Prevention Of Pancreatic Cancer Research Articles

Smoking and Pancreatic Cancer Incidence: A Pooled Analysis of 10 Population-Based Cohort Studies in Japan.

Detailed prospective evaluation of cigarette smoking associated with pancreatic cancer risk in large Asian populations is limited. The aim of this study was to examine this association in a Japanese population, with a particular focus on evaluating sex differences. We performed a pooled analysis of 10 population-based cohort studies. We calculated study-specific HRs and 95% confidence intervals (CI) using Cox proportional hazards regression, and then estimated summary HRs by pooling these estimates with a random effects model. During 4,695,593 person-years of follow-up in 354,154 participants, 1,779 incident pancreatic cancer cases were identified. We observed an increased pancreatic cancer risk for current smoking compared with never smoking in both males [HR (95% CI), 1.59 (1.32-1.91)] and females [HR (95% CI), 1.81 (1.43-2.30)]. Significant risk elevations for former smoking and small cumulative dose of ≤20 pack-years (PY) were observed only among females, regardless of environmental tobacco smoke exposure. Trend analysis indicated significant 6% and nonsignificant 6% increases in pancreatic cancer risk for every 10 PYs in males and females, respectively. Risk became comparable with never smokers after 5 years of smoking cessation in males. In females, however, we observed no risk attenuation by smoking cessation. This study supports the well-known association between smoking and pancreatic cancer and indicates potential sex differences in a Japanese population. Quitting smoking would be beneficial for pancreatic cancer prevention, especially in males. Pancreatic cancer risk is increased with cumulative smoking exposure and decreased with smoking cessation, with potential sex differences.

Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet

Obesity is a risk factor for pancreatic cancer. In mice, a high-fat diet (HFD) and expression of oncogenic KRAS lead to development of invasive pancreatic ductal adenocarcinoma (PDAC) by unknown mechanisms. We investigated how oncogenic KRAS regulates the expression of fibroblast growth factor 21, FGF21, a metabolic regulator that prevents obesity, and the effects of recombinant human FGF21 (rhFGF21) on pancreatic tumorigenesis. We performed immunohistochemical analyses of FGF21 levels in human pancreatic tissue arrays, comprising 59 PDAC specimens and 45 nontumor tissues. We also studied mice with tamoxifen-inducible expression of oncogenic KRAS in acinar cells (KrasG12D/+ mice) and fElasCreERT mice (controls). KrasG12D/+ mice were placed on an HFD or regular chow diet (control) and given injections of rhFGF21 or vehicle; pancreata were collected and analyzed by histology, immunoblots, quantitative polymerase chain reaction, and immunohistochemistry. We measured markers of inflammation in the pancreas, liver, and adipose tissue. Activity of RAS was measured based on the amount of bound guanosine triphosphate. Pancreatic tissues of mice expressed high levels of FGF21 compared with liver tissues. FGF21 and its receptor proteins were expressed by acinar cells. Acinar cells that expressed KrasG12D/+ had significantly lower expression of Fgf21 messenger RNA compared with acinar cells from control mice, partly due to down-regulation of PPARG expression-a transcription factor that activates Fgf21 transcription. Pancreata from KrasG12D/+ mice on a control diet and given injections of rhFGF21 had reduced pancreatic inflammation, infiltration by immune cells, and acinar-to-ductal metaplasia compared with mice given injections of vehicle. HFD-fed KrasG12D/+ mice given injections of vehicle accumulated abdominal fat, developed extensive inflammation, pancreatic cysts, and high-grade pancreatic intraepithelial neoplasias (PanINs); half the mice developed PDAC with liver metastases. HFD-fed KrasG12D/+ mice given injections of rhFGF21 had reduced accumulation of abdominal fat and pancreatic triglycerides, fewer pancreatic cysts, reduced systemic and pancreatic markers of inflammation, fewer PanINs, and longer survival-only approximately 12% of the mice developed PDACs, and none of the mice had metastases. Pancreata from HFD-fed KrasG12D/+ mice given injections of rhFGF21 had lower levels of active RAS than from mice given vehicle. Normal acinar cells from mice and humans express high levels of FGF21. In mice, acinar expression of oncogenic KRAS significantly reduces FGF21 expression. When these mice are placed on an HFD, they develop extensive inflammation, pancreatic cysts, PanINs, and PDACs, which are reduced by injection of FGF21. FGF21 also reduces the guanosine triphosphate binding capacity of RAS. FGF21 might be used in the prevention or treatment of pancreatic cancer.

