Inflammation and the development of pancreatic cancer

Surgical Oncology 10 (2002) 153–169

Review

Inflammation and the development of pancreatic cancer Buckminster Farrow, B. Mark Evers* Department of Surgery, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA

Abstract Objective. Pancreatic cancer has an extremely poor prognosis and the cellular mechanisms contributing to pancreatic cancer are relatively unknown. The goals of this review are to present the epidemiological and experimental data that supports inflammation as a key mediator of pancreatic cancer development, to explain how inflammatory pathways may create an environment that supports tumor formation, and to discuss how the use of novel agents directed at these pathways may be used for the treatment of pancreatic malignancy. Summary Background Data. Inflammation has been identified as a significant factor in the development of other solid tumor malignancies. Both hereditary and sporadic forms of chronic pancreatitis are associated with an increased risk of developing pancreatic cancer. The combined increase in genomic damage and cellular proliferation, both of which are seen with inflammation, strongly favors malignant transformation of pancreatic cells. Cytokines, reactive oxygen species, and mediators of the inflammatory pathway (e.g., NF-kB and COX-2) have been shown to increase cell cycling, cause loss of tumor suppressor function, and stimulate oncogene expression; all of which may lead to pancreatic malignancy. Anti-cytokine vaccines, inhibitors of pro-inflammatory NFkB and COX-2 pathways, thiazolidinediones, and anti-oxidants are potentially useful for the prevention or treatment of pancreatic cancer. Redirection of experimental interests toward pancreatic inflammation and mechanisms of carcinogenesis may identify other novel anti-inflammatory agents or other ways to screen for or prevent pancreatic cancer. Conclusion. Pancreatic inflammation, mediated by cytokines, reactive oxygen species, and upregulated pro-inflammatory pathways, may play a key role in the early development of pancreatic malignancy. r 2002 Elsevier Science Ltd. All rights reserved. Keywords: Pancreatic cancer; Pancreatitis; Anti-inflammatory drugs; Reactive oxygen species; DNA damage

Contents 1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Inflammation and the development of cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Specific types of cancer linked to inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Pancreatitis and the risk of cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Inflammatory mechanisms of pancreatic cancer development 3.1. Cytokines . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Nuclear factor kappa B . . . . . . . . . . . . . . . . 3.3. Cyclooxygenase 2 . . . . . . . . . . . . . . . . . . . . 3.4. Peroxisome proliferator-activated receptor-g . . . . . . 3.5. DNA damage . . . . . . . . . . . . . . . . . . . . . . 3.6. Genetic alterations . . . . . . . . . . . . . . . . . . .

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Novel treatment strategies 4.1. Cytokines . . . . . . 4.2. NF-kB . . . . . . . 4.3. Cyclooxygenase-2 . .

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*Corresponding author. Tel.: +1-409-772-5612; fax: +1-409-7474819. E-mail address: [email protected] (B.M. Evers). 0960-7404/02/$ - see front matter r 2002 Elsevier Science Ltd. All rights reserved. PII: S 0 9 6 0 - 7 4 0 4 ( 0 2 ) 0 0 0 1 5 - 4

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4.4. 4.5.

PPARg . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oxidative damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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5.

Experimental strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. In vivo models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. New techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

2. Inflammation and the development of cancer

Pancreatic cancer is the fourth leading cause of cancer death in the US with 28,900 patients estimated to die of this disease in the year 2001 [1]. This cancer is one of the most deadly of all malignancies with a death:incidence ratio of approximately 0.99 [2]. Adjuvant chemotherapy and radiation therapy may provide only a slight survival advantage without consistent improvement in outcome [3]. The only effective therapy is surgical excision, yet only 10–15% of patients have disease localized to the pancreas at the time of diagnosis allowing a potentially curable resection [4]. Unfortunately, the majority of these patients succumb to recurrence and metastatic spread [5]. There is no effective screening test for pancreatic cancer and risk factors for this disease are difficult to identify. Additionally, this cancer is locally aggressive and metastasizes readily. All of these factors contribute to the extremely poor prognosis. A better understanding of the early mechanisms that lead to pancreatic cancer would help to identify novel molecular targets for early screening and intervention. A number of studies have focused on genetic changes and the role of these alterations in the development of pancreatic cancer; however, comparatively few studies have focused on the role of inflammation. Pancreatic inflammation may represent an early step in the development of malignancy with genetic changes occurring as a later manifestation of the prolonged inflammatory process. In this review, the link between inflammation and development of pancreatic cancer will be presented. The risk factors that suggest a role for inflammation in the pathogenesis of pancreatic cancer will be described. We will discuss the inflammatory mediators that are upregulated in pancreatic cancer and their possible role in this disease process. Finally, we will discuss potential novel therapeutic and experimental strategies for pancreatic cancer based upon current knowledge regarding these inflammatory mediators.

The link between inflammation and the development of cancer has been recognized for a number of years. In 1863, Rudolf Virchow noted leukocytes in neoplastic tissue and suggested that this reflected the origin of cancer at sites of chronic inflammation [6]. A number of cancers have been linked to inflammatory origins (Table 1). Probably one of the best-characterized examples of inflammation leading to cancer is the development of squamous cell carcinoma (i.e., Marjolin’s ulcer) at the site of burned skin [7]. The tumor arises from the inflamed epidermis providing a clear correlation between inflammation and malignancy. Other correlations have been described as the mechanisms of tumor initiation and promotion have become more clearly defined. In the gastrointestinal (GI) tract the correlation between inflammatory bowel disease (IBD) and the lifetime risk of colorectal cancer is well established [8– 11], but precisely how chronic inflammation leads to malignancy is not well understood. There are patients with IBD (either ulcerative colitis or Crohn’s colitis) that never develop cancer and many more people who are diagnosed with colorectal tumors that have no history of colonic inflammation. Therefore, more than one pathway can lead to the final common endpoint of colonic malignancy. Vogelstein and Kinzler [12] have proposed several different mechanisms that describe how various changes in normal colonic tissue all lead to an increased risk of colorectal cancer. The ‘‘landscaper theory’’ proposes that a defective population of cells, arising from stromal tissue, make epithelial cells more susceptible to malignant transformation as a result of an abnormal microenvironment (Fig. 1). This microenvironment includes factors that favor either genomic damage (loss of tumor suppressor function or activation of oncogenes) or enhanced growth that would increase the likelihood of transformed cells proliferating. This type of abnormal stroma also exists in Peutz–Jehgers disease leading to the formation of pseudopolyps and

