stated previously are cigarette smoking [8] and obesity [9]; both of which are also linked to inducing chronic inflammation, insulin resistance and T2DM [14]. As stated previously, individuals with T2DM are also twice as likely to develop acute pancreatitis and pancreatic cancer compared to non-diabetics [9, 10]. Studies looking at the components of diet and pancreatic cancer link increased risk with consumption of high fat diets, processed and/or organ meats, the glycemic index of food, and recently high-fructose corn syrup (HFCS) as important factors contributing to obesity, T2DM and risk for carcinoma of the pancreas [15]. As many as 40-50 % of patients with chronic pancreatitis will develop diabetes mellitus (DM) from the chronic destruction of beta cell function as well (insulin deficiency rather than the hyperinsulinemia discussed later). Furthermore, 40% of patients with carcinoma of the pancreas develop insulin deficiency from tumor replacement of beta cells and the DM often precedes the diagnosis of the cancer.

In contrast, there is a reciprocal relationship between the amount of exercise and risk for obesity, T2DM, and pancreatic cancer. Exercise alone burns calories and reduces the risk and/or severity of obesity, reduces insulin resistance, and promotes the production of anti-inflammatory cytokines which counter all of the proinflammatory and oncogenic processes which are discussed below [10].


5. Molecular pathways linking obesity, inflammation, diabetes, and pancreatic cancer

When caloric intake exceeds normal metabolic demand there is a need to store this excess energy and that is the principle function of the adipocyte. Adipose tissue however, is more than just a storage depot. Adipose tissue (especially visceral fat) is composed of multiple cell types (adipocytes, pre-adipocytes, macrophages, fibroblasts, and blood vessels), and is now recognized as a significant endocrine organ that expresses and secretes multiple hormones (leptin, adiponectin, resistin), inflammatory cytokines (TNF-α, IL-6, and IFN-β), components of complement, plasminogen activator inhibitor-1 (PAI-1), vascular endothelial growth factor (VEGF) and other proteins such as monocyte chemoattractant protein (MCP-1). These adipose tissue-derived factors (Figure 1) are now thought to contribute dramatically to the induction of chronic inflammation which is expressed as insulin resistance [29], hyperinsulinemia, T2DM, hyperlipidemia, hypertension, and atherosclerosis [30], and also contributing to the oncogenesis of many solid tumors [11, 16]. Visceral obesity is the fat depot most closely associated with the production of these substances and the subsequent development of insulin resistance, T2DM, and pancreatic cancer oncogenesis.

5.1. Dietary contributions

  1. High Fat Diets (HFDs) and Excess Free Fatty Acids (FFAs):

Dietary fats (triglycerides, glycerol, and FFAs) are directly absorbed from the small intestine as chylomicrons into the thoracic duct into the subclavian vein and then into the general circulation. Chylomicrons are taken up by adipocytes and hepatocytes [31]. However, once the adipocyte storage capacity is exceeded, excess TG’s and FFA’s stimulate adipogenesis and are deposited ectopically into the liver where these excess fats accumulate in small vacuoles within hepatocytes which is the first stage of fatty liver disease (steatosis) [32, 33]. There is also increased de novo hepatic lipogenesis with consequent endogenous over-production of triglycerides (TGs) and free fatty acids (FFAs). Excess fats are also deposited in skeletal muscle and other insulin target tissues (even beta cells of pancreas) where they initiate acute inflammatory processes (lipotoxicity) with the activation of multiple inflammatory cytokines [16]. Inflammatory cytokines in turn, directly contribute to the induction of insulin resistance through down regulation of the insulin receptor (IR) and post-receptor signaling pathways in insulin target tissues [33]. In the liver, the ectopic dietary fat also initiates an inflammatory response (steatohepatitis) which contributes to the development of non-alcoholic fatty liver disease (NAFLD) [33].

Within visceral fat cells themselves, FFAs (palmitate, etc.) directly induce the release of inflammatory cytokines [16] and also trigger the pathologic signaling of toll-like receptors (TLRs); activation of TLR4, in particular, increases additional inflammatory cytokine production, contributing to the initiation of insulin resistance [34] and adipogenesis, further increasing adipocyte mass, and the chronic inflammatory state now associated with obesity, T2DM, and oncogenesis.

  1. High Fructose Corn Syrup (HFCS):

Fructose is a dietary carbohydrate normally derived from plant sources (tree and vine fruits, flowers, berries, and most root vegetables) which is much sweeter than glucose or sucrose. It is commonly used commercially in prepared foods due to its sweetness, effects on prepared food texture, and browning of baked foods. Commercially it is derived from sugar cane, sugar beets, and corn. HFCS is a mixture of glucose and fructose as monosaccharaides and as a food supplement it is now being vilified for its role in the obesity epidemic as well as induction of insulin resistance, T2DM and non-alcoholic fatty liver disease (NAFLD) [35-38]. NAFLD is now the leading cause of cirrhosis of the liver and primary hepatocellular cancer. Diets high in HFCS have also been linked directly to increased risk for pancreatic cancer [39]. Mechanisms by which HFCS induces insulin resistance are thought to be due to its unique metabolism in the liver via pathways identical to alcohol. Fructose binds to only one of the glucose transporters (GLUT 5) which is present only in enterocytes of the intestine and in the liver. Thus, although it is selectively concentrated in the liver, fructose cannot be utilized as a carbohydrate for energy in any other cell or organ of the body. Acutely, fructose ingestion results in the shunting of fructose-1-phosphate into dihydroxyacetone-phosphate and glyceraldehyde which enters the TCA cycle from pyruvate and citrate to excessively increase de novo hepatic lipogenesis and the over-production of TGs and FFAs [40]. Fructose-1-phosphate also directly induces janus kinase-1 (JNK-1) signaling, increasing serine phosphorylation of insulin receptor substrate-1 (IRS-1) in the liver and preventing normal insulin-stimulated tyrosine phosphorylation of IRS-1 [41]. TG and FFAs derived from HFCS intake also induce insulin resistance in the liver as the FFAs precipitate in hepatocytes (lipid droplet accumulation), also stimulating excessive TLR4 signaling and further amplification of multiple inflammatory cytokine pathways. Dihydroxyacetone-phosphate and glyceraldehyde are also both directly hepatotoxic while the excessive accumulation of lipid droplets in the liver induces steatosis further amplifying inflammatory cytokine release. All of these processes are thought to contribute to progressive development of hepatic fibrosis, cirrhosis, and primary hepatic cancer. Elevated TGs and FFAs produced by the liver or which cannot be cleared from the portal vein by the liver accumulate in the peripheral circulation, exerting similar effects on the insulin receptor signaling in other target tissues such as adipose tissue, skeletal muscle, and the exocrine pancreas [40].

Figure 1.

The role of dysfunctional adipose tissue in obesity. Dysfunctional adipose tissue is a critical source of molecules that mediate inflammation, cancer, insulin resistance and angiogenesis. PAI-1 (plasminogen activator inhibitor-1); FFAs (free fatty acids); IGF-1 (insulin-like growth factor 1); VEGF (vascular endothelial growth factor); IL-6 (interleukin 6); TNF-α (tumor necrosis factor alpha); TLR4 (toll-like receptor 4).