High glucose microenvironment accelerates tumor growth via SREBP1-autophagy axis in pancreatic cancer

BackgroundDiabetes is recognized to be a risk factor of pancreatic cancer, but the mechanism has not been fully elucidated. Sterol regulatory element binding protein 1 (SREBP1) is an important transcription factor involved in both lipid metabolism and tumor progression. However, the relationship between high glucose microenvironment, SREBP1 and pancreatic cancer remains to be explored.MethodsClinical data and surgical specimens were collected. Pancreatic cancer cell lines BxPc-3 and MiaPaCa-2 were cultured in specified medium. Immunohistochemistry (IHC) and western blotting were performed to detect the expression of SREBP1. MTT and colony formation assays were applied to investigate cell proliferation. Immunofluorescence, mRFP-GFP adenoviral vector and transmission electron microscopy were performed to evaluate autophagy. We used streptozotocin (STZ) to establish a high glucose mouse model for the in vivo study.ResultsWe found that high blood glucose levels were associated with poor prognosis in pancreatic cancer patients. SREBP1 was overexpressed in both pancreatic cancer tissues and pancreatic cancer cell lines. High glucose microenvironment promoted tumor proliferation, suppressed apoptosis and inhibited autophagy level by enhancing SREBP1 expression. In addition, activation of autophagy accelerated SREBP1 expression and suppressed apoptosis. Moreover, high glucose promotes tumor growth in vivo by enhancing SREBP1 expression.ConclusionOur results indicate that SREBP1-autophagy axis plays a crucial role in tumor progression induced by high glucose microenvironment. SREBP1 may represent a novel target for pancreatic cancer prevention and treatment.

Inhibition of Pancreatic Carcinoma Growth Through Enhancing ω-3 Epoxy Polyunsaturated Fatty Acid Profile by Inhibition of Soluble Epoxide Hydrolase.

Cytochrome P450 epoxygenase is a major enzyme involved in the metabolism of ω-3 polyunsaturated fatty acids (PUFAs) to produce biologically active ω-3 epoxy fatty acids (ω-3 epoxides). In general, all epoxy PUFAs including ω-3 epoxides are quickly metabolized/inactivated by soluble epoxide hydrolase (sEH) to form diol products. The aims of this study were to determine the effect and mechanism of fat-1 transgene, and ω-3 PUFA combined with sEH gene knockout or inhibitor on inhibiting pancreatic cancer and the related mechanisms involved. PK03-mutant KrasG12D murine pancreatic carcinoma cells were inoculated into mouse models including fat-1, sEH-/- and C57BL/6J mice. The mice were fed with AIN-76A diet with or without ω-3 PUFA supplementation or treated with sEH inhibitor. In addition to tumor growth (tumor size and weight), cell proliferation, mutant Kras-mediated signaling, inflammatory reaction and angiogenesis were analyzed immunohisto-chemically and by western blot assay. ω-3 PUFA metabolism, particularly focusing on ω-3 epoxy fatty acids (ω-3 epoxides), was measured using a liquid chromatography with tandem mass spectrometry (LC-MS/MS) approach. Significant decreases of weight and size of the PK03 pancreatic carcinoma were observed in the fat-1 transgenic mice treated with sEH inhibitor compared to those of C57BL/6J control mice fed with AIN-76A diet (weight: 0.28±0.04 g vs. 0.58±0.06 g; size: 187.0±17.5 mm3 vs. 519.3±60.6 mm3). In a separate experiment, sEH-/- mice fed ω-3 PUFA supplement and C57BL/6J mice treated with sEH inhibitor and fed ω-3 PUFA supplement exhibited a significant reduction in the weight and size of the pancreatic carcinoma compared to C57BL/6J control mice (weight: 0.26±.26 g and 0.39±.39 g vs. 0.69±0.11 g, respectively; size: 274.2±36.2 mm3 and 296.4±99.8 mm3 vs. 612.6±117.8 mm3, respectively). Moreover, compared to the pancreatic tumors in C57BL/6J control mice, the tumors in fat-1 transgenic mice treated with sEH inhibitor showed a significant less inflammatory cell infiltrate (62.6±9.2/HPF (high power field) vs. 8.0±1.2/HPF), tumor cell proliferation (48.5±1.7% vs. 16.5±1.6%), and angiogenesis (micro-vessel density (MVD): 35.0±1.0 vs. 11.1±0.5) immunohistochemically, as well as significantly increased caspase-3 labeled apoptosis (0.44±0.06% vs. 0.69±0.06%, respectively). Using western blot approach, significant inhibition of mutant Kras-activated signals including phosphorylated Serine/threonine kinases (cRAF), Mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (ERK) were identified in pancreatic carcinoma of fat-1 transgenic mice treated with sEH inhibitor. Eicosanoic acid metabolic profiling of the serum specimens detected a significant increase of the ratios of epoxides to dihydroxy fatty acid (DiHDPE) for docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and epoxides/dihydroxy octadecenoic acid (DiHOME) for arachidonic acid (ARA) and linoleic acid (LA), as well as a significant increase of epoxy metabolites of DHA, EPA, ARA and LA in fat-1 transgenic mice treated with a sEH inhibitor. ω-3 epoxy products from ω-3 PUFA metabolism play a crucial role in inhibiting pancreatic cancer growth, and use of ω-3 PUFAs combined with sEH inhibition is a strategy with high potential for pancreatic cancer treatment and prevention.

