Chemoprevention of pancreatic cancer—one step closer

REVIEWARTICLE

Chemoprevention of pancreatic cancer—one step closer

Volker Fendrich

Received: 24 January 2012 /Accepted: 26 January 2012 /Published online: 15 February 2012# Springer-Verlag 2012

AbstractBackground Since for pancreatic cancer the mortality rateapproaches the incidence rate with only 1–4% of all patientssurviving 5 years, it would be would be of great value toprovide chemopreventive treatment for high-risk individuals.Discussion The preclinical study of pancreatic intraepithelialneoplasia (PanINs) has recently been made possible by thegeneration of genetically modified animal models, whichrecapitulate human PanINs and invasive pancreatic canceron a genetic and histomorphologic level. Very recently, sev-eral groups have reported first evidence of chemopreventionof pancreatic cancer.

Keywords Pancreatic cancer . PanINs . Chemoprevention .

ACE inhibitor . Aspirin

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is a devastatingand almost uniformly lethal malignancy that accountsfor approximately 33,000 deaths in the USA every year,

rendering it the fourth most common cause of cancer-related mortality [1, 2]. Though the past decades have seenintense research efforts aimed at a better understanding ofthe underlying etiologic and pathophysiological mecha-nisms, this increased knowledge could so far not success-fully be translated into better clinical treatment strategiesand improved patient survival. In fact, during the past30 years, the overall median 5-year survival rates for pan-creatic cancer have improved only marginally and are cur-rently around 5%, which is among the worst of all humanmalignancies [1, 2]. As with other solid tumours, the cura-tive potential for pancreatic cancer is dependent on the stageof this disease at diagnosis. Unfortunately, for the majorityof patients diagnosed with pancreatic cancer, symptoms donot develop until it is either unresectable or metastatic, andtherefore incurable. Survival in this setting is typically mea-sured in months. Moreover, even when patients present withan early-stage disease, the likelihood of cure remains verylow with the currently available therapies. Although recentevidence suggests that screening strategies may reduce mor-tality for other common cancers such as colorectal, breastand cervical cancers, the currently available screeningapproaches for PDAC are unlikely to produce significantreductions in mortality associated with the disease. Inaddition, since the incidence rate of pancreatic cancer issubstantially lower than the rates for the more commonmalignancies, screening large segments of the adultpopulation for pancreatic cancer would require a hugeexpenditure per life saved. Because of this, emerging geneti-cally engineered mouse models of pancreatic cancer play akey role for chemopreventive studies. The goal of this reviewwas to provide current knowledge on the in vitro, in vivo andclinical studies conducted about this disease using variouschemopreventive agents.

Review criteria The data for this review were compiled by searching thePubMed and MEDLINE databases for articles published from 1 January2000 to 31 December 2011. Older key publications in the field ofchemoprevention for pancreatic cancer were also included. The search term‘chemoprevention’ was used in combination with the terms ‘pancreaticcancer’, ‘PanINs’, ‘mouse models’ and ‘agents’. The bibliography of eachrelevant article was screened for further relevant studies.

V. Fendrich (*)Department of Surgery, Philipps University Marburg,Baldingerstrasse,35043 Marburg, Germanye-mail: [email protected]

Langenbecks Arch Surg (2012) 397:495–505DOI 10.1007/s00423-012-0916-x

Genetic and molecular events in human pancreaticcarcinogenesis

Pancreatic carcinogenesis comprises an array of geneticchanges finally culminating in fully invasive cancer [3–5].Today, pancreatic cancer is regarded as a genetic disease whicharises from morphologically and genetically clearly definedprecursor lesions through a stepwise accumulation of geneticalterations [6]. These precursor lesions comprise pancreaticintraepithelial neoplasia (PanIN), which can be subclassifiedinto PanIN-1, PanIN-2 and PanIN-3 lesions depending on thedegree of cytological and architectural atypia. Pancreatic can-cer may develop from these precursor lesions (Fig. 1). For acomprehensive review on the molecular pathology of precur-sor lesions of pancreatic cancer, see [7]. Genetic modificationsoccur at several levels during the multistep process of PDACpathogenesis. These include mutations of encoding oncogenesand tumour suppressor genes as well as epigenetic changes andaberrations of transcriptional patterns. Genetic changes mayalso affect caretaker genes such as genes of the Fanconi’sanaemia DNA repair pathway that normally function to min-imize genetic alterations during DNA replication, thus leadingto the accumulation of additional genetic mutations and facil-itating progression towards invasive carcinoma. Mutations ofmitochondrial DNA are also frequently observed in PDAC andnon-malignant precursor lesions [3]. The hallmark mutationsacquired along the pathogenic cascade of pancreatic cancerdevelopment are briefly discussed below.