With regard to pancreatic cancer, there is increasing evidence of a specific dose-dependent linkage between HFCS intake and its occurrence and this risk is independent of obesity or BMI [15]. Furthermore, fructose directly stimulates increased nucleic acid synthesis through the pentose phosphate pathway (catalyzed by transketolase) which is necessary for proliferation of malignant cells and consumption of HFCS is now linked both to oncogenesis as well as tumor spread and metastasis [15].

  1. Carcinogens in Foods:

High intake of processed meats containing heterocyclic amines and benzo (a) pyrines or have been prepared at high temperatures (fried or grilled) have been linked to pancreatic cancer [42] as have other foods containing aflatoxins [43] and other mutagens, however their link to pancreatic cancer are fairly weak at this time.

5.2. Molecular pathways triggered by dietary constituents

  1. Adipocyte-Derived Inflammatory Proteins:

Inflammatory cytokines (adipokines) such as TNF-α, IL-6, IL8, VEGF, and IFN-β have been shown to be elevated in states of visceral obesity [16], as well as acute and chronic pancreatitis, and pancreatic cancer [11]. Visceral adipocytes/macrophages are major sources of the obesity-associated cytokines which are thought to promote insulin resistance [29] (see below) as well as directly contribute to oncogenesis via several pathways [16] including other growth factor receptors, cytokine receptors, or non-receptor tyrosine kinases. Each of these pathways can increase Janus kinase (JAK)/signal transduction and activator of transcription Signal Transducer and Activator of Transcription (STATs) of which STAT3 [44, 45] is directly linked to cancer of the pancreas. Both of these pathways can stimulate cellular proliferation—transformation through (1) up-regulation of genes encoding cell cycle regulators (cyclins D1/D2, c-Myc), (2) increasing the probability of mutation, (e.g., cellular proto-oncogenes, DNA, and cellular repair mechanisms), (3) inhibition of apoptosis (Bcl-xL, Mcl-1), (4) decreased cellular adhesion, and/or (5) stimulation of angiogenesis (VEGF) [46].

Leptin is also secreted by adipocytes and plays a key role in regulating metabolism and appetite. Leptin is known as the satiety hormone however serum leptin levels are elevated in obesity due to central leptin receptor resistance (by mechanisms similar to insulin discussed below). Leptin has mitogenic actions in many cancer cell lines which appear to be via mitogen-activated-protein-kinase (MAPK) mediated pathways; however in certain pancreatic cancer cell lines it inhibits growth [47] so its role in this cancer is unclear at present [48, 49].

Adiponectin is exclusively secreted by adipocytes and has both anti-inflammatory and insulin-sensitizing effects. Known as the “good adipokine” serum levels of leptin are inversely related to BMI and levels are reduced obese patients and in many cancers. High levels of adiponectin are inversely related to the incidence of pancreatic cancer [49].

PAI-1 is a serine protease inhibitor produced by adipocytes and stromal cells in visceral fat, is associated with tumor cell invasion, metastasis, and angiogenesis of many malignancies, and over-expression of PAI-1 has been demonstrated in many obesity-related tumors suggesting it contributes to the spread of malignancies [50]. Interestingly, high expression of the plasminogen activator inhibitor-2 (PAI-2) was a predictor of improved survival in patients with pancreatic adenocarcinoma [51].

VEGF is another adipocyte-derived polypeptide that has been implicated in cancer growth, shown to be over-expressed in many pancreatic cancers, and its expression in these tumors is linked to poorer survival [52, 53].

  1. Insulin Resistance, Hyperinsulinemia, and Increased Insulin/IGF-1 Receptor Signaling Pathways

The FFA’s and inflammatory cytokines produced by visceral obesity discussed earlier directly induce insulin resistance at the insulin receptor (IR) level [34, 54] resulting in compensatory beta cell insulin secretion (hyperinsulinemia) in an attempt to maintain euglycemia. The hyperinsulinemia becomes a self-perpetuating vicious cycle, in turn, as it directly contributes to insulin resistance by down-regulating its own receptor. Insulin resistance can originate anywhere in the insulin-action cascade; from a direct reduction in IR number or affinity, to reduced phosphorylation/activation of the insulin receptor itself, to down-regulation of the intracellular protein-kinase cascade normally triggered by insulin action following interaction with the IR (post-receptor signaling) [55]. Over-stimulation of the IR by hyperinsulinemia itself results in high levels of STAT3 activation, which then up-regulates suppressors of cytokine signaling-3 (socs-3); which in turn, inhibits post-receptor insulin signaling as a negative “feedback” inhibitory mechanism, thereby down-regulating its own receptor system [56]. We have shown that excessive TLR4 signaling and inflammatory cytokine release up-regulates socs-3 which contributes to insulin resistance [34]. Overall decreased insulin signaling then leads to decreased activation of GLUT4 transporters and decreased insulin-stimulated suppression of hepatic gluconeogenesis and glucose uptake into peripheral target tissues such as adipocytes and skeletal muscle which leads to the development of T2DM. Although IR-mediated pathways associated with carbohydrate and fat metabolism are down-regulated, other signaling pathways are not suppressed but rather continuously stimulated by insulin resulting in activation of the Ras/Raf/mitogen-activated-protein-kinase (MAPK) system and mTOR pathways which are known to promote abnormal cell growth and proliferation [57, 58]. Thus, in states of obesity and FFA/TLR4/cytokine-mediated insulin resistance, the principle functions of insulin action via the IR (glucose transport and suppression of gluconeogenesis) are impaired while insulin-stimulated abnormal cell growth and proliferation in target tissues continues [58]. Secondly, hyperinsulinemia induces the synthesis of insulin-like growth factor-1 (IGF-1) in liver and the high serum levels of free IGF-1 also results in over-stimulation of its own receptor (IGF-1R). Excess IGF-1R signaling also stimulates abnormal cell proliferation through the same downstream signaling networks which are being chronically stimulated by insulin; including the phosphatidylinositol 3-kinase (PI3-K)-AKT system [58]. Thus obesity induced insulin resistance results in excess insulin and IGF-1 promotion of abnormal cell growth and proliferation in multiple organ systems. Expression of IGF-1 receptors has also been demonstrated in multiple malignant tumors including pancreatic cancer, and IGF-1 contributes to cell migration and invasion in some human pancreatic carcinomas.