B. Farrow, B.M. Evers / Surgical Oncology 10 (2002) 153–169 Table 1 Inflammatory conditions and their related malignancies Condition

Malignancy

Inflammatory bowel disease H. pylori infection Chronic viral hepatitis Liver fluke infection Schistosomiasis Hashimoto’s thyroiditis

Colorectal cancer Gastric cancer Hepatocellular carcinoma Cholangiocarcinoma Bladder cancer Lymphoma/papillary cancer of the thyroid Cervical cancer Ovarian cancer Esophageal adenocarcinoma Mesothelioma Bronchial lung cancer

Human papilloma virus Pelvic inflammatory disease Esophagitis Asbestosis Cigarette smoking

possibly contributing to the increased risk of colon cancers [13,14]. Interestingly, patients with Peutz– Jehgers disease are also at increased risk for the development of pancreatic cancer [15] suggesting this abnormal stroma may create a microenvironment that favors the development of the malignant phenotype in multiple tissues. 2.1. Specific types of cancer linked to inflammation Gastric cancer was the leading cause of death in the United States in 1900 but is relatively uncommon today [16]. The reduced incidence in the US parallels a global decline in the prevalence of this malignancy. Helicobacter pylori (H. pylori) was discovered over 100 yr ago, but its role as a key factor in the development of gastric cancer was not established until the 1980s [17]. Epidemiological evidence in case-control and retrospective studies have shown a strong positive correlation between H. pylori infection and stomach cancer that parallels the duration and severity of the infection

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[18,19]. Acutely, H. pylori causes mucosal inflammation by triggering interleukin-8 (IL-8) release from gastric epithelial cells as well as cytokine release that causes chemotaxis and activation of neutrophils [20]. This inflammation can persist as a chronic infection characterized by reactive oxygen species (ROS) formation and epithelial cell proliferation [21,22]. The risk of cancer is higher when the number of dividing cells is increased since these cells are more susceptible to DNA damage during replication [23,24]. ROS can also produce DNA mutations [25], thus further compounding the effect that cellular proliferation has on tumor formation. Eradication of H. pylori decreases cellular proliferation [26–29], and the risk of cells undergoing malignant transformation would be expected to decrease as well. Hepatitis B (HBV) and hepatitis C (HCV) viral infections are significant risk factors for the development of hepatocellular carcinoma [30,31]. In transgenic mice, the overproduction of HBV envelope protein produces hepatocyte toxicity, cell death, and parenchymal inflammation [32]. In this model, inflammation was followed by chronic hepatocellular regeneration, transcriptional deregulation, aneuploidy, adenomas, and eventually hepatocellular carcinoma. Tumor development was related to the severity and duration of HBV-induced inflammation. Significant regenerative hyperplasia was observed creating the opportunity for the accumulation of genomic changes sufficient for the acquisition of the malignant phenotype [33,34]. This is a purely inflammatory model since the HBV is not believed to integrate with the genome and affect protooncogene or tumor suppressor function [35]. The ability of inflammation alone to cause malignancy is supported by the fact that other non-viral, inflammatory diseases of the liver such as alcoholism, hemochromatosis, and primary biliary cirrhosis also predispose to the

Fig. 1. Pancreatic cancer: inflammation and the landscaper theory. Chronic inflammation, as seen in inflammatory bowel disease, causes damage of stromal cells and subsequent healing allows these damaged cells to be exposed to growth factors. This combination of cell damage and proliferation may lead to the development of an abnormal microenvironment where stromal elements encourage the production of transformed cells.

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development of hepatocellular carcinoma [36,37]. In HCV, a structural protein of the RNA virus, NS5A, induces ROS formation and activates nuclear factor kappa B (NF-kB) and STAT-3 [38], which are ubiquitously expressed transcription factors known to activate inflammatory pathways [39,40]. NS5A may, similar to the envelope protein of HBV, produce chronic inflammation leading to necrosis and subsequent regeneration. NF-kB is also an inhibitor of apoptosis [41] and STAT-3 has growth stimulatory effects [40]; therefore, both of these factors could further contribute to the development of the malignant phenotype in chronic hepatitis. The risk of cholangiocarcinoma is significantly increased by liver fluke infection [42]. Similar to other infections, the organism causes inflammation and desquamation of the biliary epithelium [43,44]. Hyperplasia and goblet cell metaplasia are seen with persistent infection, and this proliferative response is associated with the accumulation of an inflammatory infiltrate composed of neutrophils, macrophages, and eosinophils [45]. The ability of this organism to cause a chronic inflammatory response and premalignant lesions supports a role for inflammation in the early stages of cholangiocarcinoma development. Schistosoma haematobium infection is strongly associated with urinary bladder cancer [46]. Infection of this organism is endemic to many areas of the world, and the distribution of infection within geographic areas closely parallels the distribution of bladder cancer [47]. The relative risk of developing bladder cancer is 2–14 times higher with S. haematobium infection, which destroys the mucosal layers of the bladder [48]. Inflammation is mediated by ROS, and cellular turnover increases in an attempt to repair the damaged mucosa [49]. Micronuclei are formed from damage to chromosomes or the spindle apparatus of cells; these micronuclei are increased 9-fold in the urothelial cells of individuals infected with S. haematobium [50]. Treatment of this infection causes micronuclei levels to return to normal, suggesting that genetic damage strongly correlate with active infection and inflammation [51]. Hashimoto’s thyroiditis is characterized by inflammation, necrosis, and regeneration of thyroid tissue and has been associated with the development of thyroid lymphomas and papillary carcinoma of the thyroid [52]. The frequency of papillary cancer in patients with Hashimoto’s thyroiditis is believed to be between 3–9% [53,54]. Two classes of growth-promoting antibodies are found in this form of thyroiditis [55], which may encourage the development of tumors from transformed cells. In addition to the examples listed above, inflammation is thought to play a major role in the pathogenesis of cervical cancer, ovarian cancer, esophageal adenocarcinoma, mesothelioma, and bronchial lung cancer [6]. In all of these cancers, chronic inflammation produces a