Activating mutations of oncogenes in PDAC

KRAS

Activating point mutations of the oncogene KRAS occur in80–90% of all PDAC cases.Most commonly, they affect codon12, 13 or 61 and result in the abrogation of the intrinsic GTPaseactivity of the RAS protein, which leads to the constitutiveactivation of the intracellular signalling cascade [3]. Acquisi-tion of constitutively active KRAS is among the first geneticchanges observed in PDAC and is already present in non-malignant precursor lesions. About 30% of PanIN-1 lesionsharbour an activating point mutation of the KRAS gene [8].

CMYC, AKT2 and EGFR

Other oncogenes involved in the molecular pathogenesis ofpancreatic cancer are CMYC, AKT2 and epidermal growthfactor receptor (EGFR). Although mutations of those onco-genes are less frequent, they represent potential therapeutictargets, and experimental evaluation is currently underway[3]. CMYC is amplified and subsequently overexpressed in50–60% of pancreatic cancers, whilst amplifications of AKT2are detected in <5% of cases [3]. Nevertheless, the Akt

signalling pathway is activated in 30–60% of pancreatic can-cers, indicating additional activating mechanisms and under-scoring the potential therapeutic relevance of Akt targeting [9,10]. Constitutive EGFR pathway activation by amplificationof the EGFR gene and other mechanisms has likewise beendescribed in pancreatic cancer [3].

Mutations of tumour suppressor genes

CDKN2A/p16

The CDKN2A/p16 gene is located on the short arm of chro-mosome 9 (9p) and encodes the cell cycle regulator proteinp16INK4A, which exerts function via the p16/Rb pathway andinhibits cell cycle progression through the G1-S checkpoint.In >90% of PDAC, it is inactivated by either homozygousdeletion (~40% of cases), intragenic mutation (40%) or epige-netically by hypermethylation of its promoter (10–15%) [11].The loss-of-function mutation of the CDKN2a gene is thoughtto be an early event during the multistep process towardsinvasive carcinoma and can already be observed in 30% ofPanIN-1, 55% of PanIN-2 and 71% of PanIN-3 lesions [12]. Ofnote is that in mouse models of pancreatic cancer, bothp16INK4A as well as p19Arf (corresponding to p14Arf inhumans) inactivation seem to contribute to PDAC development[13, 14].

DPC4/SMAD4/MADH4

Deleted in pancreatic carcinoma 4 (DPC4/SMAD4/MADH4)is located on chromosome 18q21, and loss-of-function muta-tions of DPC4 can be observed in ~55% of all PDAC cases,whilst they occur only very rarely in other malignancies [3].Inactivation is mediated by the mutation of one allele withconcomitant loss of the second allele (25% of cases) or ho-mozygous mutation (30% of cases), resulting in reducedgrowth inhibition and increased proliferation via impairedTGF-b signalling. Loss of DPC4 constitutes a rather late eventin pancreatic cancer development and can only be observed ina minority of PanIN-3 lesions [15].

TP53

The oncogene TP53 on chromosome 17p usually inducescell cycle arrest and apoptosis in response to DNA damageand is inactivated due to intragenic mutation with loss of thesecond allele in 50–75% of pancreatic cancers. Loss offunction of TP53 facilitates the acquisition of additionalgenetic mutations and is considered to be a late event inpancreatic cancer development as the nuclear accumulationof mutated TP53 can only be observed in advanced PanIN-3lesions [15].

496 Langenbecks Arch Surg (2012) 397:495–505

Risk factors associated with pancreatic tumorigenesis

Due to the relative rarity of pancreatic cancer, the use ofchemopreventive agents would be of special value for individ-uals being at high risk to develop pancreatic cancer. As treat-ment options are still limited and the survival prognosisremains poor, the identification of individuals at high riskbecomes particularly important. Some factors, such as smok-ing can be controlled, whilst others such as age or familyhistory cannot (Table 1).

Smoking

Cigarette smoking represents one of the most significant andmost widely studied risk factors for pancreatic cancer. The

carcinogenic effect of tobacco smoke on pancreatic tissue isexplained as the direct action of N-nitrosamines or theirsecretion into bile and their subsequent reflux into the pancre-atic duct [16]. Smoking increases the relative risk of pancre-atic cancer 1.5-3-fold, depending on the number of cigarettessmoked and the duration of this habit. But abandonment ofsmoking will be the method of choice rather than an additionalchemopreventive agent.

Obesity

The same is true for obesity. Although there is a significantassociation between body mass index and the relative risk todevelop PDAC, one would rather suggest physical activitythan chemopreventive agents [16].

