Development Of Pancreatic Carcinoma Research Articles

Autoimmune pancreatitis as arisk factor of pancreatic cancer.

Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis that presents clinically with obstructive icterus, histologically with infiltration of pancreatic parenchyma by inflammatory cells leading to chronic inflammation with fibrosis, and therapeutically with good response to corticosteroid therapy. Clinically, it may resemble malignant disease, making diagnosis difficult and requiring a multidisciplinary team (gastroenterologist, endoscopist, radiologist, surgeon, pathologist). Two types of AIP are distinguished. Type 1 is associated with elevated serum immunoglobulin IgG4 and systemic manifestations (IgG4 related diseases). Type 2, without IgG4 elevation, is typically associated with the occurrence of idiopathic inflammatory bowel disease, especially ulcerative colitis. The first line treatment of symptomatic AIP is corticotherapy with an initial dose of 0.6-1 mg/kg/day for the first 2-4 weeks, followed by a gradual de-escalation to prevent frequent relapses. Chronic inflammation, or chronic pancreatitis, is a well-known risk factor for the development of malignancy. The association between carcinogenesis and AIP is widely discussed, but due to the rarity of the disease and a small number of studies, risk estimates vary. Pancreatic carcinoma development is most common in patients with type 1 autoimmune pancreatitis. However, it has been observed that the incidence of extra-pancreatic cancer (stomach, lung, and prostate cancer) is often equal or even higher. It is also considered that AIP may develop from coexisting malignancies as a paraneoplastic syndrome. Screening of patients with AIP for potential carcinogenesis should not be overlooked. The aim of this review article is to point out a rare (autoimmune) form of chronic pancreatitis with the necessity of follow up with regard to the potential risk of malignancy.

Genetic features of pathogenesis in pancreatic adenocarcinomas

To date, the problem of pancreatic cancer is the high mortality rate. The IARC predicts that pancreatic cancer will become the second leading cause of cancer deaths by 2030. Because patients usually present with advanced disease and respond poorly to broad-spectrum chemotherapy, overall survival is only 10%. This highlights the urgent clinical need to identify new therapeutic approaches for patients with pancreatic adeno-carcinoma. Objective: To identify patterns of genetic changes in the development of pancreatic carcinoma and to consider pathogenesis of this process. Materials and methods: data from multi-genetic panels of Memorial Sloan Kettering Cancer Center, articles of the journal Cancers, and PubMed re-source articles. Results: the work has uncovered major and alternative pathways in the pathogenesis of pancreatic cancer, established hypotheses of similar pathways in tumors of other localizations and the presence of fundamental pathogenetic links in pathogenesis, indicating the universality of certain genetic changes in tumor growth.

Neuraminidase-1: A Sialidase Involved in the Development of Cancers and Metabolic Diseases.

Simple SummaryCancers and metabolic diseases represent a leading cause of death in both developing and developed countries. Thus, new diagnostic and prognostic targets are urgently required. NEU-1 is a sialidase which regulates many membrane receptors through desialylation which results in either the activation or inhibition of the receptors. At the plasma membrane, NEU-1 is the catalytic subunit of the elastin receptor complex. This sialidase is not only required for the biological effects that are mediated by the elastin-derived peptides on several metabolic disorders, but NEU-1 is also involved in the development of various cancers. The aim of this review is to describe the role of NEU-1 in several metabolic diseases and cancers and to show that this protein could be considered in some cases as a link between these two physiopathological contexts. Consequently, NEU-1 could represent a common pharmacological target to treat putative metabolic syndrome-associated cancers like colorectal, hepatocellular and postmenopausal breast cancer.Sialidases or neuraminidases (NEU) are glycosidases which cleave terminal sialic acid residues from glycoproteins, glycolipids and oligosaccharides. Four types of mammalian sialidases, which are encoded by different genes, have been described with distinct substrate specificity and subcellular localization: NEU-1, NEU-2, NEU-3 and NEU-4. Among them, NEU-1 regulates many membrane receptors through desialylation which results in either the activation or inhibition of these receptors. At the plasma membrane, NEU-1 also associates with the elastin-binding protein and the carboxypeptidase protective protein/cathepsin A to form the elastin receptor complex. The activation of NEU-1 is required for elastogenesis and signal transduction through this receptor, and this is responsible for the biological effects that are mediated by the elastin-derived peptides (EDP) on obesity, insulin resistance and non-alcoholic fatty liver diseases. Furthermore, NEU-1 expression is upregulated in hepatocellular cancer at the mRNA and protein levels in patients, and this sialidase regulates the hepatocellular cancer cells’ proliferation and migration. The implication of NEU-1 in other cancer types has also been shown notably in the development of pancreatic carcinoma and breast cancer. Altogether, these data indicate that NEU-1 plays a key role not only in metabolic disorders, but also in the development of several cancers which make NEU-1 a pharmacological target of high potential in these physiopathological contexts.