cycle of repeated cellular damage and subsequent healing, which can lead to the development of malignancy. Cellular damage includes DNA damage and subsequent mutations that can alter tumor suppressor or proto-oncogene function. The healing response is characterized by stimulation of cell proliferation and growth factor release that would favor the clonal expansion of transformed cells. It is likely that inflammatory mediators can lead to similar changes in the pancreas, which could lead to pancreatic cancer in certain instances. In fact, there is accumulating evidence to suggest a link between inflammation and pancreatic cancer. 2.2. Pancreatitis and the risk of cancer The identification of pancreatic cancer in patients with a rare form of pancreatitis has provided evidence for a link between pancreatic inflammation and cancer [56]. Hereditary pancreatitis, a rare disease accounting for o1% of all forms of pancreatitis, is caused by a mutation of the trypsinogen gene on chromosome 7 [57]. The mutation is thought to either impede autolysis of inappropriately activated trypsinogen within the pancreas or enhance trypsinogen activation resulting in acinar cell autodigestion and subsequent pancreatitis. This hereditary defect causes frequent recurrent episodes of acute inflammation that lead to progressive destruction, fibrosis, and chronic pancreatitis in afflicted patients [58]. The risk of developing pancreatic cancer in patients with hereditary pancreatitis is 53 times the risk in unaffected individuals, which is much higher than the risk noted with many other inflammatory diseases [57]. By age 70, approximately 40% of patients with hereditary pancreatitis are diagnosed with pancreatic cancer [59]. The inflammation associated with hereditary pancreatitis is persistent, progressive, and affects the entire organ, which may explain the high risk of subsequent cancer development. Screening programs have been suggested for these patients [58]; however, the current methods to screen for pancreatic cancer are neither sensitive nor specific enough to diagnose cancer at an early stage. Therefore, patients with hereditary pancreatitis that develop cancer have the same poor prognosis as other patients with pancreatic cancer. Current epidemiological data suggests an increased risk of pancreatic cancer in patients with sporadic chronic pancreatitis that correlates with the duration of inflammation. Patients with chronic pancreatitis are 17 times more likely to develop pancreatic cancer compared to age matched controls [56]. Although only a small percentage of pancreatic cancers are due to chronic pancreatitis, this chronic inflammatory state, analogous to that seen in inflammatory bowel disease, could also create a ‘‘landscaper defect’’. Persistent

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inflammation could favor the malignant transformation of pancreatic ductal cells leading to dysplasia and eventual cancer. Similar to colon cancer, the loss of tumor suppressor genes and mutation of proto-oncogenes have been implicated in pancreatic cancer development [60]. K-ras mutations are found in a majority of pancreatic adenocarcinomas [61], and the additional loss of p53 and DPC4/SMAD function are believed to be the major etiologic factors involved with tumorigenesis [62,63]. Some of these changes are noted in tissue samples from patients with chronic pancreatitis, but only when dysplasia is already present [64]. The frequency of these changes parallels the increasing dysplasia in premalignant lesions [65], but what then precedes the dysplasia? It seems likely that the inflammatory changes, which represent the earliest events, could lead to the dysplastic changes. The pathophysiology of pancreatitis involves the aberrant release of proteolytic enzymes that cause acinar cell injury and a subsequent inflammatory response [66]. This inflammatory response in acute pancreatitis involves cytokine release, generation of ROS, and activation of the arachidonic acid pathway [67]. In most cases, this acute inflammation is associated with gradual resolution without long-term sequelae. In chronic pancreatitis, the acinar injury is believed to recur causing repeated bouts of inflammation with a persistent infiltration of inflammatory cells eventually leading to atrophy and fibrosis [68]. Chronic inflammation occurring simultaneously with cell proliferation would be an ideal ‘‘landscape’’ for malignancy to develop.

3. Inflammatory mechanisms of pancreatic cancer development A number of cytokines, transcription factors, and pro-inflammatory enzymes are associated with pancreatic cancer. These proteins appear to play a role in the inflammatory response and the fibrotic reaction that occurs with healing. The exact role that these mediators play in the development of cancer is not known, but there is accumulating experimental data to suggest how these factors may contribute to tumor formation. 3.1. Cytokines Cytokines are released during pancreatitis, and together with reactive oxygen species, produce inflammation and cellular damage [69]. Moreover, some of these cytokines are (e.g., TNF-a; IL-6, IL-8 and interferon g) increased in pancreatic cancer [70,71]. In acute pancreatitis, wound healing restores the pancreatic tissue to its normal function usually without significant alteration of pancreatic parenchymal structure [72]. In chronic pancreatitis, inflammation persists and healing