Fig. 1 Progression ofnormal pancreatic ductsinto invasive pancreaticadenocarcinomas

Table 1 Risk factorsfor pancreaticcancer

Factor Gene Type Relative risk to average ratio

Smoking – Exogenous 3

Alcohol – Exogenous Non-significant

Obesity – Exogenous 1.7

Family history ?? Endogenous 32

Peutz–Jeghers STK11/LKB1 Endogenous 132

FAMMM syndrome P16/CDKN2A Endogenous 13

Hereditary breast andovarial carcinoma

BRCA2/BRCA1 Endogenous 5

HNPCC MLH1, MSH2, MSH6, PMS2 Endogenous 7

Hereditary pancreatitis PRSS1 Endogenous 40

Chronic pancreatitis – Endogenous 14–18

Diabetes mellitus – Endogenous 2

Langenbecks Arch Surg (2012) 397:495–505 497

Alcohol

An analysis of 14 prospective studies has not confirmed anyassociation between alcohol consumption and a higher riskof pancreatic cancer [17].

Diabetes mellitus

Diabetes mellitus (DM) is widely considered to be as-sociated with risk of PDAC; however, whether DM is acause or a consequence of PDAC is still controversial.Ben et al. [18] conducted a detailed meta-analysis ofcohort studies. They included a total of 35 cohort stud-ies. DM was associated with an increased risk of PDAC(the summary RRs01.94, 95% CI01.66–2.27), with sig-nificant evidence of heterogeneity among these studies(p<0.001). In addition, the relative risk of PDAC wascorrelated negatively with the duration of DM, with thehighest risk of PDAC found among patients diagnosedwithin less than 1 year. The authors concluded thatthese findings strongly support that diabetes is associat-ed with an increased risk of PDAC in both males andfemales and that DM is both an early manifestation andan etiologic factor of pancreatic cancer.

Chronic inflammation/pancreatitis

Although no more than 5% of diagnosed cases of pancreaticcancer can be explained by recurrent attacks of chronicpancreatitis, the same genetic changes have been detectedin individuals with chronic inflammation of the pancreasand pancreatic cancer. Chronic inflammation is thought toinduce genetic alterations in tissue, whilst the ongoing heal-ing process exposes defective cells to growth factors; theresult is a pathological microenvironment in which stromalelements facilitate the neoplastic process in epithelial cells[19]. Chronic pancreatitis has long been suspected as a riskfactor for the development of pancreatic cancer. In 1993,Lowenfels et al. [20] contributed tremendously in thisfield. In total, 2,015 patients with chronic pancreatitis wererecruited and the incidence of pancreatic cancer comparedwith the expected incidence from population data. Thestandardised incidence ratio was 14.4 and the risk of devel-oping pancreatic cancer, 20 years after diagnosis, was ashigh as 4%. A smaller study from Italy demonstrated astandardised incidence ration of 18.5 using a similar meth-odology [21]. Because many patients with chronic pancrea-titis also smoke, it has been difficult to define the relativecontribution of smoking and chronic pancreatitis to pancre-atic cancer risk. A study in 497 patients revealed a twofoldincrease in pancreatic cancer risk in smokers compared withnon-smokers [22].

Hereditary pancreatitis

Hereditary pancreatitis is a rare autosomal dominant condi-tion with 80% penetrance. In patients with hereditary pan-creatitis, trypsin becomes activated whilst still in thepancreas. This accounts for the partial digestion of the pan-creatic tissue, which causes irritation and inflammation. Astrong genetic association exists with mutations found in thePRSS1, SPINK1 and CFTR genes and is associated with acumulative risk of pancreatic cancer by age 70 years of some40% [23].

Hereditary tumour syndromes

The existence of hereditary PDAC was initially suggestedby several case reports of a familial aggregation of ductalpancreatic adenocarcinomas. Lynch et al. [24] was the firstto systematically describe a larger cohort of families withfamilial pancreatic cancer (FPC) in 1989. Two prospectivestudies from Sweden and Germany demonstrated a familialaggregation of PDAC of only 2.7% and 1.9%, respectively,if the strict criteria of confirmation by histology and medicalrecords were used [25, 26]. An inherited predisposition toPDAC is currently believed to occur in three distinct clinicalsettings. First, it occurs in hereditary tumour predispositionsyndromes that are defined primarily by a clinical phenotypeother than PDAC, but are known to be associated with anincreased risk of PDAC. These syndromes include Peutz–Jeghers syndrome, melanoma pancreatic cancer syndromeor familial atypical multiple mole melanoma (FAMMM),hereditary breast and ovarian cancer, and others, respectively(see Table 1). The second setting is hereditary pancreatitis andcystic fibrosis in which genetically determined early changesof the pancreas can predispose to the development of PDAC.The third setting is FPC in which two or more first-degreerelatives have PC without fulfilling the criteria of anotherinherited tumour syndrome. Several studies have shown thatfamily members of patients with PC have an increased risk forthe development of PC [27–29]. The risk increases with thenumber of family members affected. Individuals with three ormore affected first-degree relatives have an estimated 32-foldincreased risk [28].