Primary and Secondary Prevention of Pancreatic Cancer

Pancreatic cancer remains one of the most lethal of malignancies with 5-year survival of only 8%. A number of reasons account for the high fatality rate including few known modifiable risk factors, no effective screening tools, and lack of early diagnostic symptoms. Therefore, in this review, we aim to summarize existing evidence from major studies concerning (1) risk factors for risk assessment and risk stratification, and (2) screening modalities and early detection markers to better understand the ways to prevent pancreatic cancer or identify it at earlier stages. Improvements in primary and secondary prevention of pancreatic cancer are critical to reduce the morbidity and mortality of this deadly disease. We searched the published literature and identified studies of pancreatic cancer risk published prior to September 30, 2018, with an emphasis on manuscripts publicized during the last 5–10 years. Known and suspected risk factors include familial and genetic risk, smoking, obesity, alcohol, poor diet including sugary sweetened beverages, diabetes, and periodontal disease. Recent advances have identified potential early detection markers (e.g., ctDNA, circulating cancer cells, metabolites, and miRNA). Currently, pancreatic cancer has few known and suspected risk factors, and risk assessment tools have limited utility given their modest discriminatory power. Although emerging evidence suggests blood-based biomarkers may be useful as early detection markers, findings need to be confirmed in prospective studies. Due to the rarity of disease, future studies should consider a two-tiered approach in which risk assessment is used to identify high-risk individuals for screening, and then effective imaging and biomarkers in pathways known to affect pancreatic cancer risk are employed; these combination approaches may reduce false positives and mortality compared with just risk assessment or screening alone.

Interethnic differences in pancreatic cancer incidence and risk factors: The Multiethnic Cohort.

While disparity in pancreatic cancer incidence between blacks and whites has been observed, few studies have examined disparity in other ethnic minorities. We evaluated variations in pancreatic cancer incidence and assessed the extent to which known risk factors account for differences in pancreatic cancer risk among African Americans, Native Hawaiians, Japanese Americans, Latino Americans, and European Americans in the Multiethnic Cohort Study. Risk factor data were obtained from the baseline questionnaire. Cox regression was used to estimate the relative risks (RRs) and 95% confidence intervals (CIs) for pancreatic cancer associated with risk factors and ethnicity. During an average 16.9‐year follow‐up, 1,532 incident pancreatic cancer cases were identified among 184,559 at‐risk participants. Family history of pancreatic cancer (RR 1.97, 95% CI 1.50‐2.58), diabetes (RR 1.32, 95% CI 1.14‐1.54), body mass index ≥30 kg/m2 (RR 1.25, 95% CI 1.08‐1.46), current smoking (<20 pack‐years RR 1.43, 95% CI 1.19‐1.73; ≥20 pack‐years RR 1.76, 95% CI 1.46‐2.12), and red meat intake (RR 1.17, 95% CI 1.00‐1.36) were associated with pancreatic cancer. After adjustment for these risk factors, Native Hawaiians (RR 1.60, 95% CI 1.30‐1.98), Japanese Americans (RR 1.33, 95% CI 1.15‐1.54), and African Americans (RR 1.20, 95% CI 1.01‐1.42), but not Latino Americans (RR 0.90, 95% CI 0.76‐1.07), had a higher risk of pancreatic cancer compared to European Americans. Interethnic differences in pancreatic cancer risk are not fully explained by differences in the distribution of known risk factors. The greater risks in Native Hawaiians and Japanese Americans are new findings and elucidating the causes of these high rates may improve our understanding and prevention of pancreatic cancer.

Towards a Personalized Approach in Pancreatic Cancer Diagnostics Through Plasma Amino Acid Analysis.