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occurs simultaneously producing fibrosis, scarring, and impaired exocrine and endocrine function [73]. Growth factors, such as platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-b), are released during the early stages of inflammation. TNFa; normally expressed in response to acinar cell injury, upregulates PDGF expression in cultured pancreatic cancer cells, and PDGF is known to strongly stimulate fibrogenesis [70]. TNFa also upregulates the epidermal growth factor receptor (EGFr) and its activating ligand, transforming growth factor-alpha (TGF-a) in certain pancreatic cancer cell lines [74]. Thus, as part of the normal healing process, growth factors are released leading to cell proliferation. In the presence of ongoing inflammation and possible DNA damage, this may result in increased populations of transformed cells. Tumor associated macrophages are a common component of the tumor infiltrate, as initially noted by Virchow [6], and tissue macrophages are also noted in association with chronic pancreatitis [75]. These inflammatory cells are capable of producing growth and angiogenic factors as well as proteolytic enzymes capable of degrading extracellular matrix [76,77]. Macrophages may then be involved with tumor cell proliferation, promotion of angiogenesis, invasiveness, and metastatic potential. Macrophage proinflammatory human chemokine-3alpha (Mip-3a) is overexpressed in human pancreatic cancer cells and infiltrating macrophages adjacent to the tumor; Mip-3a stimulates growth and enhances migration [78]. Therefore, both tumor cells and adjacent inflammatory cells may influence tumor growth and metastasis. The inflammatory reaction that occurs in response to the presence of tumors varies from minimal infiltration of leukocytes to intense desmoplasia. This stromal tissue, which represents the body’s normal attempt to fight transformed cells, may actually facilitate tumor spread and growth [79]. Pancreatic cancers usually exhibit an intense desmoplastic reaction around the primary tumor [80]. Experimental studies have shown that these stromal cells release cytokines, growth factors, and angiogenic factors, which can positively influence tumor growth [81]. These cellular factors may also increase the ability of transformed cells to metastasize by increasing microvascular permeability in the rich blood supply adjacent to the tumor [82]. The mechanisms contributing to this desmoplastic response and the intercellular signals that may affect adjacent stromal elements are not entirely known. Breast cancer also creates a dense tumor stroma, similar to that seen in pancreatic cancer [83]. Recent work with breast cancer cells in vitro has shown that the release of TNFa and IL-11 from malignant cells inhibits the differentiation of co-cultured adipocytes, which

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contributes to the desmoplastic reaction noted with these tumors [84]. This effect in adipocytes was at least partially mediated by the peroxisome proliferatoractivated receptor-g (PPARg), a transcription factor known to regulate inflammatory and cell cycling pathways [85]. Therefore, it appears that a synergistic relationship exists between malignant cells and tumor stroma; both influence the development and growth of each other. TNFa inhibits apoptosis of pancreatic cancer cells in vitro through the activation of NF-kB [86]. In pancreatic cancer, the observed constitutive expression of NFkB suggests that normal regulatory pathways are lost and apoptosis is inhibited aberrantly. Transformed cells are more likely to survive when apoptosis is inhibited and cytokines, such as TNFa; may act synergistically with other inflammatory factors (e.g., NF-kB) to favor development and growth of malignant cells in the pancreas.

3.2. Nuclear factor kappa B NF-kB is an ubiquitously expressed transcription factor, which regulates the expression of various inflammatory, apoptotic, and oncogenic genes [39]. The functional NF-kB protein is composed of two subunits, usually the heterodimer of p65/RelA and p50 [87]. Inhibitor of kappa B (IkB) proteins normally sequester the NF-kB dimer in the cytoplasm of unstimulated cells [88]. Activation of NF-kB occurs by the phosphorylation and subsequent degradation of IkB by IkB kinases (IKK), allowing nuclear translocation of the dimer (Fig. 2). Upregulated or constitutive expression of NF-kB has been identified in many forms of cancer including other GI malignancies such as colorectal cancer and hepatocellular carcinoma [89]. The expression of both IL-1b and TNFa is stimulated by NF-kB [90], suggesting an autoregulatory loop that can amplify the inflammatory response. NF-kB also

Fig. 2. Activation of the NF-kB pathway. NF-kB is activated by a number of cell surface receptors, which stimulate IKK activity. This induces phosphorylation of the IkB subunit marking it for degradation. Loss of the interaction between IkB and the NF-kB dimer allows the molecule to cross the nuclear membrane and exert its effects. (Adapted from Collins T and Cybulsky MI, Journal of Clinical Investigation 2001;107(3):255–264, American Society for Clinical Investigation, with permission).

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stimulates the inducible form of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), both key mediators of the inflammatory process [91]. NF-kB activates cyclin D1 expression, a regulatory protein that promotes cell cycle activity [91], and cyclin D1 is upregulated in several pancreatic cancer cell lines [92]. This suggests a link between activation of inflammatory pathways and loss of normal cell cycle regulation in pancreatic cancer. Activated RelA, a subunit of the active NF-kB complex, was constitutively activated in 67% (16 of 24) human pancreatic cancer specimens and in none of the normal pancreatic tissue specimens examined [93]. This strongly suggests that elevated NF-kB activity contributes to dysregulation of normal cell cycling and the activation of NF-kB in this case is likely due to inflammatory mediators. Non-insulin dependent diabetes mellitus (NIDDM) is a proposed risk factor for pancreatic carcinoma [94]. The potential effects of hyperglycemia in the pancreas may be mediated by NF-kB. Hyperglycemia promotes upregulation of leukocyte adhesion molecules in endothelial cells through activation of NF-kB [95]. Advanced glycation end products (AGEs), which are bound to albumin, are found in the serum of diabetic patients [96]. These AGEs bind to specific cell surface receptors and can induce production of ROS, which are known to induce NF-kB activation [97]. Recently, aspirin has been shown to improve insulin resistance in diabetic mice by inhibiting a chronic subacute inflammatory process produced by NF-kB [98]. The role of NF-kB in insulin resistance was further supported by observing improved insulin sensitivity in obese mice when they are breed with IKKb heterozygous knockout mice (thus, inhibiting NF-kB activation). NF-kB is involved with inflammation and carcinogenesis in the pancreas and its activation by hyperglycemia suggests a role for diabetes in initiating this process. NF-kB induces IL-8 expression in vitro in response to hypoxia, which is commonly found at the center of tumors where the blood supply is limited [99]. IL-8, which is constitutively expressed at high levels in pancreatic cancer cells, produces an autocrine growth stimulatory effect in certain cell lines [71,100]. Inhibition of IL-8 activity in transplanted pancreatic tumor cells led to suppression of tumor growth and metastasis in nude mice [101]. Therefore, NF-kB can stimulate growth of tumors cells by upregulating inflammatory pathways (e.g., IL-8) in pancreatic cancer. Since NF-kB regulates both inflammatory and oncogenic pathways, the finding that it is upregulated in pancreatic cancer is significant. Multiple inflammatory mediators may produce their physiological effects by activating NF-kB and subsequent overexpression may result in loss of normal regulatory function. This in