Mouse models of pancreatic cancer for chemopreventiveresearch

Various mouse models of pancreatic cancer have been de-veloped in the past few years, providing a crucial platformfor the investigation of chemopreventive agents andtheir impact on cancer development and tumour biology[30]. Years ago, the most often used mouse models forPDAC were xenograft mouse models where tumours in


immunodeficient mice were generated by subcutaneous in-jection or orthotopic transplantation of PDAC cell lines. Ahuge advantage of these models is that they are simple to setup and human cancer cells can be assessed in the murine invivo environment. However, the biggest disadvantage is themissing immunological reaction of the cancer cells to themurine environment, making conclusions about the tumour–stroma relation impossible, something which is very impor-tant for PDAC [31]. Nowadays, genetically engineeredmouse models (GEMM) are an elegant alternative to in vitroand xenotransplantation studies, although their breeding andhousing is both very time-consuming as well as expensive.For PDAC studies, GEMM possess the potential whichrecapitulates human PanINs and invasive pancreatic canceron a genetic and histomorphologic level in a syngenicsystem with a fully intact host immune system [30]. There-fore, these models might at least, to some extent, also carrythe potential to predict the response of human pancreaticcancer to therapeutic intervention or chemoprevention. TwoGEMM were recently developed that bear striking resem-blance to human PDAC. The first is based on mutation ofthe endogenous murine Kras gene specifically in pancreaticprogenitor cells by crossing mice with a conditionally acti-vated Kras allele (LSL-KrasG12D) to transgenic strains thatexpress Cre recombinase in pancreatic lineages (PdxCre orp48Cre). These ‘KC’ mice develop murine PanIN lesionswith 100% penetrance, but only a small subset of theseanimals progress to PDAC at an advanced age, suggestingthat additional genetic alterations are necessary for tumourformation [32]. To accelerate the process of tumorigenesis,PdxCre-expressing compound mutant mice were generatedwith conditional mutations in both Kras and Trp53 in anal-ogy to the genetic alterations in human PDA. These ‘KPC’mice develop advanced PDA with 100% penetrance at anearly age, thus recapitulating human PDAC including his-topathological similarities in neoplastic cells, tumour–stro-ma reaction, metastasis and comorbidities such as cachexia[33]. ‘KC’ mice are considered a very valuable tool to studyPanIN biology since it mimics a rather slow progressionfrom PanIN-1 over PanIN-2 and PanIN-3 lesions to invasivecancer in around 12–15 months. Furthermore, ‘KPC’mice manifest widely metastatic pancreatic ductal ade-nocarcinoma that recapitulates the human spectrum. Theuse of these models provides now the opportunity toconduct chemopreventive studies on pancreatic cancer.Further important work was done by Guerra et al. [34],providing evidence that temporal expression of endoge-nous Kras in acinar cells of adult mice results in PanINsand invasive PDAC only in the context of caerulein-inducedpancreatitis. Since then, more and more GEMM forpancreatic cancer were constructed (overview in [35]), pro-viding now perfect abilities to perform preclinical chemopre-ventive studies.

Chemopreventive agents

As mentioned above, our ability to identify patients at risk ofdeveloping pancreatic cancer has improved, although we haveno interventions that can reduce this risk other than partial ortotal pancreatectomy. Clearly, surgical resection is a radicalintervention for patients whose lifetime risk of developingpancreatic cancer may be only elevated slightly over thebaseline risk in the general population. As shown in Fig. 1,PDAC is thought to evolve through non-malignant precursorlesions to fully invasive carcinoma. The following agents haveshown first evidence that this process can be slowed down, ifnot even stopped.

Aspirin, NSAIDs and other selective cyclooxygenaseinhibitors

Many in chemoprevention are beginning to think that perhapsthe best way to catch cancer is to target inflammation. Chronicinflammation appears to encourage tumours by prompting thegrowth of new blood vessels and a remodelling of the extra-cellular matrix, creating a prime setting for normal cell growthto turn malignant. This theory led chemoprevention research-ers to turn to two drugs—celecoxib and aspirin—that targetthe cyclooxygenase enzymes (COX-1 and COX-2), whichplay key roles in inflammation and pain. Both are non-steroidal anti-inflammatory drugs (NSAIDs), which epidemi-ological studies suggest may reduce the risk of colon and othercancers.