Body fluid biomarkers may provide means for early pancreatic cancer diagnosis, patient stratification, application of personalized approaches and, finally, improved outcomes. Amino acids are the most frequently distinguished metabolite class in the metabolomics of pancreatic cancer patients. They have been identified as pre-diagnostic and diagnostic markers and associated with pancreatic cancer risk factors. Deep phenotyping and quantitative amino acid analysis were performed in patients scheduled for pancreatic surgery due to pancreatic tumors (n=75). Significant differences in plasma amino acid concentrations were observed between diagnostic categories (malignant vs. benign lesions and histological cancer types) and pancreatic ductal adenocarcinoma stages. Characteristic patterns of plasma amino acid concentration dynamics according to cancer stage were identified. Standardization of metabolomics methods and deep phenotyping may provide means for improved patient stratification and effective personalized approaches in pancreatic cancer prevention, early diagnosis and treatment.

Inhibition of pancreatic cancer stem cell characteristics by α-Mangostin: Molecular mechanisms involving Sonic hedgehog and Nanog.

The current investigation was intended to elucidate the molecular mechanism of α‐Mangostin in the regulation of pancreatic cancer stem cell (CSC) characteristics. Here, we demonstrate that α‐Mangostin inhibited cell proliferation in pancreatic CSCs and cancer cell lines while it showed no effect on human pancreatic normal ductal epithelial cells. Also, α‐Mangostin inhibited colony formation and induced apoptosis in these cells. Further, α‐Mangostin inhibited the self‐renewal capacity of CSCs isolated from human primary tumours and KrasG12D mice. Furthermore, α‐Mangostin inhibited the invasive and metastatic ability of pancreatic CSCs by suppressing the epithelial‐to‐mesenchymal transition (EMT) via up‐regulation of E‐cadherin and down‐regulation of mesenchymal phenotype by inhibiting N‐cadherin, Snail and Slug expression. Interestingly, the pluripotency maintaining factors and CSC markers were inhibited by α‐Mangostin thus suggesting that α‐Mangostin can target CSCs to inhibit pancreatic cancer effectively. Gli signalling plays a crucial role in the self‐renewal and pluripotency of CSCs. α‐Mangostin inhibited the Gli transcription and the expression of Gli target genes (Nanog, Oct4, c‐Myc, Sox‐2 and KLF4) in CSCs. Using ChIP assay, we demonstrated that Nanog could directly bind to promoters of Cdk2, Cdk6, FGF4, c‐Myc and α‐Mangostin inhibited Nanog binding to these promoters. Conversely, the inhibitory effects of the α‐Mangostin on CSC proliferation and Gli or Nanog transcription and their targets were abrogated by either enforced activation of sonic hedgehog (Shh) or by the overexpression of Nanog. Taken together, our studies suggest that α‐Mangostin may act as Gli inhibitor and establishes the pre‐clinical significance of α‐Mangostin for the prevention and treatment of pancreatic cancer.

Triacetyl resveratrol upregulates miRNA‑200 and suppresses the Shh pathway in pancreatic cancer: A potential therapeutic agent.

Trans‑3,4',5‑trihydroxystilbene (resveratrol) is a naturally occurring polyphenolic phytoalexin with marked anticancer activities, and is mainly found in grapes, berries and peanuts. However, due to a low bioavailability, it has not progressed to clinical practice for cancer treatment. Therefore, the aims of the present study were to examine the anticancer activities of the resveratrol derivative, triacetyl resveratrol(TCRV), in pancreatic cancer cells. Apoptosis was measured by fluorescence‑activated cell sorting and terminal deoxynucleotidyl transferase(TdT)‑mediated dUTP nick‑end labeling assays. Gene expression was measured by reverse transcription‑quantitative polymerase chain reaction. TCRV inhibited colony formation and induced apoptosis through caspase‑3 activation in human pancreatic cancer AsPC‑1 and PANC‑1 cells, whereas it exerted no effect on human pancreatic normal ductal epithelial cells (HPNE). TCRV inhibited epithelial‑mesenchymal transition (EMT) by upregulating the expression of E‑cadherin and suppressing the expression of N‑cadherin and the transcription factors, Snail, Slug and Zeb1. TCRV inhibited Zeb1 3'UTR‑luciferase activity through the upregulation of microRNA (miR)‑200 family members. The inhibitory effects of TCRV on pancreatic cancer cell migration and invasion were counteracted by anti‑miR‑200 family members. The inhibitory effects of TCRV on EMT and the induction of apoptosis were exerted through the suppression of the sonic hedgehog (Shh) pathway, and through the modulation of cyclinD1 and Bcl‑2 expression. The hyperactivation of the Shh pathway by either Shh protein or Gli1 overexpression abrogated the biological effects of TCRV. Taken together, the results of this study demonstrate that TCRV inhibits pancreatic cancer growth and EMT by targeting the Shh pathway and its downstream signaling mediators. TCRV inhibited EMT through the upregulation of miR‑200 family members. Since TCRV effectively inhibited the growth of human pancreatic cancer cells by modulating the Shh pathway, without affecting the growth of HPNE cells, our findings suggest the possible use of TCRV as a promising candidate for the treatment and/or prevention of pancreatic cancer.