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turn would stimulate oncogenic pathways and favor tumor growth and metastasis. 3.3. Cyclooxygenase 2 Cyclooxygenase isoforms, COX-1 and COX-2, catalyze the stereospecific oxidation of arachidonate to form prostaglandins and other lipid mediators [66]. COX-1 is expressed constitutively in a variety of tissues and products of this enzyme are important for homeostatic processes. COX-2, however, is an inducible isoform activated by cytokines and growth factors that produce predominately pro-inflammatory prostaglandins [102]. Furthermore, expression of COX-2 is upregulated in a variety of malignancies [103]. Pancreatitis is associated with increased expression of COX-2 in pancreatic acinar cells; inhibition of its activity significantly reduces the effect of cerulein-induced pancreatitis in mice (Ethridge et al, preliminary data), suggesting a key role for COX-2 in pancreatic inflammation. Similar to other malignancies, COX-2 expression is increased in pancreatic cancer, which further suggests a link between the inflammatory and oncogenic pathways. COX-2 was expressed in 57% of human pancreatic carcinoma specimens [104], and mRNA levels were increased more than 60-fold in human pancreatic cancer samples compared to normal controls [105]. COX-2 was also expressed in 62% of intraductal papillary mucinous adenomas, a pre-malignant pancreatic lesion, again suggesting an early role for inflammation [104]. The mechanisms responsible for the carcinogenic effects of COX-2 are multiple. It is known to convert chemical carcinogens to mutagenic derivatives, which may help to explain the increased risk of smoking with pancreatic cancer. COX-2 synthesis of prostaglandins favors the growth of malignant cells by stimulating proliferation and angiogenesis [106]. COX-2 overexpression inhibits apoptosis [105] and, in transgenic mice with overexpression of COX-2 targeted to the mammary glands, causes hyperplasia, dysplasia, and transformation into metastatic tumors [107]. There is no consensus regarding which cell type in the pancreas undergoes malignant transformation and develops into pancreatic adenocarcinoma. Pour et al. [108] hypothesize that the islet cell is the cell of origin in pancreatic cancer based upon histological examination of the islets following exposure to known carcinogens. Islet atrophy prevented carcinogen-induced tumor formation and in 75% of the adenocarcinomas, islet cells were seen mixed with the malignant cells [109]. This hypothesis is further supported by epidemiological evidence that patients with NIDDM (but not type I diabetics) are at increased risk for the development of pancreatic adenocarcinoma [94]. In fact, many patients diagnosed with pancreatic cancer have a recent onset of NIDDM [110]. If the islet cells are functioning at increased levels to produce enough insulin to overcome

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the peripheral resistance associated with this disease, the chance that this stimulation would favor expansion of transformed cells is reasonable. It is interesting to note that, in immunohistochemistry studies of human pancreatic cancer, COX-2 expression is largely confined to the islet cells [111]. If COX-2 overexpression is a marker for islet cell inflammation, and if these same cells are hypertrophic and overproduce insulin, the chance of malignant transformation would be expected to be high. The relationship between islet inflammation, insulin resistance, growth stimulation, and diabetes may be a key factor for the development of pancreatic cancer. 3.4. Peroxisome proliferator-activated receptor-g Peroxisome proliferator-activated receptor-g (PPARg) is a nuclear receptor that functions as a transcription factor mediating glucose homeostasis, cellular differentiation, and apoptotic pathways [112]. Ligands for this receptor include endogenously produced prostaglandins and the anti-diabetic thiazolidinediones (TZDs) which are thought to sensitize tissues to insulin, and account for the therapeutic effects of the TZDs [113]. PPARg ligands exert anti-inflammatory effects in vitro by inhibiting cytokine production and antagonizing the activity of NF-kB [85] leading to inhibition of iNOS. In experimental studies of atherosclerotic vascular disease, use of these agents inhibited cell cycling and induced differentiation of smooth muscle cells [114]. Activation of the PPARg receptor induces anti-tumor effects in lung [115], colon [116], and liposarcoma cell lines in vitro [117]. In an experimental model of pancreatitis, PPARg ligand activity attenuated the severity of pancreatitis at least in part by inhibiting COX-2 and NF-kB activity (K. Hashimoto, unpublished data). In the pancreas, this receptor/transcription factor is related to these inflammatory pathways, known to be involved, with cancer development. Also interesting are studies performed in vitro examining the effects of TZDs on pancreatic cancer cell growth. Troglitazone inhibited pancreatic cancer growth via increases in the cell cycle inhibitor p27kip1 [118]. Other studies have confirmed these findings and have shown not only growth arrest, but also induction of cellular differentiation in pancreatic cancer after treatment with TZDs [119]. PPARgdependent inhibition of pancreatic cancer cell growth has been associated with COX-2 expression, suggesting relationships to other inflammatory pathways (K. Hashimoto, unpublished data). In vitro studies have demonstrated induction of apoptosis and reduced MMP-2 and MMP-9 activity suggesting a role for PPARg in invasion and metastasis (K. Hashimoto, unpublished data). The fact that TZDs have both antidiabetic and anti-tumor effects is intriguing, especially in light of the hypothesis that pancreatic cancer may arise