Aspirin has been used to control pain and inflammationfor over a century. Epidemiological studies associated adecreased incidence of colorectal cancer with the long-term use of aspirin in the early 1980s. In subsequent years,the use of other NSAIDs, which inhibit COX enzymes, waslinked to reduced cancer risk in multiple tissues includingthose of the breast, prostate and lung [36, 37]. As in manyother types of malignant tissue, COX-2 is also overex-pressed in pancreatic carcinoma. Maitra et al. [38] foundan upregulation of COX-2 in a subset of PanINs, whichmakes it a potential target for chemoprevention with selec-tive COX-2 inhibitors. However, recent epidemiologic stud-ies investigating the preventive value of aspirin in pancreaticcarcinoma reached conflicting findings, perhaps due to thesubstantial differences in patient populations, exposure in-formation and outcome information [39–42]. Wang et al.[43] were the first to show that NF-κB activity is foundconstitutively in about 70% of pancreatic cancers, but not innormal pancreatic tissue. The findings of Sclabas et al. [44]showed that aspirin-mediated inhibition of NF-κB activa-tion in response to inflammation is a possible mechanism forthe cancer preventive effect of aspirin. They used an ortho-topic mouse model with human pancreatic carcinoma celllines to study the inhibitory effects of aspirin on pancreatic


tumour formation. Animals given aspirin for 6 days beforetumour cell injection showed a lower incidence of tumourformation compared with those receiving aspirin 2 weeksafter inoculation. They suggested that aspirin-mediated anti-inflammatory approaches could be an effective strategy toprevent pancreatic carcinoma. These in vivo results are inline with several epidemiological studies [40, 41]. Recently,in a prospective study conducted by Anderson et al. [40], theuse of aspirin was associated with a reduced risk of pancre-atic cancer among 28,232 postmenopausal women. To fur-ther evaluate the association between aspirin, NSAID andacetaminophen use with pancreatic cancer risk, Tan et al.[45] used a clinic-based case–control study of 904 pancre-atic ductal adenocarcinoma cases and 1,224 age- and sex-matched healthy controls evaluated at Mayo Clinic from2004 to 2010. Aspirin use for 1 day/month or greater wasassociated with a significantly decreased risk of pancreaticcancer (OR00.74, 95% CI00.60–0.91, p00.005) comparedwith never or <1 day/month. This inverse association wasalso found for those who took low-dose aspirin for heartdisease prevention (OR00.67, 95% CI00.49–0.92, p00.013). Instead, they found no relationship between non-aspirin NSAID or acetaminophen use and risk of pancreaticcancer. The authors concluded that aspirin use, but not non-aspirin NSAID use, is associated with a lowered risk ofdeveloping pancreatic cancer.

In an elegant, preclinical study, Funahashi et al. [46] eval-uated the efficacy of the selective COX-2 inhibitor nimesulideto prevent the progression of PanINs in the KPC mousemodel. Mice were randomly allocated to a diet supplementedwith nimesulide or a control diet. After 10 months, the pan-creas of KPC mice was analysed for the presence of PanINs.Animals fed the COX-2 inhibitor had significantly fewerPanIN-2and PanIN-3 lesions than control animals (p<0.05).Ten per cent of all pancreatic ducts in the nimesulide-fedanimals showed PanIN-2 or PanIN-3 lesions, whereas 40%of the pancreatic ducts in the control animals had PanIN-2 orPanIN-3 lesions. Intrapancreatic prostaglandin E2 levels werereduced in nimesulide-fed animals. The authors concludedthat inhibition of COX-2 may represent an intriguing strategyto prevent pancreatic cancer in high-risk patients [46]. Recent-ly, our group extended these results and showed that aspirindelayed the progression of PanINs and partially inhibited theformation of invasive murine pancreatic cancer formation inKPC mice [47]. Aspirin delayed the progression from normalducts to PanIn1A and to PanIN1B. Because only PanIN3 areclassified as carcinoma in situ, delaying the progression to-wards PanIN3 would have a major impact on cancer devel-opment. Therefore, our study is strengthening the conclusionof Funahasi et al. [46] that aspirin or a COX-2 inhibitor mightbe an effective chemopreventive agent for pancreatic cancerprobably by the inhibition of NF-kappa B-driven Cox-2expression by blocking MAPK and Akt/protein kinase B

signalling [48]. NF-κB orchestrates the expression of genesthat encode key determinants in inflammation, tumorigenesis,and apoptosis and thus promotes the cardinal clinical featuresof pancreatic carcinoma of locally aggressive growth andmetastasis [49]. Constitutive activation of NF-κB is a frequentmolecular alteration in pancreatic carcinoma and is also foundin human pancreatic carcinoma cell lines, but not in immor-talized, non-tumorigenic pancreatic epithelial cells [50]. As-pirin inhibits NF-κB activation through the specific inhibitionof IKK-2 activity by binding to IKK-2 and reducing ATPbinding [51]. This could be an important step in pancreaticcancer because NF-κB is a critical downstream mediator ofcell transformation mediated by oncogenic ras [52]. In thiscontext, the transcriptional activity of RelA is significantlyincreased in Ras-transformed cells as compared with non-transformed cells [53]. It is thus reasonable to expect that theactivation of the Ras pathway in human tumours may yet beanother means to induce constitutive NF-κB activity and on-cogenesis. In agreement with this hypothesis, RelA has beenobserved to be constitutively activated in 67% of pancreaticadenocarcinomas and the human K-ras oncogene to be fre-quently mutated in pancreatic cancer [43].