Abstract C41: Establishment of a novel mouse model of pancreatic squamous carcinoma

Abstract Pancreatic cancer is a lethal malignancy with the highest mortality rate among all cancers and a 5-year survival rate of 9% in the US. Among all subtypes of pancreatic cancers, the molecular mechanisms underlying the development of squamous carcinomas are not well understood. While pure squamous carcinoma makes up only 0.05-5% of all pancreatic cancers, it is very aggressive and leads to the worst prognosis among all pancreatic cancers. However, animal models to study the initiation and progression of pancreatic squamous carcinoma are lacking. Genetic studies have recently revealed the molecular signature of pancreatic cancers and identified the transcription factor p63 as a candidate that contributes to the development of pancreatic carcinomas. In one study (Bailey et al., Nature 2016;47-52), upregulation of the p63-mediated transcriptional network was reported. Another genome-wide analysis has identified a SNP in the p63 gene as a risk factor for the development of pancreatic cancers (Childs et al., Nat Genet 2015;911-6). Furthermore, it has been shown that expression of TAp63, an isoform of p63 with a tumor suppressor function, is frequently suppressed in pancreatic cancers (Bailey et al., Nature 2016;47-52). While p63 is rarely mutated in human cancers, ΔNp63α, the predominant isoform of p63 in epithelia, is overexpressed in a variety of human cancers of squamous cell origin. Notably, although p63 proteins are not expressed in normal pancreatic cells, they are expressed at high levels in areas of squamous differentiation of pancreatic cancers (Basturk et al., Modern Pathol 2005;1193-8). We hypothesize that aberrant expression of ΔNp63α in the pancreatic epithelia drives the tumorigenesis of pancreatic squamous carcinomas. To test this hypothesis, we have created transgenic (Tg) mice conditionally expressing ectopic ΔNp63α upon crossing with tissue/cell type-specific Cre-Tg mice in the presence of the K-rasG12D mutation (Hingorani et al., Cancer Cell 2003;437-50), a pancreatic cancer-promoting factor. Our data show that Pdx1Cre:KrasG12D:ΔNp63α-Tg mice develop pancreatic squamous carcinoma as determined by the cellular morphology and the shift of the expression of cytokeratin 8 (K8), a pan-pancreatic epithelial cell marker, into K5, a squamous epithelial cell marker. Interestingly, the absence of the K-ras mutation did not lead to the development of pancreatic tumors, indicating that de novo expression of ΔNp63α alone is not sufficient for the generation of pancreatic squamous carcinomas. None of the mice in our control cohort of the Pdx1Cre:KrasG12D:p53+/- genotype (Bardeesy et al., PNAS 2006;5947-52) developed pancreatic squamous carcinomas or showed p63 expression, emphasizing the functional differences between the two p53 family members. We aim to further characterize our novel animal model and determine the molecular mechanisms by which p63 contributes to the squamous pathogenesis of pancreatic cancer. Citation Format: Filipa Pinto, Tachira Pichardo, Adrien Leu, Makoto Senoo. Establishment of a novel mouse model of pancreatic squamous carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C41.

MicroRNA-383 suppresses pancreatic carcinoma development via inhibition of GAB1 expression.

Pancreatic carcinoma (PC) is a serious malignancy associated with high morbidity and mortality rates. Previous studies have identified various microRNAs (miRNAs) involved in the development of PC; however, the role of miR-383 still remains unclear. This study investigates the role of miR-383 in the malignant transformation of PC. Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was used to quantify miR-383 and Grb2 associated binding protein 1 (GAB1) RNA levels, and Western blot analysis was performed to measure protein expression. The ability of miR-383 to bind and regulate the expression of GAB1 was assessed using a Luciferase reporter assay. Cell Counting Kit-8 (CCK-8) experiments and flow cytometry analysis were used to assess cell proliferation and apoptosis, respectively. Down-regulation of miR-383 was associated with adverse clinical results and poor prognosis in PC patients. Mechanistically, miR-383 inhibited cell proliferation and promoted apoptosis of PANC-1 (human pancreatic cancer cell) cells. Our results show that miR-383 can act directly on GAB1 to inhibit its expression in PC. This downregulation of GAB1 limits cell proliferation and induced apoptosis of PANC-1 cells. MiR-383 suppresses tumor development and progression through the downregulation of GAB1 expression.

LncRNA TUSC7 suppresses pancreatic carcinoma progression by modulating miR-371a-5p expression.