Epigenomics of Pancreatic Cancer: A Critical Role for Epigenome-Wide Studies.

Several challenges present themselves when discussing current approaches to the prevention or treatment of pancreatic cancer. Up to 45% of the risk of pancreatic cancer is attributed to unknown causes, making effective prevention programs difficult to design. The most common type of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), is generally diagnosed at a late stage, leading to a poor prognosis and 5-year survival estimate. PDAC tumors are heterogeneous, leading to many identified cell subtypes within one patient’s primary tumor. This explains why there is a high frequency of tumors that are resistant to standard treatments, leading to high relapse rates. This review will discuss how epigenetic technologies and epigenome-wide association studies have been used to address some of these challenges and the future promises these approaches hold.

Resveratrol inhibits the growth of tumor cells under chronic stress via the ADRB‑2‑HIF‑1α axis.

Resveratrol is a type of polyphenol that is abundantly present in knotweed and grapes, and has been confirmed to have tumor‑inhibitory properties. However, the effect of resveratrol on tumor cells under chronic stress conditions remains unclear. The aim of the present study was to demonstrate that resveratrol exerts a significant inhibitory effect on the growth and proliferation of tumor cells under chronic stress in a dose‑dependent manner. Furthermore, resveratrol was able to induce apoptosis of cancer cells under chronic stress conditions. Moreover, resveratrol was found to inhibit tumor cells under chronic stress by decreasing the expression of the β2‑adrenergic receptor (ADRB‑2); in addition, the protein expression of hypoxia‑inducible factor (HIF)‑1α was suppressed by resveratrol in a dose‑dependent manner. Thus, these data suggest that resveratrol inhibits the growth of cancer cells under chronic stress by regulating the ADRB‑2‑HIF‑1α axis. In summary, the present study may provide a new basis supporting the use of resveratrol for the prevention and treatment of pancreatic cancer.

The Microbiome and Pancreatic Cancer: An Evidence-based Association?

Many risk factors for pancreatic cancer are related with microbiome alteration. In the past few years, the human microbiome and its relation with the immune system have been linked with carcinogenesis of different organs distant from the gut, including the pancreas. Patterns of oral microbiome associated with periodontitis are associated with an increased risk of pancreatic cancer, possibly because of the increased systemic inflammatory response, or to the capacity of some specific bacteria to alter the host immune response, making it more favorable to cancer cells. Helicobacter pylori infection when affecting the gastric body mucosa with subsequent hypochlorhydria also seems associated with an increased risk of pancreatic cancer. The composition of the intestinal microbiome is different in animal models and in humans with pancreatic cancer who have a distinct microbiome population compared with controls. Some specific bacteria can migrate from the intestine to the pancreas, and their ablation restores the immune system activity through its reprogramming with a switch toward a Th1 response and displays a protective effect toward tumor growth. More research in this area might lead to progress in terms of pancreatic cancer prevention and treatment, possibly in association with immunotherapy.

A prospective clinical and biological database for pancreatic adenocarcinoma: the BACAP cohort

BackgroundThe prognosis for pancreatic cancer remains poor despite diagnostic advances and treatments with new chemotherapeutic regimens. The five year survival rate remains below 3%. Consequently, there is an urgent need for new treatments to significantly improve the prognosis. In addition, there is a big gap in terms of the screening, early diagnosis and prevention of pancreatic cancer the incidence of which is increasing dramatically.MethodsDesign: the BACAP cohort is a prospective multicenter pancreatic cancer cohort (pancreatic ductal carcinoma) with clinical and multiple biological samples; Participating centers: 15 French academic and private hospitals; Study Population: any cytologically and/or histologically proven pancreatic carcinoma regardless of the stage (resectable, borderline, locally advanced or metastatic) or treatment (surgery, palliative chemotherapy, best supportive care). At least 1500 patients will be included. Clinical data collected include: disease presentation, epidemiological and social factors, baseline biology, radiology, endoscopic ultrasound, staging, pathology, treatments, follow-up (including biological and radiological), and survival. All these data are collected and stored through an e-observation system at a centralized data center. Biological samples and derived products (i.e. before any treatment): blood, saliva, endoscopic ultrasound-guided fine needle aspiration materials from the primary tumor, fine needle biopsy of metastases and surgically resected tissue. DNA and RNA are extracted from fine needle aspiration materials and are quantified and characterized for quality. Whole blood, plasma and serum are isolated from blood samples. Frozen tissues were specifically allocated to the cohort. All derived products and saliva are stored at − 80 °C. Main end-points: i) to centralize clinical data together with multiple biological samples that are harmonized in terms of sampling, the post sampling process and storage; ii) to identify new molecular markers for the diagnosis, prognosis and possibly the predictive response to pancreatic cancer surgery and or chemotherapy.DiscussionThe BACAP cohort is a unique prospective biological clinical database that provides the opportunity to identify correlations between the presence/expression of a broad panel of biomarkers (DNA, RNA, miRNA, proteins, etc.), epidemiological and social data, various clinical situations, various stages and the differentiation of the tumor, treatments and survival.Trial registrationClinicalTrials.gov Identifier: NCT02818829. Registration date: June 30, 2016.