  1. Hyperglycemia Induces Pancreatic Cancer Epidermal Growth Factor Expression

As we have previously discussed in this chapter, diabetes is associated with an increased risk of pancreatic cancer by a variety of cytokine and hormone receptor signaling pathways and that large numbers of patients with pancreatic cancer develop diabetes and elevated glucoses. The direct effect of hyperglycemia on oncogenesis, pancreatic cancer growth and spread is of interest as well. Epidemiologic studies have demonstrated that glucose control in patients with pancreatic cancer results in improved survival, suggesting that high glucose levels might directly promote tumor growth and progression [59]. Recent in vitro cell culture studies have demonstrated that glucose in a dose-dependent manner promotes different pancreatic cancer cell line growth and perineural invasion through the regulation of expression of glial cell line-derived neurotropic factor (GDNF) and epidermal growth factor (EGF) via increased epidermal growth factor receptor (EGFR) transactivation [60]. These observations support intensive glucose control as a potential target for improving patient survival in pancreatic cancer.


6. Obesity, toll-like receptors, and pancreatic oncogenesis

Toll-Like Receptors (TLRs) are pathogen recognition receptors (PRRs) critical for the activation of the innate and adaptive immune responses to foreign pathogens. Functional TLRs are not only expressed in immune cells but also in many non-immune cells [61]. Their activation, signaling, and proinflammatory responses have been shown to be mediators of multiple inflammatory and autoimmune diseases, as well as, contribute to oncogenesis, tumor growth and metastasis. Pathologic signaling of multiple TLRs have been implicated in many cancers including; melanoma, breast, prostate cancer, colorectal, lung, cervical, liver, and pancreatic cancer [62-64]. Obesity and T2DM are associated with an increased risk for many of these same malignancies; especially pancreatic cancer. FFA’s are capable of activating TLR4 signaling in adipocytes which stimulates adipocyte differentiation, high fat diet (HFD)-mediated induction of visceral obesity, TLR4-mediated cytokine signaling, insulin resistance, and glucose intolerance [34, 65]. This in turn stimulates insulin/IGF-1 signaling pathways which also promote tumor growth. Fructose also stimulates abnormal TLR4 signaling [36] and as mentioned earlier, HFCS diets are associated with induction of visceral obesity, T2DM, chronic pancreatitis, and cancer of the pancreas as well. Since both FFA’s and fructose are potent ligands for TLR4 and both are present in high concentrations in the diets of developed countries it is logical that they could promote pancreatic oncogenesis via TLR mediated pathways to be described. Finally, as just mentioned hyperglycemia in the form of glucose intolerance and overt T2DM also stimulates abnormal TLR4 signaling [66] as well as EGFR transactivation in pancreatic tissue in a glucose dependent manner thus also serving as a ligand to promote tumor growth and spread.

Chronic inflammation has been shown to be an important risk factor for the onset and progression of multiple cancers, including pancreatic cancer [67-72] [72-75]. Chronic inflammation is thought to induce malignant transformation via activation of oncogenes, induction of immunosuppression, and inhibition of tumor suppressor genes and lymphocytes. Pathologic activation of TLRs play a critical role in the inflammatory response induced by high fat diets and HFCS by inducing the production of multiple pro-inflammatory cytokines and they have been shown to be important for the induction, proliferation, survival, metastasis, and escape from immune surveillance of many of these cancers as well [70, 76]. Some of the most important TLR-induced cytokines implicated in cancer include TNF-α, IL-1, IL-6, IL-8, IL-10 and IL-23. Proinflammatory cytokine production then leads to the activation of many tumor promoting transcription factors and anti-apoptotic genes. Nuclear factor kappa beta (NF-κB) and signal transducer and activator of transcription 3 (STAT3) are two of the most well studied oncogenic transcription factors.


7. Pathologic toll-like receptor signaling, pancreatic cancer growth, and resistance to therapy

We have previously described the relationship between obesity and pancreatic cancer risk as well as the direct correlation between increasing BMI and hyperglycemia to lower responses to treatment and over-all worse outcomes in this all too common disease. Obesity-induced TLR activation of NF-κB and STAT3 signaling pathways are major mediators of this process in multiple cancers including pancreatic cancer. NF-κB and STAT3 are activated by a variety of similar stimuli (stressors, cytokines, etc.) and both control expression of proliferation-enhancing, anti-apoptotic, angiogenic, and immune-modulating genes; however they are regulated by entirely different signaling mechanisms. NF-κB’s pro-inflammatory cytokine receptors such as; TNF-α and IL-1 [77-80] promote not only tumor transformation, but also proliferation, angiogenesis, invasion, metastasis, and chemo/radio resistance [81-89]. STAT3 activation by TLR-mediated cytokines also activates the IL-6 family (IL-6, IL-11, IL-27, etc.), IL-10 family (IL-10, IL-22, IL-19, IL-20), and the epidermal growth factor (EGF) family (VEGF, IL-21, IL-23, HGF) of growth factors which also stimulate tumor transformation, growth and resistance to therapy. NF-κB and STAT3 activate anti-apoptotic genes such as Bcl-xL, Bcl-2, and c-IAP2 [90-92] and also interact and mediate crosstalk between tumor cells and inflammatory cells within the tumor microenvironment to promote the development and progression of multiple types of human cancers including but not limited to pancreatic, colon, gastric, skin, head and neck, and liver cancers [44, 90, 93-96]. Finally, Wnt5a a member of the Wnt family has also been implicated in carcinogenesis and inflammation. Non-canonical Wnt5a activates β-catenin-independent pathways important for cell migration and polarity. Wnt5a has been found in tissue samples of pancreatic adenocarcinomas [97] and is highly expressed in advanced pancreatic cancer [98]. Recently, a TLR / IL-6 / STAT3 / Wnt5a signaling loop was described [62, 99].


8. TLRs as a potential therapeutic target

Several recent studies have evaluated the potential therapeutic use of TLR activators and inhibitors in multiple cancer models. The theory for activation of TLR signaling pathways in a tumor environment is that it would possibly induce tumor cell apoptosis or inhibit the production of various factors described in this review that control tumor growth. In addition, it induction of TLR signaling could elicit an antitumor immune response that could lead to tumor cell destruction by the host’s immune system. Treatment with TLR agonists have shown to induce an antitumor response by enhancing dendritic cell (DC) vaccination or T cell adoptive therapies. A recent study reported that the use of TLR agonists such as poly(I:C) or CpG combined with adoptive transfer immunotherapy directly to a B16F10 melanoma model inhibited tumor growth [100]. Also, in a mouse breast xenograft model, the antitumor effect of the TLR3 activator was shown to be dependent on the expression of TLR3 expression in tumor cells. This was further validated in humans where treatment with dsRNA improved outcomes in patients harboring TLR3-positive breast tumors [101]. Similarly, CpG treatment via TLR9 activation induced tumor cell death in human neuroblastoma cells, and tumor-targeted delivery of this TLR9 agonist increased survival in a xenograft model of neuroblastoma [102].

In contrast, it has also been shown that TLR agonists can promote cancer cell survival and migration, and tumor progression. For example, TLR agonists have been shown to increase tumor viability and metastasis of human lung cancer (TLR7/8) [103] ; proliferation of human myeloma (TLR3) [104] ; adhesion and metastasis of human colorectal cancer (TLR4) [105] ; and migration of human glioblastoma (TLR4) or human breast cancer (TLR2) [106]. In regards to pancreatic cancer, TLR7 was recently reported not only be highly expressed in mouse and human pancreatic cancers, but ligation of TLR7 led to accelerated tumor progression through the STAT3 growth pathways previously discussed. Thus, there appears to be a double edged sword between reducing or promoting tumor growth using agonists based therapies for different TLRs.