Angiotensin I-converting enzyme inhibitors

Inhibitors of angiotensin I-converting enzyme (ACE inhibi-tors) inhibit stimulation by angiotensin II (AngII) by decreas-ing its conversion from AngI. ACE inhibitors (ACE-Is) weredeveloped and applied clinically as first-line drugs for hyper-tension. Interestingly, much evidence has accumulated toshowing that ACE-Is suppress the growth of a wide varietyof cultured cancer cells in vitro and inhibit tumorigenesis andangiogenesis induced in cancer animal models in vivo [54, 55].AngII is a multifunctional bioactive peptide, and recent reportshave suggested that it is a pro-angiogenic growth factor. It hasbeen shown that AngII selectively increases blood flow andthat ACE-Is decrease intratumoral blood flow without affect-ing blood flow in healthy organs. In experimental models,ACE-Is reduced the tumour cell growth rate and modulatedgene expression in vitro. In vivo, captopril was shown toinhibit tumour growth and angiogenesis [56].

Lever et al. [57] conducted a retrospective cohort study toassess the risk of cancer in hypertensive patients receivingACE-Is or other antihypertensive drugs. The relative risk ofcancer was lowest in women on ACE-Is. They concluded thatlong-term use of ACE-Is may protect against cancer. A retro-spective cohort study on 5,207 patients receiving ACE-I orother anti-hypertensive drugs with a 10-year follow-up dem-onstrated that ACE-I treatment may decrease the incidence ofadult cancer [57]. Furthermore, a study of 483,733 US veter-ans has found that ACE-Is can significantly reduce the risk ofpancreatic cancer (odds ratio00.48, p<0·01) [58]. Arafat et al.[59] analysed the expression and localization of ACE and


AngII type 1 receptor (AT1) in relation to vascular endothelialgrowth factor (VEGF) in invasive human pancreatic cancer.VEGF is a crucial pro-angiogenic component in pancreaticductal adenocarcinoma, and its high expression levels havebeen correlated with poor prognosis and early postoperativerecurrence. They found an upregulation of ACE and AT1R in75% of analysed cancers when compared with matching con-trols. VEGF expression was significantly higher in tissues thatexpressed high levels of AT1 and ACE. The same groupexplored the signalling mechanisms involved in the AngII-mediated VEGF induction and correlated AT1 and VEGFexpression in noninvasive precursor lesions. An AT1 antago-nist inhibited the AngII-mediated induction of the VEGFmessenger RNA and protein in all PDA cell lines [60].

Recently, our group used KP and KPC mice to evaluateenalapril as a chemopreventive agent for pancreatic cancer[47]. Drug treatment was initiated at the age of 5 weeks.LsL-KrasG12D; Pdx1-Cre or LsL-KrasG12D; LsL-Trp53R172H;Pdx1-Cre transgenic mice were randomly assigned to re-ceive either mock treatment or enalapril. After 3 and5 months of treatment, enalapril was able to significantlydelay the progression of PanINs in LsL-KrasG12D; Pdx1-Cremice. Furthermore, the development of invasive pancreaticcancer in LsL-KrasG12D; LsL-Trp53R172H; Pdx1-Cre trans-genic mice was partially inhibited by enalapril. Invasivepancreatic cancer was identified in 15 of 25 (60%) LsL-KrasG12D; LsL-Trp53R172H; Pdx1-Cre untreated controlmice, but in 4 of 17 (23.5%, p00.03) mice treated withenalapril alone. Using real-time PCR, we found a significantdownregulation of the target gene VEGF, demonstrating theability to achieve effective pharmacological levels of ena-lapril during pancreatic cancer formation in vivo.

Taken together, several studies suggest the involvement ofAT1 and AngII in PDAC progression and therefore mayprovide valuable chemopreventive targets.