Omega-3 Fatty Acids Prevent Early Pancreatic Carcinogenesis via Repression of the AKT Pathway.

Pancreatic cancer remains a daunting foe despite a vast number of accumulating molecular analyses regarding the mutation and expression status of a variety of genes. Indeed, most pancreatic cancer cases uniformly present with a mutation in the KRAS allele leading to enhanced RAS activation. Yet our understanding of the many epigenetic/environmental factors contributing to disease incidence and progression is waning. Epidemiologic data suggest that diet may be a key factor in pancreatic cancer development and potentially a means of chemoprevention at earlier stages. While diets high in ω3 fatty acids are typically associated with tumor suppression, diets high in ω6 fatty acids have been linked to increased tumor development. Thus, to better understand the contribution of these polyunsaturated fatty acids to pancreatic carcinogenesis, we modeled early stage disease by targeting mutant KRAS to the exocrine pancreas and administered diets rich in these fatty acids to assess tumor formation and altered cell-signaling pathways. We discovered that, consistent with previous reports, the ω3-enriched diet led to reduced lesion penetrance via repression of proliferation associated with reduced phosphorylated AKT (pAKT), whereas the ω6-enriched diet accelerated tumor formation. These data provide a plausible mechanism underlying previously observed effects of fatty acids and suggest that administration of ω3 fatty acids can reduce the pro-survival, pro-growth functions of pAKT. Indeed, counseling subjects at risk to increase their intake of foods containing higher amounts of ω3 fatty acids could aid in the prevention of pancreatic cancer.

Regulatory Role of G Protein-coupled Receptors in Pancreatic Cancer Development and Progression.

Pancreatic cancer is the fourth leading cause of cancer deaths with rising incidence and a high mortality rate. Smoking, psychological stress, diabetes, pancreatitis and alcohol abuse are known risk factors for pancreatic cancer. Targeting G protein-coupled receptor signaling for the prevention and therapy of pancreatic cancer. Review of published literature. All known risk factors for pancreatic cancer cause hyperactive cyclic adenosine monophosphate (cAMP) signaling via cancer stimulating Gαs-coupled beta-adrenergic and prostaglandin E2 receptors and/or by suppressing signaling via inhibitory Gαi-coupled GABAB-receptors. Psychological stress in mice promotes the progression of pancreatic cancer xenografts via stress neurotransmitter-mediated increase in betaadrenergic signaling and suppression of GABA while stress reduction inhibits pancreatic cancer by reversing these effects. The activation of Gαi-coupled GABAB-receptor signaling by treatment with GABA, inhibition of beta-adrenergic signaling by a beta-blocker and/or suppression of Gαs-coupled PGE2 receptor signaling by a cyclooxygenase (COX) inhibitor prevent the development and progression of pancreatic cancer induced in hamsters by carcinogenic nitrosamines and in transgenic mice. The re-purposing of cardiovascular therapeutics (beta-blockers, COX-2 inhibitors, Ca2+-channel blockers) that inhibit betaadrenergic and PGE2 signaling for pancreatic cancer intervention is problematic due to undesirable side effects under chronic treatment protocols. To avoid such side effects while effectively reducing excessive cAMP signaling, nutritional GABA supplementation or positive allosteric modulators (PAMs) of Gαi-coupled receptors (GABAB-Rs) currently in clinical trials for the treatment of addiction should be explored for pancreatic cancer intervention.