On the other hand, the use of TLR antagonists has shown to be beneficial at inhibiting tumor growth in animal models in which the tumor microenvironment promotes survival and metastasis via TLR signaling. TLR antagonists might also decrease the level of activation of stromal cells such as tumor-associated macrophages. Macrophages express an array of TLRs and are able to produce several growth factors via TLR signaling [107]. Moreover, abrogation of TLR-4 signaling in tumor-associated macrophages decrease tumor growth in vivo [108].

Our group demonstrated that in papillary thyroid carcinoma cells, IL-6, a TLR3 signaling product, activates STAT3, results in overexpression of Wnt5a which mediates tumor growth and spread [62]. Further, we demonstrated that phenylmethimazole (C10), a small molecule derivative of methimazole, blocked TLR3 signaling, and subsequent IL-6 production, STAT3 activation, Wnt5a overexpression, and subsequent growth and migration of papillary thyroid carcinoma cells [62]. Toll-like receptors were first implicated in the pathogenesis of pancreatic cancer in 2009. Our laboratory demonstrated that TLR3 and Wnt5a were coordinately constitutively expressed in a human pancreatic cell line (PANC-1), activation of signaling also played a key role in the regulation of pancreatic cancer growth and migration and that C10, inhibited its growth and migration both in vitro and in vivo [63]. Another study reported that activation of the TLR4 signaling pathway-increased invasiveness of pancreatic cancer cells while blockade of TLR4 signaling decreased invasive ability [109]. These studies were the first to implicate both TLR3 or TLR4 expression and signaling as playing a role in pancreatic tumor growth and migration and demonstrated that inhibition of TLR signaling pathways were potential therapeutic targets. Gemcitabine is currently the standard of care chemotherapeutic for pancreatic cancer; however, its efficacy is diminished due to toxicity and the chemoresistance of the tumors. Recently, another group combined TLR4/NF-κB antagonist with gemcitabine in an orthotopic model of pancreatic cancer and the combination therapy significantly delayed tumor growth and decreased tumor size compared to gemcitabine alone or the control groups. Thus, TLR antagonists, when combined with other chemotherapeutic agents may prove to be effective adjunctive therapies to suppress the inflammatory cytokine/growth factor microenvironment which contributes to the induction and/or support of tumor growth and progression and reduce the dose/toxicity of established agents.


9. Prevention of obesity associated pancreatic cancer

There is now compelling evidence that obesity, chronic inflammation, and the associated secretion of numerous inflammatory cytokines, hormones and growth factors described herein contribute both directly and indirectly to the increased risk for pancreatic cancer, more aggressive tumor growth, as well as poor response to therapeutic intervention. Thus, in addition to smoking cessation and moderation in alcohol consumption, life-style modification with exercise, maintenance of normal BMI’s, consumption of higher amounts of fresh fruits and vegetables, less animal fat and processed foods; especially those fortified with HFCS are obvious recommendations. In addition, there is increasing evidence that other anti-inflammatory agents such as the non-steroidal anti-inflammatory drugs (NSAIDS) [110], the Statin lipid-lowering medications, and T2DM medications such as the thiazolidinediones (TZD’s) [111] and metformin [112, 113] have specific protective effects against oncogenesis as well as tumor growth and response to treatment.


10. Conclusion

Obesity contributes to increased risk for multiple solid cancers including pancreatic cancer. For pancreatic cancer in particular, obesity promotes a proinflammatory environment which promotes oncogenesis, tumor growth, metastatic spread as well as resistance to therapy through a variety of molecular pathways. The principle obesity-linked pathways include increases in TNF-α, IL-1, IL-6, IL-8, IL-10 and IL-23 as well as activation of NF-κB and STAT3. The current diets of industrialized nations which contain too much low glycemic-index carbohydrates, saturated fats, and HFCS are major environmental triggers of pathologic TLR3 and TLR4 signaling pathways in adipocytes which then contribute to the development of insulin resistance, ectopic fat deposition in multiple tissues including the pancreas which in turn amplify the growth and signaling pathways described herein which lead to oncogenesis and tumor spread.