Gefitinib

The chemopreventive efficacy of gefitinib, an EGFR inhib-itor, was evaluated against the progression of PanINs toPDAC in conditional LSL-KrasG12D/+ transgenic mice[61]. Mice were fed (AIN-76A) diets containing 0, 100and 200 ppm of gefitinib for 35 weeks. Dietary gefitinib at100 and 200 ppm significantly suppressed PDAC incidenceby 77% and 100%, respectively (p<0.0001) when comparedwith the control diet. Importantly, a significant inhibition ofcarcinoma and a dose-dependent suppression of PanINs[PanIN-1, 37–62% (p<0.002); PanIN-2, 38–41% (p<0.001); and PanIN-3, 7–34% (p<0.0141)] were observedin mice treated with gefitinib. Furthermore, mice treatedwith gefitinib exhibited 67.6–77.3% of the pancreas to befree from ductal lesions. Also, gefitinib reduced EGFR,proliferating cell nuclear antigen, cyclin D1, C2GNT,

RhoA, β-catenin, p38, phospho-extracellular signal-regulated kinase, caveolin-1, and mucin and increasedcyclin B1 in the pancreatic lesions/PDAC. These resultsshow that gefitinib can prevent the progression of pancreaticcancer precursor lesions to PDAC in a preclinical model[61].

Dietary cancer prevention

Citrus fruits

Flavonoids, one of the major classes of compounds in citrus,have been shown to have antiproliferative, antioxidant, anti-tumour, anti-inflammatory and pro-apoptotic activities [62].Carotenoids are also found in citrus fruits, and there areseveral studies that have shown that high carotenoid intakemay decrease the risk of cancer [63]. Several epidemiolog-ical studies have examined the effects of citrus fruits on therisk of developing pancreatic cancer (overview in [62]).Most of these studies show an inverse association betweenthe consumption of citrus fruit and the risk of developingpancreatic cancer. However, some of the studies are under-powered and show a huge variety in the comparison of theexposure level.

Curcumin

Curcumin is a fat-soluble polyphenolic compound that is themain and most active curcuminoid found in turmeric (Cur-cuma longa L.) [62]. It is commonly used as a spice in Asiancountries as well as a natural food colouring agent. Curcuminhas been a bioactive compound of interest for many types ofcancer, including breast, prostate, oral, ovarian and others [64].Its many pharmacological properties include antioxidant, anti-inflammatory, antimicrobial, antitumour, antidepressant andanti-atherogenic activities. The anticancer effects of curcuminon pancreatic cancer in vitro have been widely researched anddocumented (overview in [62]). Bar-Sela et al. [65] published adetailed review about the clinical trials that have been con-ducted or are currently ongoing that use curcumin as an anti-cancer agent. In these trails, curcumin was used in an adjuvantsetting rather than chemopreventive.

Flavonoids

Flavonoids are a large class of polyphenols, with over 5,000 ofthem described. They are water-soluble secondary metabolitesand are responsible of the flavour and colour of vegetables andfruits. In humans, flavonoids have a wide range of bioactivitiesincluding anticancer, anti-inflammatory and anti-hypertensiveproperties [62].


Apigenin in vitro inhibits DNA synthesis and induces cellcycle arrest at G2/M phase through the downregulation ofcyclin A and B, phosphorylated cdc2, cdc25A and cdc25C inAsPC-1, MIA PaCa-2, CD18 and S2-013 cells [66]. In anotherstudy, it induces apoptosis and enhances the inhibitory andapoptotic effects of gemcitabine through the downregulation ofNFκB activity with the suppression of Akt activation and thereduction of Bcl-2 expression in MIA PaCa-2 and AsPC-1cells [67] and through the induction of both S and G2/Mphase cell cycle arrest [68]. Furthermore, it decreases glucoseuptake through the downregulation of GLUT-1 in CD18 andS2-013 cells and interferes with the PI3K/Akt pathway [69]. Invivo studies with Apigenin have shown that it potentiates theinhibitory effects of gemcitabine on tumour growth and abro-gates gemcitabine-induced activation of the Akt-NFκBpathway [67].

Kaempferol inhibits cell growth and induces apoptosis inMIA PaCa-2 and PANC-1 cells and provides an additive effecton the inhibition of MIA PaCa-2 cell proliferation when com-bined with 5-fluorouracil [70]. Quercetin shows antiprolifera-tive effects on BxPC-3, MIA PaCa-2 and PANC-1 cells andinduces apoptosis by upregulating caspase-3 and caspase-9and downregulating Hsp70 In nude mice, it decreases tumourgrowth and Hsp70) [71].