Abstract 4087: Investigating the novel role of Hippo signaling in mouse pancreas

Abstract Background: Large tumor suppressor kinase 1 and 2 are the core kinases of the Hippo signaling pathway, and play critical roles in regulating cell growth and organ size during animal development. Inactivation of the Hippo signaling pathway has been demonstrated to initiate tumor development in certain organs. However, the function of Lats1&amp;2 in the pancreas is still elusive. Methods and results: To investigate the function of Lats1&amp;2 in the pancreas, we generated mice with adult pancreatic acinar cell-specific deletion of Lats1&amp;2 genes. Interestingly, instead of enlarging of the pancreas or pancreatic tumorigenesis, the deletion of Lats1&amp;2 genes in pancreatic acinar cells resulted in severe inflammation of the pancreas. To further examine the mechanisms, we took advantage of a Rosa26 reporter to trace individual Lats1&amp;2 null cells in vivo. We found that the loss of Lats1&amp;2 did not affect cell growth directly but activated pancreatic stellate cells. This was followed by immune cell infiltration and acinar-to-ductal metaplasia in Lats1&amp;2 null pancreas. Our RNA seq data revealed several cytokines and chemokine genes, such as ctgf, spp1, cxcl12, cxcl16, were gradually unregulated with time in Lats1&amp;2 null pancreas before immune cell infiltration. Finally, we revealed the phenotype of Lats1&amp;2 DKO mouse was in a YAP1/TAZ-dependent manner. Conclusion and significance: In our present study, our data suggested that deletion of the Lats1&amp;2 genes in acinar cells caused pancreatitis through activation of pancreatic stellate cells directly. Our study discovered a new mechanism of the inflammatory response initiated by pancreatic epithelial cells and regulated by the Hippo signaling pathway, which is likely to be useful for the identification of new strategies for controlling pancreatic inflammation and prevention of pancreatic cancer. Citation Format: Ming Gao, Jun Liu, Francis E. Sharkey, Howard C. Crawford, Randy L. Johnson, Yidong Chen, Pei Wang. Investigating the novel role of Hippo signaling in mouse pancreas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4087.

Nimesulide inhibits proliferation and induces apoptosis of pancreatic cancer cells by enhancing expression of PTEN

Pancreatic cancer is the fourth leading cause of cancer-associated cases of mortality worldwide. Prostaglandin-endoperoxide synthase 2 (COX-2) is considered a therapeutic target for prevention of pancreatic cancer. Nimesulide, a selective COX-2 inhibitor, can induce cell apoptosis, resulting in an anti-cancer effect. However, the mechanism underlying this effect remains to be elucidated. The present study aimed to evaluate the effects of nimesulide on proliferation of PANC-1 cells using an MTT assay. Apoptosis was evaluated by DNA laddering and Annexin V-fluorescein isothiocyanate/propidium iodide-stained flow cytometry. Furthermore, western blot analysis was used to elucidate the mechanism underlying nimesulide treatment in PANC-1 cells. It was determined that proliferation of PANC-1 cells was inhibited by nimesulide in a dose-dependent manner. Nimesulide promoted apoptosis of PANC-1 cells. Western blot analysis demonstrated that nimesulide increased expression of cleaved caspase-3 and apoptosis regulator Bax (Bcl-2 associated protein X), and decreased the expression of pro-caspase-3 and apoptosis regulator Bcl-2 (B-cell lymphoma 2). Furthermore, nimesulide enhanced expression of phosphatase and tensin homolog (PTEN), and decreased the expression level of COX-2 and vascular endothelial growth factor. In summary, the results of the present study demonstrated that nimesulide could induce apoptosis and inhibit growth of PANC-1 cells by enhancing the expression of PTEN, which indicates the potential of nimesulide to prevent tumor angiogenesis.

Abstract A05: Investigating mechanisms of obesity-mediated pancreatic cancer progression

Abstract Genetically engineered mouse models (GEMMs) that faithfully recapitulate the genetics and histology of human tumors are an underutilized tool to understand how modifiable risk factors influence tumor development. Prospective cohort studies have shown that obesity is associated with an increased risk of developing pancreatic cancer, more advanced disease at diagnosis, and worse survival, though the precise mechanisms behind which obesity contributes to cancer progression remain elusive. We crossed mice harboring loss-of-function mutations in the leptin gene (ob/ob) with Pdx1-Cre; LSL-KrasG12D (KC) mice predisposed to initiate pancreatic cancers. KC; ob/ob mice are obese and exhibit markedly shortened survival (~4 months vs. ~1 year), increased primary tumor burden, and enhanced progression to adenocarcinoma compared to nonobese KC mice. Interestingly, early correction of leptin deficiency using an adeno-associated virus (AAV)-based approach induces rapid normalization of body weight and hyperglycemia and completely prevents the emergence of enhanced tumor burden. In contrast, late leptin restoration following tumor progression does not impact survival. These data suggest a causal and reversible role for obesity in early pancreatic cancer progression. Furthermore, by evaluating the degree by which alternative interventions phenocopy the effects of leptin restoration, we have developed a model to rapidly interrogate mechanisms of obesity-mediated tumor progression. As a proof of principle, we have tested the ability of immunomodulatory (aspirin) and antidiabetic (metformin) agents, observed to impact pancreatic cancer risk and survival in human cohorts, to intercept cancer progression in this model. Finally, combined molecular and biochemical analyses of tumors reveal increased immune cell activation and fibrosis in KC; ob/ob mice compared to nonobese KC and KC; p53 mutant mice and provide specific molecular targets to evaluate for pancreatic cancer therapy and prevention. Citation Format: Mandar Deepak Muzumdar, Kimberly Judith Dorans, Katherine Minjee Chung, Arjun Bhutkar, Charles Fuchs, Tyler Jacks. Investigating mechanisms of obesity-mediated pancreatic cancer progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A05.