  1. 1. Hariharan D, Saied A, Kocher HM. Analysis of mortality rates for pancreatic cancer across the world. HPB (Oxford). 2008;10(1):58-62. PubMed PMID: 18695761. Pubmed Central PMCID: 2504856. Epub 2008/08/13. eng.
  2. 2. American Cancer Society: Facts and Figures. 2010:4 for incidence & 19 for survival.
  3. 3. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. Jul-Aug;61(4):212-36. PubMed PMID: 21685461. Epub 2011/06/21. eng.
  4. 4. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. Mar-Apr;61(2):69-90. PubMed PMID: 21296855. Epub 2011/02/08. eng.
  5. 5. Klein AB. Genetic Susceptibility to Pancreatic Cancer. Molec Carcinog. 2012;51(1):14-24.
  6. 6. Lowenfels AB, Maisunneuve, P., DiMagno, E.P., Elitser, Y., Gates, L. K., Perralt, J., Whticomb, D. C. Heriditary Pancreatitis and risk for Pancreatic Cancer. J Nat Cancer Institute. 1997 Mar 19, 1997;89(6):443-6.
  7. 7. Trevino JG, Pillai S, Kunigal S, Singh S, Fulp WJ, Centeno BA, et al. Nicotine induces inhibitor of differentiation-1 in a Src-dependent pathway promoting metastasis and chemoresistance in pancreatic adenocarcinoma. Neoplasia. Dec;14(12):1102-14. PubMed PMID: 23308043. Pubmed Central PMCID: 3540937. Epub 2013/01/12. eng.
  8. 8. Alguacil J, Silverman DT. Smokeless and other noncigarette tobacco use and pancreatic cancer: a case-control study based on direct interviews. Cancer Epidemiol Biomarkers Prev. 2004 Jan;13(1):55-8. PubMed PMID: 14744733. Epub 2004/01/28. eng.
  9. 9. Martinez J, Sanchez-Paya J, Palazon JM, Suazo-Barahona J, Robles-Diaz G, Perez-Mateo M. Is obesity a risk factor in acute pancreatitis? A meta-analysis. Pancreatology. 2004;4(1):42-8. PubMed PMID: 14988657. Epub 2004/02/28. eng.
  10. 10. Bracci PM. Obesity and pancreatic cancer: overview of epidemiologic evidence and biologic mechanisms. Mol Carcinog. Jan;51(1):53-63. PubMed PMID: 22162231. Pubmed Central PMCID: 3348117. Epub 2011/12/14. eng.
  11. 11. Gumbs A. Obesity, Pancreatitis, and Pancreatic Cancer. Obes Rev. 2008;18:1183-87.
  12. 12. Everhart J, Wright D. Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis. JAMA. 1995 May 24-31;273(20):1605-9. PubMed PMID: 7745774. Epub 1995/05/24. eng.
  13. 13. Huxley R, Ansary-Moghaddam A, Berrington de Gonzalez A, Barzi F, Woodward M. Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Cancer. 2005 Jun 6;92(11):2076-83. PubMed PMID: 15886696. Pubmed Central PMCID: 2361795. Epub 2005/05/12. eng.
  14. 14. Wang F, Herrington M, Larsson J, Permert J. The relationship between diabetes and pancreatic cancer. Mol Cancer. 2003 Jan 6;2:4. PubMed PMID: 12556242. Pubmed Central PMCID: 149418. Epub 2003/01/31. eng.
  15. 15. Liu H, Huang D, McArthur DL, Boros LG, Nissen N, Heaney AP. Fructose induces transketolase flux to promote pancreatic cancer growth. Cancer Res. Aug 1;70(15):6368-76. PubMed PMID: 20647326. Epub 2010/07/22. eng.
  16. 16. Gilbert CA, Slingerland JM. Cytokines, obesity, and cancer: new insights on mechanisms linking obesity to cancer risk and progression. Annu Rev Med.64:45-57. PubMed PMID: 23121183. Epub 2012/11/06. eng.
  17. 17. van Kruijsdijk RC, van der Wall E, Visseren FL. Obesity and cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol Biomarkers Prev. 2009 Oct;18(10):2569-78. PubMed PMID: 19755644. Epub 2009/09/17. eng.
  18. 18. Li D, Tanaka M, Brunicardi FC, Fisher WE, Gibbs RA, Gingras MC. Association between somatostatin receptor 5 gene polymorphisms and pancreatic cancer risk and survival. Cancer. Jul 1;117(13):2863-72. PubMed PMID: 21692047. Pubmed Central PMCID: 3135720. Epub 2011/06/22. eng.
  19. 19. Dong X, Tang H, Hess KR, Abbruzzese JL, Li D. Glucose metabolism gene polymorphisms and clinical outcome in pancreatic cancer. Cancer. Feb 1;117(3):480-91. PubMed PMID: 20845477. Epub 2010/09/17. eng.
  20. 20. Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet. 1996 Oct;14(2):141-5. PubMed PMID: 8841182. Epub 1996/10/01. eng.
  21. 21. Pfutzer RH, Whitcomb DC. SPINK1 mutations are associated with multiple phenotypes. Pancreatology. 2001;1(5):457-60. PubMed PMID: 12120224. Epub 2002/07/18. eng.
  22. 22. Maisonneuve P, Marshall BC, Lowenfels AB. Risk of pancreatic cancer in patients with cystic fibrosis. Gut. 2007 Sep;56(9):1327-8. PubMed PMID: 17698876. Pubmed Central PMCID: 1954996. Epub 2007/08/19. eng.
  23. 23. Cohn JA, Mitchell RM, Jowell PS. The impact of cystic fibrosis and PSTI/SPINK1 gene mutations on susceptibility to chronic pancreatitis. Clin Lab Med. 2005 Mar;25(1):79-100. PubMed PMID: 15749233. Epub 2005/03/08. eng.
  24. 24. Lucenteforte E, La Vecchia C, Silverman D, Petersen GM, Bracci PM, Ji BT, et al. Alcohol consumption and pancreatic cancer: a pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4). Ann Oncol. Feb;23(2):374-82. PubMed PMID: 21536662. Pubmed Central PMCID: 3265544. Epub 2011/05/04. eng.
  25. 25. Ye W, Lagergren J, Weiderpass E, Nyren O, Adami HO, Ekbom A. Alcohol abuse and the risk of pancreatic cancer. Gut. 2002 Aug;51(2):236-9. PubMed PMID: 12117886. Pubmed Central PMCID: 1773298. Epub 2002/07/16. eng.
  26. 26. Lin RK, Hsieh YS, Lin P, Hsu HS, Chen CY, Tang YA, et al. The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients. J Clin Invest. Feb;120(2):521-32. PubMed PMID: 20093774. Pubmed Central PMCID: 2810088. Epub 2010/01/23. eng.
  27. 27. Larsson SC, Orsini N, Wolk A. Body mass index and pancreatic cancer risk: A meta-analysis of prospective studies. Int J Cancer. 2007 May 1;120(9):1993-8. PubMed PMID: 17266034. Epub 2007/02/03. eng.
  28. 28. Michaud DS, Giovannucci E, Willett WC, Colditz GA, Stampfer MJ, Fuchs CS. Physical activity, obesity, height, and the risk of pancreatic cancer. JAMA. 2001 Aug 22-29;286(8):921-9. PubMed PMID: 11509056. Epub 2001/08/31. eng.
  29. 29. Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000 Aug;106(4):473-81. PubMed PMID: 10953022. Pubmed Central PMCID: 380258. Epub 2000/08/23. eng.
  30. 30. Lau D, Dhillon, B Szmitko, P, Verma, S. Adipokines: molecular links between obesity and atherosclerosis. Am J Phys Heart and Circ Physiology. 2005;288:2031-41.
  31. 31. Newsholm EaL, Anthony. Functional Biochemistry in Health and Disease. New York: John Wiley & Sons; 2009.