from islet cells. Because of its relationship to inflammatory and cell cycle pathways, PPARg may be intimately involved in the development of malignancy in the pancreas. Furthermore, ligands that activate PPARg are safe for use in humans and may represent novel antineoplastic agents active against pancreatic cancer. 3.5. DNA damage Inflammation causes damage of cellular organelles by release of proteolytic enzymes and ROS. These ROS are produced by activated neutrophils and macrophages locally at the site of inflammation [120]. Many genotoxic effects are induced by ROS such as DNA strand breaks, sister chromatid exchanges, mutations, and formation of adducts with DNA [121]. Peroxidated lipids and DNA adducts such as 8-hydroxy-20 -deoxyguanosine (8HdG) are markers for ROS activity. The role of ROS in producing genomic DNA damage and cancer has been well studied in H. pylori infection and gastric cancer [122]. H. pylori causes inflammation of the gastric epithelium leading to IL-8 mediated release of ROS from neutrophils and macrophages [20]. Specific mutations caused by oxidative damage are noted in over 50% of p53 mutations in intestinal type gastric tumors, suggesting that ROS can cause loss of tumor suppressor function [123]. iNOS produces ROS and reactive nitrogen oxide species (RNOS), and nitrotyrosine is a marker for levels of RNOS, which increased in the gastric mucosa of patients infected with H. pylori [124]. Nitric oxide has also been found to inhibit a DNA repair enzyme that repairs 8HdG adducts in bacteria [125]. The overall effect of these molecules is mutation of normal genomic structure as well as inhibition of DNA adduct repair [51]. Smoking creates ROS and is also an independent risk factor for pancreatic cancer [126], not unlike the increased risk seen with other GI malignancies [127,128]. The risk of pancreatic cancer is increased approximately 2.5 times for patients who have smoked more than one pack per day for 17 yr [129]. Cigarette smoke contains polycyclic aromatic hydrocarbons that are activated in vivo to highly reactive oxygen species and can produce inflammation and DNA damage [130]. Hyperplastic changes in pancreatic duct cells with atypical nuclear patterns have been observed in smokers at autopsy [131]. The number of acinar cells with atypical nuclei was 30% in individuals who smoked 20– 39 cigarettes a day and 70% in those who smoked 40 or more cigarettes a day. Smoking does not cause pancreatic inflammation, but systemic exposure to carcinogens could certainly increase the cancer risk. If there were an additive effect of systemic exposure to carcinogens and localized inflammation, the risk of pancreatic cancer could be even higher. Epidemiological studies indicate that the majority of patients with

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chronic pancreatitis are smokers [132] and the relative contribution of both of these risk factors is often difficult to isolate [133]. Interestingly, in rodent models, tumors were produced preferentially at sites of wounding and inflammation with administration of systemic carcinogens [130]. ROS and RNOS can produce nucleotide transitions by changing nucleotide structure and generating incorrect pairing with subsequent transcription [134]. In patients with ulcerative colitis, a high frequency of these transitions were noted within mutated p53 alleles [135]. These were predominately identified in the inflamed portions of the colon without cancer suggesting that they may represent early changes prior to the development of malignancy. Nitrotyrosine was also found in these lesions [136], which explains an earlier observation that iNOS activity correlated with mutations of the p53 gene. The G to T transversion can be induced by ROS when 8-HdG lesions are transcribed (Fig. 3). This transversion is often found in K-ras and H-ras muta-

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tions in non-melanoma skin tumors [137]. Mispairing of A to G nucleotides has been demonstrated in the mutated ras and p53 genes from patients with ulcerative colitis and associated cancer or dysplasia [138]. The high frequency of K-ras mutations in pancreatic cancer suggests that these types of inflammatory changes may contribute significantly to carcinogenesis. Chronic pancreatitis is characterized by the persistence of inflammatory cells within the parenchyma that can produce the constant release of ROS and RNOS. Levels of peroxidated lipids in these patients are much higher than normal [139], which argues strongly for the ongoing ROS-mediated damage of all cellular organelles including genetic material. The levels of malondialdehyde (MDA) and other markers of lipid peroxidation measured in the serum of patients with chronic pancreatitis were increased even more than those seen in patients with acute pancreatitis [140]. Lipid-peroxidation intermediates can also modify DNA and act as an endogenous source of ROS, exclusive of inflammatory cells, thus multiplying the ROS effect [141]. In summary, there is a great deal of evidence supporting the role for ROS and nitric oxide species in DNA damage and predisposition toward malignancy. These molecules are active in the pancreas during inflammation and probably play a key role in the progression of neoplasia. 3.6. Genetic alterations

Fig. 3. ROS-mediated G to T transversion. The majority of ROSmediated mutations involve modification of guanine, in particular 8oxoguanine from singlet oxygen exposure. The hydroxylated base pair becomes mispaired with adenine and with subsequent replication, G to T transversion occurs. The 8-oxoguanine mutation induces activation of k-ras and G to T transversions are among the most frequent hot spot mutations of the tumor suppressor p53.

Mutations noted in pancreatic cancer are numerous and have been extensively described [5]. The most common mutation noted in pancreatic cancer is a mutation of the K-ras proto-oncogene, which leads to uncontrolled cell growth [61]. Tumor suppressor genes (e.g., p53, p16, and DPC4/SMAD) are mutated in a number of pancreatic cancers [60,62,63]. Of all the genetic changes described, it appears that K-ras mutations occur relatively early while p53 and DPC4/SMAD occur later in the malignant process [65]. However, it is difficult to determine whether genetic alterations occur first in the development of this disease or whether they are preceded by inflammatory changes. As described above, genetic changes may result from the production of ROS, but other inflammatory factors can also alter gene structure and function that may contribute to the development of malignancy. The development of colorectal cancer in patients with IBD appears to differ compared to sporadic cases based on studies of mutation patterns and genetic composition of the tumors [138]. Sporadic colon cancer involves the adenoma to carcinoma sequence while IBD-related cancers most often arise from flat, dysplastic epithelium. Genomic instability appears to be an early event in the progression pathway of cancers that develop in patients with ulcerative colitis [142,143]. Non-dysplastic areas of inflamed colonic epithelium from patients with ulcera-