The isoflavone genistein inhibits cell growth, induces apo-ptosis and inhibits NFκB activity in BxPC-3 cells and poten-tiates the effects of cisplatin and docetaxel by inhibiting cellgrowth and inducing apoptosis inhibits [72]. It enhances thecell growth inhibition of gemcitabine on COLO 357 andL3.6pl cell lines, abrogates gemcitabine-induced activationof NFκB DNA-binding activity and sensitizes gemcitabine-treated cells to apoptosis by the induction of caspase-3-mediated PARP cleavage and the downregulation of Bcl-2,Bcl-XL and p-Akt. In the same study, it reduces tumour weightwhen combined with gemcitabine treatment and inhibitsgemcitabine-induced activation of NFκB activity [73]. It indu-ces apoptosis through the downregulation of Notch-1, whichleads to the inhibition of IKK protein and therefore reducedNFκB activity [74, 75]. It potentiates the growth inhibition oferlotinib-treated and increases the apoptotic effect of erlotinibin BxPC-3 cells through the downregulation of EGFR, pAkt,NFκB activation and survivin [76]. It inhibits cell proliferationin BxPC-3, HPAC, MIA PaCa-2 and PANC-28 cell lines anddownregulates the expression of FoxM1, thus leading to theinhibition of cdc25a, survivin, MMP-9 and VEGF, therebydecreasing the penetration of pancreatic cancer cells throughthe Matrigel-coated membrane [77].

Taken together, several flavonoids found in a variety offruits and vegetables have been proven to inhibit pancreaticcancer at various molecular targets including cell cycle, Akt,NFκB, extracellular signal-regulated kinase (ERK) and manyothers. The isoflavone genistein is one of the more studiedflavonoids in pancreatic cancer. It has been shown that it has

the ability to abolish the activation of NFκB induced by thechemotherapeutic drugs gemcitabine and cisplatin when usedas a pretreatment for either of them. Currently, there is onephase II clinical trial on the use of genistein for pretreatingpatients with resectable pancreatic cancer which was completedin 2011 (http://clinicaltrials.gov/ct2/show/NCT00882765).However, more clinical trials are needed to explore the efficacyand application of genistein in treating pancreatic cancer.

Capsaicin

Capsaicin is a major biologically active ingredient of chilipeppers. Studies indicate that capsaicin is a cancer-suppressing agent via blocking the activities of severalsignal transduction pathways including nuclear factor kap-paB, activator protein 1 and signal transducer and activatorof transcription 3. Very recently, the effect of capsaicin onpancreatitis and PanINs was determined in a mutant Kras-driven and caerulein-induced pancreatitis-associated carci-nogenesis in KPC mice [78]. KPC mice were subjected toone dose of caerulein at age 4 weeks to induce and synchro-nize the development of chronic pancreatitis and PanINlesions. One week after caerulein induction, animals weredistributed into three groups and fed with either AIN-76Adiet or AIN-76A diet containing 10 ppm capsaicin or20 ppm capsaicin for a total of 8 weeks. The results showedthat capsaicin significantly reduced the severity of chronicpancreatitis, as determined by evaluating the loss of acini,inflammatory cell infiltration and stromal fibrosis. Further-more, the progression of PanIN-1 to high-grade PanIN-2 andPanIN-3 were significantly inhibited by capsaicin. Furtherimmunochemical studies revealed that treatment with capsai-cin significantly reduced proliferating cell nuclear antigen-labelled cell proliferation and suppressed the phosphorylationof ERK and c-Jun as well blocked Hedgehog/GLI pathwayactivation. These results indicate that capsaicin could be apromising agent for the chemoprevention of pancreatic carci-nogenesis, possibly via inhibiting pancreatitis and mutantKras-led ERK activation [78].

Outlook—prevention strategies for pancreatic cancer

A chemoprevention agent that blocks the very first step wouldbe best. But most researchers would consider a drug success-ful if it could stop the disease progressing from any stage tothe next. That is the basic idea of cancer chemoprevention: toarrest or reverse the progression of premalignant cells towardsfull malignancy.

Complicating the problem is the fact that people feel finestarting a long-term drug regimen—one that can cause trou-blesome side effects or even put them at risk for anotherdisease. So we need to identify individuals or groups being


http://clinicaltrials.gov/ct2/show/NCT00882765

at high risk for developing pancreatic cancer. Therefore, weshould not doing clinical chemoprevention trials in largepopulations of people at relatively low risk and instead focuson groups at the highest risk. There are many such groups:patients with hereditary pancreatitis, Peutz–Jeghers syndromeor familial pancreatic cancer. Chemoprevention trials on suchgroups will provide much more definitive results and withmuch less effort.

There are two major prevention strategies involved incancer research: cancer chemoprevention and dietary cancerprevention. Cancer chemoprevention is defined as the use ofnatural, synthetic or biologic chemical agents for pharmaco-logic intervention to prevent, inhibit or reverse carcinogenesis[79]. Dietary cancer prevention, on the other hand, means themodification or changes of food consumption patterns that canbe accompanied by lifestyle changes in order to decrease therisk [79].Which strategy will be the better one still needs to bedefined.

GEMM of pancreatic cancer are helping close the hugegap between in vitro results and clinical trials. The valuableinsights these mice provide will maybe help us designclinical trials leading to the prevention of this lethal diseasemalignancy.

Conflicts of interest None.

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Chemoprevention of pancreatic cancer—one step closer