  32. 32. Ryysy L, Hakkinen AM, Goto T, Vehkavaara S, Westerbacka J, Halavaara J, et al. Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes. 2000 May;49(5):749-58. PubMed PMID: 10905483. Epub 2000/07/25. eng.
  33. 33. Yki-Jarvinen H. Ectopic fat accumulation: an important cause of insulin resistance in humans. J R Soc Med. 2002;95 Suppl 42:39-45. PubMed PMID: 12216326. Pubmed Central PMCID: 1308944. Epub 2002/09/10. eng.
  34. 34. McCall KD, Holliday D, Dickerson E, Wallace B, Schwartz AL, Schwartz C, et al. Phenylmethimazole blocks palmitate-mediated induction of inflammatory cytokine pathways in 3T3L1 adipocytes and RAW 264.7 macrophages. J Endocrinol. Dec;207(3):343-53. PubMed PMID: 20813836. Epub 2010/09/04. eng.
  35. 35. Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, Diehl AM, et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. 2008 Jun;48(6):993-9. PubMed PMID: 18395287. Pubmed Central PMCID: 2423467. Epub 2008/04/09. eng.
  36. 36. Spruss A, Kanuri G, Wagnerberger S, Haub S, Bischoff SC, Bergheim I. Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice. Hepatology. 2009 Oct;50(4):1094-104. PubMed PMID: 19637282. Epub 2009/07/29. eng.
  37. 37. Lim JS M-SM, Valente A, Schwarz JM, Lustig RH. The role of fuctose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol. 2010 May;7(5):251-64.
  38. 38. Tobey TA, Mondon CE, Zavaroni I, Reaven GM. Mechanism of insulin resistance in fructose-fed rats. Metabolism. 1982 Jun;31(6):608-12. PubMed PMID: 7043185. Epub 1982/06/01. eng.
  39. 39. Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol. Nov;10(11):656-65. PubMed PMID: 24080776. Epub 2013/10/02. eng.
  40. 40. Metin Basaranoglu GB, Tevfik Sabuncu, Hakan Sentürk. Fructose as a key player in the development of fatty liver disease. World J Gastroenterol. 2013;28(19 (8)): 1166-72.
  41. 41. Wei YW, E. Moran, G. Estrada, A. Pagliassotti, M. Fructose-induced stress signaling in the liver involves methylglyoxal. Nutri Metab. 2013;8(10):38-40.
  42. 42. Li D1 DR, Bondy ML, Sinha R, Nguyen NT, Evans DB, Abbruzzese JL, Hassan MM. Dietary mutagen exposure and risk of pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2007;16(4):655-61.
  43. 43. Suárez-Bonnet E1 CM, Méndez-Ramírez I, Castillo-Urueta P, Cortés-Eslava J, Gómez-Arroyo S, Melero-Vara JM. Aflatoxin (B1, B2, G1, and G2) contamination in rice of Mexico and Spain, from local sources or imported. J Food Sci. 2013;78(11):1822-9.
  44. 44. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, et al. Stat3 as an oncogene. Cell. 1999 Aug 6;98(3):295-303. PubMed PMID: 10458605. Epub 1999/08/24. eng.
  45. 45. Bromber JW, T.. Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell. 2009;15:79-80.
  46. 46. Chen J. Multiple signal pathways in obesity-associated cancer. Obes Rev. 2011;12:1063-70.
  47. 47. Somasundar P, Yu AK, Vona-Davis L, McFadden DW. Differential effects of leptin on cancer in vitro. J Surg Res. 2003 Jul;113(1):50-5. PubMed PMID: 12943810. Epub 2003/08/29. eng.
  48. 48. Krechler T, Zeman M, Vecka M, Macasek J, Jachymova M, Zima T, et al. Leptin and adiponectin in pancreatic cancer: connection with diabetes mellitus. Neoplasma.58(1):58-64. PubMed PMID: 21067267. Epub 2010/11/12. eng.
  49. 49. Gasiorowska A, Talar-Wojnarowska R, Kaczka A, Borkowska A, Czupryniak L, Malecka-Panas E. Role of adipocytokines and its correlation with endocrine pancreatic function in patients with pancreatic cancer. Pancreatology. Jul-Aug;13(4):409-14. PubMed PMID: 23890140. Epub 2013/07/31. eng.
  50. 50. Bajou K, Maillard C, Jost M, Lijnen RH, Gils A, Declerck P, et al. Host-derived plasminogen activator inhibitor-1 (PAI-1) concentration is critical for in vivo tumoral angiogenesis and growth. Oncogene. 2004 Sep 9;23(41):6986-90. PubMed PMID: 15286708. Epub 2004/08/03. eng.
  51. 51. Smith R, Xue A, Gill A, Scarlett C, Saxby A, Clarkson A, et al. High expression of plasminogen activator inhibitor-2 (PAI-2) is a predictor of improved survival in patients with pancreatic adenocarcinoma. World J Surg. 2007 Mar;31(3):493-502; discussion 3. PubMed PMID: 17219285. Epub 2007/01/16. eng.
  52. 52. Zorgetto VA, Silveira GG, Oliveira-Costa JP, Soave DF, Soares FA, Ribeiro-Silva A. The relationship between lymphatic vascular density and vascular endothelial growth factor A (VEGF-A) expression with clinical-pathological features and survival in pancreatic adenocarcinomas. Diagn Pathol.8(1):170. PubMed PMID: 24138811. Pubmed Central PMCID: 3816792. Epub 2013/10/22. eng.
  53. 53. Georgiadou D, Sergentanis TN, Sakellariou S, Filippakis GM, Zagouri F, Vlachodimitropoulos D, et al. VEGF and Id-1 in pancreatic adenocarcinoma: Prognostic significance and impact on angiogenesis. Eur J Surg Oncol. Jan 18. PubMed PMID: 24480377. Epub 2014/02/01. Eng.
  54. 54. Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF. Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem. 2002 Jan 11;277(2):1531-7. PubMed PMID: 11606564. Epub 2001/10/19. eng.
  55. 55. Tanti JF, Jager J. Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. Curr Opin Pharmacol. 2009 Dec;9(6):753-62. PubMed PMID: 19683471. Epub 2009/08/18. eng.
  56. 56. Kim JH, Yoon MS, Chen J. Signal transducer and activator of transcription 3 (STAT3) mediates amino acid inhibition of insulin signaling through serine 727 phosphorylation. J Biol Chem. 2009 Dec 18;284(51):35425-32. PubMed PMID: 19875458. Pubmed Central PMCID: 2790971. Epub 2009/10/31. eng.
  57. 57. A. A. Samani SY, D. LeRoith, and P. Brodt,. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocrine Reviews. 2007;28(1):20-47.
  58. 58. Sung MK, Yeon JY, Park SY, Park JH, Choi MS. Obesity-induced metabolic stresses in breast and colon cancer. Ann N Y Acad Sci. Jul;1229:61-8. PubMed PMID: 21793840. Epub 2011/07/29. eng.
  59. 59. Han L, Ma Q, Li J, Liu H, Li W, Ma G, et al. High glucose promotes pancreatic cancer cell proliferation via the induction of EGF expression and transactivation of EGFR. PLoS One.6(11):e27074. PubMed PMID: 22087246. Pubmed Central PMCID: 3210779. Epub 2011/11/17. eng.
  60. 60. Liu H, Ma Q, Li J. High glucose promotes cell proliferation and enhances GDNF and RET expression in pancreatic cancer cells. Mol Cell Biochem. Jan;347(1-2):95-101. PubMed PMID: 20960036. Epub 2010/10/21. eng.