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tive colitis were analyzed for evidence of genomic damage and found to have a significant amount of chromosomal instability [144]. Aneuploidy was also noted in over 30% of samples from patients with pancolitis but without dysplasia. The level of aneuploidy paralleled the increase in p53 mutations as dysplasia developed. Both of these changes preceded ras mutations that were found only with high-grade dysplasia or carcinoma [145]. The relative frequency of aneuploidy was higher than any of the genetic changes in this inflamed epithelium, suggesting that it occurs before the mutations seen with more advanced dysplastic lesions. In colon cancers occurring in patients with IBD, it appears that inflammation can produce genetic changes even prior to the development of dysplasia, supporting the early role of inflammation in cancer development. Microsatellites are normally stable repetitive sequences of DNA scattered throughout the genome [140]. Instability within these sequences is a marker of genome-wide mutations and DNA repair deficiencies [146]. Microsatellite instability (MSI) is believed to be a major mechanism of colorectal tumor development in hereditary non-polyposis colorectal carcinoma, as these patients are deficient in DNA repair function [147]. MSI has been found in non-neoplastic but chronically inflamed mucosa of patients with ulcerative colitis [143]. In addition, MSI was found in 100% of brushings from patients with acute or chronic pancreatitis suggesting a role for MSI in the development of pancreatic cancer [148]. Oxidative stress due to inflammation may cause DNA damage in excess of the capacity of DNA repair mechanisms [135]. Cytokines can also regulate gene function providing a potential mechanism for inflammation to interfere with tumor suppressor function or stimulate proto-oncogene activation. Macrophage migration inhibitory factor (MIF) is normally released at sites of inflammation by T cells and macrophages and enhances the antimicrobial activity of macrophages [149]. MIF was shown to directly suppress transcriptional activation of p53, indicating that inflammatory pathways may enhance carcinogenesis [150]. ROS produced during inflammation can alter gene expression without inducing DNA damage. Hydrogen peroxide displaces IKK from the NF-kB complex allowing it to migrate to the nucleus and activate its downstream targets. Hydrogen peroxide also can stimulate the transcription of c-jun and can activate extracellular signal-related kinases (ERKs) in vitro [137]. Under oxidative conditions, p53 can be functionally destabilized, and the loss of the G1 checkpoint could lead to the proliferation of cells with DNA damage [135]. Mutations and functional changes in tumor suppressor genes induced by oxidative stress in the pancreas could encourage the development of cancer.

4. Novel treatment strategies Treatment strategies based upon novel molecular targets in inflammatory pathways have been suggested and are currently being evaluated in experimental and clinical trials. Inflammatory components targeted by these therapies include agents that inhibit or block cytokines, NF-kB activity, COX-2, PPARg; or oxidative damage (Table 2). 4.1. Cytokines A new generation of vaccines directed against cytokine activity could be beneficial in the treatment of cancer [151]. Abnormal cytokine production is noted in many types of cancers and contributes to the altered level of growth stimulation and genomic damage. These new vaccines could be targeted to agents that directly stimulate tumor cell growth, such as TGFb or IL-10, or could remove inappropriate suppression of immune function by aberrantly expressed cytokines. Clinical trials using vaccines directed against EGF and VEGF in cancer patients have shown some potentially encouraging results [152]; further studies directed at cytokines and inflammatory pathways may further improve the potential benefit of these vaccines. A phase I trial using granulocyte–monocyte colony stimulating factor (GMCSF) vaccine in patients after pancreatic cancer resection has shown no toxicity and some improvement in cell-mediated immunity [153]. Cytokines with antiinflammatory activity, such as interleukin 12 and interleukin 15, have been shown to inhibit growth of pancreatic cancer cells in vitro [154,155], which suggests another mechanism of tumor prevention by inhibiting inflammation. 4.2. Nf-kB NF-kB activity is upregulated in a number of malignancies [156]. Therapeutic options directed at inhibiting its function could possibly reduce inflammation and subsequent repair processes. Salicylates and corticosteroids are known to inhibit NF-kB function [86,157], but their effects are non-specific. A number of different agents have been developed that directly inhibit NF-kB activation by either blocking proteasomes (e.g., MG 132), inhibiting normal NF-kB activation pathways (e.g., geldanamycin), or blocking NF-kB transcription (e.g., antisense oligonucleotides) [158]. Anti-oxidants have also been used since ROS are known to activate NF-kB. Inhibition of NF-kB activation by salicylates sensitizes cancer cells to TNFa-mediated apoptosis [86]. Other compounds have sensitized cancers to radiationinduced apoptosis and reduction of tumor growth [158]. The therapeutic potential for these compounds as adjuvant cancer agents seems very high, although their

B. Farrow, B.M. Evers / Surgical Oncology 10 (2002) 153–169 Table 2 Anti-inflammatory targets for the prevention of pancreatic cancer Cytokines Anti-cytokine vaccines Anti-inflammatory cytokines (Interleukin-12) NF-kB Salicylates Corticosteroids Proteosome inhibitors (MG132) Inhibitors of NF-kB activation (Geldanamycin) COX-2 Non-steroidal anti-inflammatory drugs Selective COX-2 inhibitors (celecoxib) PPARg Prostaglandins Thiazolidinediones (troglitazone, rosiglitazone, pioglitazone) Selective PPARg ligands (GW 7845) Reactive Oxygen Species Traditional anti-oxidants (e.g., vitamin E, b carotene) Phytochemicals/free radical scavengers

effects are likely to be dependent on other functional pathways (e.g., apoptosis). They may be most effective as potentiators of other treatment strategies. Future studies will hopefully provide a better understanding of the safety and clinical efficacy of these novel therapeutic agents. 4.3. Cyclooxygenase-2 COX-2 expression is regulated in part, by NF-kB thus inhibitors of the NF-kB pathway may also reduce COX2 activity [159]. Specific inhibitors of COX-2 are available and have a safety and clinical efficacy profile that is better than NF-kB pathway inhibitors. Selective COX-2 inhibitors, such as celecoxib, are effective against osteoarthritis and have a lower incidence of side effects compared to standard NSAIDs. Celecoxib suppressed growth of lung and colon cancer cells implanted in nude mice [160]. Similar to its effects in other related cancers, aspirin has been shown to inhibit the growth of pancreatic cancer cells in vitro [104] and in vivo [111]. If inflammation in the pancreas were shown to predispose patients to the development of cancer, COX-2 inhibitors could be used for their anti-inflammatory effects in addition to other potential anti-tumor effects.