Metabolome analysis for pancreatic cancer risk in nested case-control study: Japan Public Health Center-based prospective Study.

Discovery of a high‐risk group for pancreatic cancer is important for prevention of pancreatic cancer. The present study was conducted as a nested case‐control study including 170 pancreatic cancer cases and 340 matched controls of our population‐based cohort study involving 30 239 subjects who answered a baseline questionnaire and supplied blood samples. Twelve targeted metabolites were quantitatively analyzed by gas chromatography/tandem mass spectrometry. Odds ratios (OR) and their corresponding 95% confidence intervals (CI) were calculated using conditional logistic regression models. Statistically significant P‐value was defined as P < .05. Increasing 1,5‐anhydro‐d‐glucitol (1,5‐AG) levels were associated with a decreasing trend in pancreatic cancer risk (OR of quartile 4 [Q4], 0.50; 95% CI, 0.27‐0.93; P = .02). Increasing methionine levels were also associated with an increasing trend of pancreatic cancer risk (OR of Q4, 1.79; 95% CI, 0.94‐3.40: P = .03). Additional adjustment for potential confounders attenuated the observed associations of 1,5‐AG and methionine (P for trend = .06 and .07, respectively). Comparing subjects diagnosed in the first 0‐6 years, higher levels of 1,5‐AG, asparagine, tyrosine and uric acid showed a decreasing trend for pancreatic cancer risk (P for trend = .04, .04, .04 and .02, respectively), even after adjustment for potential confounders. We found that the 12 target metabolites were not associated with pancreatic cancer risk. However, metabolic changes in the subjects diagnosed in the first 0‐6 years showed a similar tendency to our previous reports. These results might suggest that these metabolites are useful for early detection but not for prediction of pancreatic cancer.

The advanced glycation end-product Nϵ -carboxymethyllysine promotes progression of pancreatic cancer: implications for diabetes-associated risk and its prevention.

Diabetes is an established risk factor for pancreatic cancer (PaC), together with obesity, a Western diet, and tobacco smoking. The common mechanistic link might be the accumulation of advanced glycation end-products (AGEs), which characterizes all of the above disease conditions and unhealthy habits. Surprisingly, however, the role of AGEs in PaC has not been examined yet, despite the evidence of a tumour-promoting role of receptor for advanced glycation end-products (RAGE), the receptor for AGEs. Here, we tested the hypothesis that AGEs promote PaC through RAGE activation. To this end, we investigated the effects of the AGE Nϵ -carboxymethyllysine (CML) in human pancreatic ductal adenocarcinoma (PDA) cell lines and in a mouse model of Kras-driven PaC interbred with a bioluminescent model of proliferation. Tumour growth was monitored in vivo by bioluminescence imaging and confirmed by histology. CML promoted PDA cell growth and RAGE expression, in a concentration-dependent and time-dependent manner, and activated downstream tumourigenic signalling pathways. These effects were counteracted by RAGE antagonist peptide (RAP). Exogenous AGE administration to PaC-prone mice induced RAGE upregulation in pancreatic intraepithelial neoplasias (PanINs) and markedly accelerated progression to invasive PaC. At 11 weeks of age (6 weeks of CML treatment), PaC was observed in eight of 11 (72.7%) CML-treated versus one of 11 (9.1%) vehicle-treated [control (Ctr)] mice. RAP delayed PanIN development in Ctr mice but failed to prevent PaC promotion in CML-treated mice, probably because of competition with soluble RAGE for binding to AGEs and/or compensatory upregulation of the RAGE homologue CD166/ activated leukocyte cell adhesion molecule, which also favoured tumour spread. These findings indicate that AGEs modulate the development and progression of PaC through receptor-mediated mechanisms, and might be responsible for the additional risk conferred by diabetes and other conditions characterized by increased AGE accumulation. Finally, our data suggest that an AGE reduction strategy, instead of RAGE inhibition, might be suitable for the risk management and prevention of PaC. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.