  61. 61. Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol. 2001 Nov;1(2):135-45. PubMed PMID: 11905821. Epub 2002/03/22. eng.
  62. 62. McCall KD, Harii N, Lewis CJ, Malgor R, Kim WB, Saji M, et al. High Basal Levels of Functional Toll-Like Receptor 3 (TLR3) and Non-Cannonical Wnt5a Are Expressed in Papillary Thyroid Cancer (PTC) and Are Coordinately Decreased by Phenylmethimazole Together with Cell Proliferation and Migration. Endocrinology. 2007;148(9):4226-37.
  63. 63. Schwartz AL, Malgor R, Dickerson E, Weeraratna AT, Slominski A, Wortsman J, et al. Phenylmethimazole decreases Toll-like receptor 3 and noncanonical Wnt5a expression in pancreatic cancer and melanoma together with tumor cell growth and migration. Clin Cancer Res. 2009 Jun 15;15(12):4114-22. PubMed PMID: 19470740. Pubmed Central PMCID: 2765042. Epub 2009/05/28. eng.
  64. 64. Sato Y, Goto Y, Narita N, Hoon DS. Cancer Cells Expressing Toll-like Receptors and the Tumor Microenvironment. Cancer Microenviron. 2009 Sep;2 Suppl 1:205-14. PubMed PMID: 19685283. Pubmed Central PMCID: 2756339. Epub 2009/08/18. eng.
  65. 65. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006 Nov;116(11):3015-25. PubMed PMID: 17053832. Pubmed Central PMCID: 1616196. Epub 2006/10/21. eng.
  66. 66. Dasu MR, Jialal I. Free fatty acids in the presence of high glucose amplify monocyte inflammation via Toll-like receptors. Am J Physiol Endocrinol Metab. Jan;300(1):E145-54. PubMed PMID: 20959532. Pubmed Central PMCID: 3023203. Epub 2010/10/21. eng.
  67. 67. Berstein LM. Clinical usage of hypolipidemic and antidiabetic drugs in the prevention and treatment of cancer. Cancer Lett. 2005 Jun 28;224(2):203-12. PubMed PMID: 15914271.
  68. 68. Otake S, Takeda H, Suzuki Y, Fukui T, Watanabe S, Ishihama K, et al. Association of visceral fat accumulation and plasma adiponectin with colorectal adenoma: evidence for participation of insulin resistance. Clin Cancer Res. 2005 May 15;11(10):3642-6. PubMed PMID: 15897559.
  69. 69. von Hafe P, Pina F, Perez A, Tavares M, Barros H. Visceral fat accumulation as a risk factor for prostate cancer. Obes Res. 2004 Dec;12(12):1930-5. PubMed PMID: 15687393.
  70. 70. Lu H, Ouyang W, Huang C. Inflammation, a key event in cancer development. Mol Cancer Res. 2006 Apr;4(4):221-33. PubMed PMID: 16603636.
  71. 71. Garcia M, Fernandez-Garcia NI, Rivas V, Carretero M, Escamez MJ, Gonzalez-Martin A, et al. Inhibition of xenografted human melanoma growth and prevention of metastasis development by dual antiangiogenic/antitumor activities of pigment epithelium-derived factor. Cancer Res. 2004 Aug 15;64(16):5632-42. PubMed PMID: 15313901.
  72. 72. Kuper H, Adami HO, Trichopoulos D. Infections as a major preventable cause of human cancer. J Intern Med. 2000 Sep;248(3):171-83. PubMed PMID: 10971784. Epub 2000/09/06. eng.
  73. 73. Khatami M. Unresolved inflammation: 'immune tsunami' or erosion of integrity in immune-privileged and immune-responsive tissues and acute and chronic inflammatory diseases or cancer. Expert Opin Biol Ther. 2011 Jun 11. PubMed PMID: 21663532. Epub 2011/06/15. Eng.
  74. 74. Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004 Aug;4(8):579-91. PubMed PMID: 15286738. Epub 2004/08/03. eng.
  75. 75. Khatami M. Unresolved inflammation: 'immune tsunami' or erosion of integrity in immune-privileged and immune-responsive tissues and acute and chronic inflammatory diseases or cancer. Expert Opin Biol Ther. Jun 11. PubMed PMID: 21663532. Epub 2011/06/15. Eng.
  76. 76. Garcea G, Dennison AR, Steward WP, Berry DP. Role of inflammation in pancreatic carcinogenesis and the implications for future therapy. Pancreatology. 2005;5(6):514-29. PubMed PMID: 16110250.
  77. 77. Bezbradica JS, Medzhitov R. Integration of cytokine and heterologous receptor signaling pathways. Nat Immunol. 2009 Apr;10(4):333-9. PubMed PMID: 19295629. Epub 2009/03/20. eng.
  78. 78. Dinarello CA. The interleukin-1 family: 10 years of discovery. Faseb J. 1994 Dec;8(15):1314-25. PubMed PMID: 8001745. Epub 1994/12/01. eng.
  79. 79. Karin M, Gallagher E. TNFR signaling: ubiquitin-conjugated TRAFfic signals control stop-and-go for MAPK signaling complexes. Immunol Rev. 2009 Mar;228(1):225-40. PubMed PMID: 19290931. Epub 2009/03/18. eng.
  80. 80. Kruglov AA, Kuchmiy A, Grivennikov SI, Tumanov AV, Kuprash DV, Nedospasov SA. Physiological functions of tumor necrosis factor and the consequences of its pathologic overexpression or blockade: mouse models. Cytokine Growth Factor Rev. 2008 Jun-Aug;19(3-4):231-44. PubMed PMID: 18502680. Epub 2008/05/27. eng.
  81. 81. Chaturvedi MM, Sung B, Yadav VR, Kannappan R, Aggarwal BB. NF-kappaB addiction and its role in cancer: 'one size does not fit all'. Oncogene. 2011 Apr 7;30(14):1615-30. PubMed PMID: 21170083. Epub 2010/12/21. eng.
  82. 82. Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science. 1996 Nov 1;274(5288):782-4. PubMed PMID: 8864118. Epub 1996/11/01. eng.
  83. 83. Liu ZG, Hsu H, Goeddel DV, Karin M. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Cell. 1996 Nov 1;87(3):565-76. PubMed PMID: 8898208. Epub 1996/11/01. eng.
  84. 84. Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM. Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science. 1996 Nov 1;274(5288):787-9. PubMed PMID: 8864120. Epub 1996/11/01. eng.
  85. 85. Wang CY, Mayo MW, Baldwin AS, Jr. TNF-and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. Science. 1996 Nov 1;274(5288):784-7. PubMed PMID: 8864119. Epub 1996/11/01. eng.
  86. 86. Joyce D, Albanese C, Steer J, Fu M, Bouzahzah B, Pestell RG. NF-kappaB and cell-cycle regulation: the cyclin connection. Cytokine Growth Factor Rev. 2001 Mar;12(1):73-90. PubMed PMID: 11312120. Epub 2001/04/20. eng.
  87. 87. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008 Jul 24;454(7203):436-44. PubMed PMID: 18650914. Epub 2008/07/25. eng.
  88. 88. Huang TT, Miyamoto S. Postrepression activation of NF-kappaB requires the amino-terminal nuclear export signal specific to IkappaBalpha. Mol Cell Biol. 2001 Jul;21(14):4737-47. PubMed PMID: 11416149. Pubmed Central PMCID: 87155. Epub 2001/06/21. eng.