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studies demonstrate decreased invasiveness of pancreatic cancer cells following treatment with PPARg ligands (K. Hashimoto, unpublished data). The TZD troglitazone inhibits tumor growth of prostate cancer cells transplanted into athymic nude mice [161]. Clinical studies have not been performed to evaluate the effects of TZDs in patients with pancreatic cancer, but in patients with prostate cancer troglitazone they produced a significant improvement in PSA levels [162]. Transfection of Drg-1, a gene related to differentiation and a downstream target of PPARg activation, reduced the rate of metastases from colon cancer cells injected into the spleen of nude mice [163]. Troglitazone has been removed from the market over concerns of hepatotoxicity but rosiglitazone and pioglitazone are newer TZDs approved for the treatment of NIDDM in humans and are considered to be safe. Similar to troglitazone, rosiglitazone and pioglitazone appear to have growth inhibitory and differentiation effects in vitro [164], therefore it is possible that they have similar anti-tumor effects in humans. New ligands with high binding affinity for PPARg; such as compound GW 7845 [165], may also possess anti-tumor activity with minimal toxicity. 4.5. Oxidative damage ROS appear to be a major factor in allowing the inflammatory process to redirect normal cellular function towards carcinogenesis. The potential role for antioxidants is therefore very appealing. Increased levels of vitamin E and b carotene have been associated with a modest improvement in mortality in patients with lung and colon cancers [166]. b carotene, selenium, and to a lesser extent, vitamin C inhibit azaserine-induced pancreatic carcinogenesis in rats [167]. Intake of fresh fruit and vegetables appears to be inversely correlated with cancer of the esophagus, stomach, and pancreas [137], although the specific factors involved remain undefined. A potential protective effect of specific vegetable components, suggested by a reduction of urinary ROS excretion, might be due to phytochemicals that induce enzymes scavenging electrophiles [168]. There are a number of compounds with anti-oxidant activity, which suggests that it is the functional level of all anti-oxidants together that protect cells from damage and not one single agent. Initial studies are promising, but a better understanding of how anti-oxidants exert their effects will be required to determine whether they may be useful adjuvant therapies for pancreatic cancer.

4.4. PPARg 5. Experimental strategies Ligands for PPARg have been shown to inhibit cell cycling, induce differentiation, and induce apoptosis in pancreatic cancer cells in vitro [118,119]. Recent in vitro

Shifting the focus in pancreatic cancer research to inflammatory mechanisms may help to define early

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changes in the pancreas that lead to cancer. Experimental strategies designed to elucidate how inflammation causes cell cycle changes, resistance to apoptosis, and increased invasiveness may show that genetic alterations are the direct result of inflammatory-induced changes. 5.1. In vivo models Transgenic mouse models of pancreatic cancer have been created based on mutations of tumor suppressor or proto-oncogenes such as p53 and p21waf1, respectively [169]. Frequently, another stimulus, such as the addition of a carcinogen or partial pancreatectomy is required to induce tumor formation, which suggests that inflammation or subsequent healing may be a necessary factor in the development of pancreatic tumors. In vivo studies using transgenic mice with upregulated or overexpressed inflammatory mediators would provide a very interesting model to study how genetic and inflammatory changes are related in tumor development. The formation of tumors from inflamed pancreata in transgenic models without experimentally induced genetic changes would argue strongly for an important early role of inflammation in pancreatic cancer. Experimental models of diabetes could also help to elucidate the role of glucose homeostasis in the development of pancreatic cancer, and how it may be related to pancreatic inflammation. Experimentally, pancreatic inflammation could be induced in mice with insulin resistance or streptozotocin-induced islet degeneration to examine if these effects act synergistically to favor pancreatic cancer development. This model would be especially useful since it would examine two major epidemiological factors known to favor pancreatic cancer formation in humans, that is, diabetes and pancreatitis.

anti-inflammatory or anti-diabetic agents on the expression of genes implicated in cancer development.

6. Conclusion Pancreatic cancer is a relatively common malignancy with a dismal prognosis. If enhanced survival is to be achieved, the mechanisms involved must be clearly defined. Hereditary and chronic pancreatitis produce pancreatic inflammation and are associated with an increased risk of pancreatic cancer, thus establishing a link between cancer and inflammation on an epidemiological level. Pancreatic inflammation is associated with ROS production, cytokine release, and upregulation of pro-inflammatory transcription factors. Mediators of the inflammatory response can induce genetic damage, cell proliferation, and inhibition of apoptosis in the pancreas. Malignant transformation occurs from loss of tumor suppressor function, expression of oncogenes, and upregulation of genes that stimulate cell cycling (e.g., NF-kB). Once established, colonies of transformed

5.2. New techniques Gene array technology allows the rapid examination of thousands of genes making it a powerful tool for identifying factors involved in the development of pancreatic cancer. Gene arrays could be used to examine human samples and tumor cells for new mediators of the inflammatory response that may be involved with the establishment of the malignant phenotype. Initial analysis of differential gene expression in pancreatic cancer cells has revealed upregulation of cell cycle activators (e.g., cyclin D2, p21waf1), heat shock response proteins (Hsp 24 and 70), apoptotic factors (Bcl-2, Bclx), and genes involved in DNA replication and repair (topo II, uv exc/repair) following treatment with MK 886, a lipooxygenase inhibitor [170]. Array technology can also be used to investigate the effect of different

Fig. 4. Proposed mechanism of inflammation and the development of pancreatic cancer.

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cells proliferate since growth factors are produced and secreted to repair pancreatic tissue damaged from the inflammatory response. Eventually, the cumulative effect of the inflammatory response produces genetic alterations leading to tumorigenesis. A proposed pathway for the development of pancreatic cancer is shown in Fig. 4. Novel treatments directed at the inflammatory mechanisms that allow this process to occur (e.g., TZDs, NSAIDs, and selective COX-2 inhibitors) may prevent the development of these tumors. New strategies and techniques focused on the role of inflammation in the development of pancreatic cancer may help to improve the overall prognosis for patients with pancreatic cancer.

Acknowledgements We wish to thank Eileen Figueroa and Karen Martin for assistance in manuscript preparation.

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