  89. 89. Luo JL, Maeda S, Hsu LC, Yagita H, Karin M. Inhibition of NF-kappaB in cancer cells converts inflammation-induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression. Cancer Cell. 2004 Sep;6(3):297-305. PubMed PMID: 15380520. Epub 2004/09/24. eng.
  90. 90. Yu H, Jove R. The STATs of cancer--new molecular targets come of age. Nat Rev Cancer. 2004 Feb;4(2):97-105. PubMed PMID: 14964307. Epub 2004/02/18. eng.
  91. 91. Chang L, Kamata H, Solinas G, Luo JL, Maeda S, Venuprasad K, et al. The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover. Cell. 2006 Feb 10;124(3):601-13. PubMed PMID: 16469705. Epub 2006/02/14. eng.
  92. 92. Rebouissou S, Amessou M, Couchy G, Poussin K, Imbeaud S, Pilati C, et al. Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature. 2009 Jan 8;457(7226):200-4. PubMed PMID: 19020503. Pubmed Central PMCID: 2695248. Epub 2008/11/21. eng.
  93. 93. Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004 Aug 6;118(3):285-96. PubMed PMID: 15294155. Epub 2004/08/06. eng.
  94. 94. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009 Nov;9(11):798-809. PubMed PMID: 19851315. Epub 2009/10/24. eng.
  95. 95. Lin L, Hutzen B, Zuo M, Ball S, Deangelis S, Foust E, et al. Novel STAT3 phosphorylation inhibitors exhibit potent growth-suppressive activity in pancreatic and breast cancer cells. Cancer Res. Mar 15;70(6):2445-54. PubMed PMID: 20215512. Pubmed Central PMCID: 2843552. Epub 2010/03/11. eng.
  96. 96. Grivennikov SI, Karin M. Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. Feb;21(1):11-9. PubMed PMID: 20018552. Pubmed Central PMCID: 2834864. Epub 2009/12/19. eng.
  97. 97. Crnogorac-Jurcevic T, Efthimiou E, Capelli P, Blaveri E, Baron A, Terris B, et al. Gene expression profiles of pancreatic cancer and stromal desmoplasia. Oncogene. 2001 Nov 1;20(50):7437-46. PubMed PMID: 11704875.
  98. 98. Ripka S, Konig A, Buchholz M, Wagner M, Sipos B, Kloppel G, et al. WNT5A--target of CUTL1 and potent modulator of tumor cell migration and invasion in pancreatic cancer. Carcinogenesis. 2007 Jun;28(6):1178-87. PubMed PMID: 17227781.
  99. 99. Katoh M. STAT3-induced WNT5A signaling loop in embryonic stem cells, adult normal tissues, chronic persistent inflammation, rheumatoid arthritis and cancer (Review). Int J Mol Med. 2007 Feb;19(2):273-8. PubMed PMID: 17203201. Epub 2007/01/05. eng.
  100. 100. Amos SM, Pegram HJ, Westwood JA, John LB, Devaud C, Clarke CJ, et al. Adoptive immunotherapy combined with intratumoral TLR agonist delivery eradicates established melanoma in mice. Cancer Immunol Immunother. 2011 May;60(5):671-83. PubMed PMID: 21327636. Epub 2011/02/18. eng.
  101. 101. Salaun B, Zitvogel L, Asselin-Paturel C, Morel Y, Chemin K, Dubois C, et al. TLR3 as a biomarker for the therapeutic efficacy of double-stranded RNA in breast cancer. Cancer Res. 2011 Mar 1;71(5):1607-14. PubMed PMID: 21343393. Epub 2011/02/24. eng.
  102. 102. Brignole C, Marimpietri D, Di Paolo D, Perri P, Morandi F, Pastorino F, et al. Therapeutic targeting of TLR9 inhibits cell growth and induces apoptosis in neuroblastoma. Cancer Res. 2010 Dec 1;70(23):9816-26. PubMed PMID: 20935225. Epub 2010/10/12. eng.
  103. 103. Cherfils-Vicini J, Platonova S, Gillard M, Laurans L, Validire P, Caliandro R, et al. Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance. J Clin Invest. 2010 Apr 1;120(4):1285-97. PubMed PMID: 20237413. Pubmed Central PMCID: 2846035. Epub 2010/03/20. eng.
  104. 104. Chiron D, Pellat-Deceunynck C, Amiot M, Bataille R, Jego G. TLR3 ligand induces NF-{kappa}B activation and various fates of multiple myeloma cells depending on IFN-{alpha} production. J Immunol. 2009 Apr 1;182(7):4471-8. PubMed PMID: 19299748. Epub 2009/03/21. eng.
  105. 105. Hsu RY, Chan CH, Spicer JD, Rousseau MC, Giannias B, Rousseau S, et al. LPS-induced TLR4 signaling in human colorectal cancer cells increases beta1 integrin-mediated cell adhesion and liver metastasis. Cancer Res. 2011 Mar 1;71(5):1989-98. PubMed PMID: 21363926. Epub 2011/03/03. eng.
  106. 106. Thuringer D, Hammann A, Benikhlef N, Fourmaux E, Bouchot A, Wettstein G, et al. Transactivation of the epidermal growth factor receptor by heat shock protein 90 via Toll-like receptor 4 contributes to the migration of glioblastoma cells. J Biol Chem. 2010 Feb 4;286(5):3418-28. PubMed PMID: 21127066. Pubmed Central PMCID: 3030348. Epub 2010/12/04. eng.
  107. 107. Pinhal-Enfield G, Ramanathan M, Hasko G, Vogel SN, Salzman AL, Boons GJ, et al. An angiogenic switch in macrophages involving synergy between Toll-like receptors 2, 4, 7, and 9 and adenosine A(2A) receptors. Am J Pathol. 2003 Aug;163(2):711-21. PubMed PMID: 12875990. Pubmed Central PMCID: 1868201. Epub 2003/07/24. eng.
  108. 108. Lee CH, Wu CL, Shiau AL. Toll-like receptor 4 signaling promotes tumor growth. J Immunother. 2009 Jan;33(1):73-82. PubMed PMID: 19952954. Epub 2009/12/03. eng.
  109. 109. Ikebe M, Kitaura Y, Nakamura M, Tanaka H, Yamasaki A, Nagai S, et al. Lipopolysaccharide (LPS) increases the invasive ability of pancreatic cancer cells through the TLR4/MyD88 signaling pathway. J Surg Oncol. 2009 Dec 15;100(8):725-31. PubMed PMID: 19722233. Epub 2009/09/02. eng.
  110. 110. Yanga HHK, J. Ikhlas, A. Khana,C. Walker, L. Shabana, I. Khana, C. Nonsteroidal anti-inflammatory drug activated gene-1 (NAG-1)modulators from natural products as anti-cancer agent. Life Sci. 2014:1-10.
  111. 111. Galli A CE, Crabb DW, Mello T, Salzano R, Grappone C, Milani S, Surrenti E, Surrenti C, Casini A. Antidiabetic thiazolidinediones inhibit invasiveness of pancreatic cancer cells via PPARgamma independent mechanisms. Gut. 2004;53(11):1688-97.
  112. 112. Bao B1 AA, Azmi AS, Ali S, Sarkar FH. Overview of cancer stem cells (CSCs) and mechanisms of their regulation: implications for cancer therapy. Curr Protoc Pharmacol. 2013 (June).
  113. 113. Lonardo E CM, Sancho P, Sanchez-Ripoll Y, Trabulo SM, Dorado J, Balic A, Hidalgo M, Heeschen C. Metformin targets the metabolic achilles heel of human pancreatic cancer stem cells. PloS One. 2013;18(8).

Written By

Kelly McCall, Anthony L Schwartz and Frank L Schwartz

Submitted: 19 September 2013 Published: 14 May 2014