Pancreatic carcinoma is one of the most common and lethal human malignancies worldwide. Long noncoding RNAs (lncRNAs) are a well-known type of nonprotein-coding transcripts implicated in cancer development and progression. Increasing evidence has indicated that lncRNA tumor suppressor candidate 7 (TUSC7) is a novel cancer suppressor gene in various cancers. Nevertheless, the function of TUSC7 in pancreatic carcinoma is urgent to be clarified. We found that TUSC7 was notably decreased in tissues and cell lines of pancreatic carcinoma. Moreover, the low expression of TUSC7 was correlated with advanced clinical grades and poorer overall survival. Our findings revealed that TUSC7 repressed cell proliferation, migration, invasion, epithelial-mesenchymal transition, and stemness whereas facilitated cell apoptosis of pancreatic carcinoma cells. Further investigations demonstrated that miR-371a-5p directly bound with TUSC7 and negatively regulated by TUSC7. MiR-371a-5p rescued the inhibitory effects of TUSC7 on the development of pancreatic carcinoma. We conclude that lncRNA TUSC7 suppresses pancreatic carcinoma progression by modulating miR-371a-5p expression, indicating an innovative therapeutic strategy for pancreatic carcinoma.

Identification of unique microRNAs associated with pancreatic cancer radioresistance using deep sequencing

Background: Pancreatic cancer is the most aggressive tumor type and is characterized by a poor prognosis. The main cause of treatment failure is the presence of tumor cells resistant to conventional therapies. MicroRNAs (miRNAs) play important roles in modulating the development of pancreatic carcinoma (PC). Methods: In this study, we established radioresistant cell lines from the commonly used human PC parental cell lines. We used high throughput sequencing to screen miRNA expression in both radioresistant and parental cell lines. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to confirm the results. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological processes (BPs) were performed to analyze gene set enrichment. Results: In total, 242 differentially expressed miRNAs were identified between these two groups. Compared with the parental line, SW1990-R exhibited with 97 upregulated and 145 downregulated miRNAs. qRT-PCR confirmed five upregulated (miR-497-5p, miR-146b-3p, miR-181a-3p, miR-33a-3p, and miR-32-5p) and five downregulated (miR-7-5p, miR-30b-5p, miR-181a-5p, miR-296-5p, and miR-216a-5p) miRNAs. GO and KEGG enrichment analyses revealed that some of the differentially expressed miRNAs regulated classical functions and pathways, including signal transduction, global and overview map, and immune system. Conclusions: Differential expression of miRNAs in relation to radioresistance suggests that various miRNAs may be predictive biomarkers or therapeutic targets in PC.

Regulation of intracellular zinc homeostasis: Role in occurrence and development of pancreatic carcinoma

Regulation of intracellular zinc homeostasis: Role in occurrence and development of pancreatic carcinoma

Expression of PTEN and KAI1 tumor suppressor genes in pancreatic carcinoma and its association with different pathological factors

Pancreatic carcinoma is a common cancer type with a poor prognosis. The aim of the present study was to examine the expression of tumor suppressor genes phosphatase and tensin homolog deleted in chromosome 10 (PTEN) and KAI1 in pancreatic carcinoma and its association with clinical pathological factors. A total of 50 hospitalized cases of pancreatic cancer including 28 males and 22 females aged 31–82 years were included in the present study. Ten cases of normal pancreatic tissue were obtained from cadavers and served as the controls. The pancreatic specimens were embedded in paraffin blocks and slides were prepared for immunohistochemical analysis to determine the expression of PTEN and KAI1 in normal pancreatic tissue and pancreatic carcinoma samples. The positive expression rate of PTEN in the normal pancreatic tissue was higher than that in pancreatic carcinoma (P<0.05), while the positive expression rate of KAI1 in the normal pancreatic tissue was lower than that in pancreatic carcinoma (P<0.05). Pathological factors such as clinical stage of disease, histological grade and the presence or absence of lymphatic metastasis significantly affected the expression of PTEN and KAI1 (P<0.05). In conclusion, the positive expression of PTEN and KAI1 in pancreatic carcinoma is closely associated with the development of pancreatic carcinoma.

Cell motility and spreading promoted by CEACAM6 through cyclin D1/CDK4 in human pancreatic carcinoma.

Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) belongs to the human carcino-embryonic antigen (CEA) family. Numerous lines of studies have indicated that altered expression of CEACAM6 may have a role in carcinogenesis and development. However, few studies have defined functional roles and mechanisms of action. In the present study, the relationship between clinical and pathological parameters was also analyzed. The relative CEACAM6 protein expression of pancreatic carcinoma was significantly higher than that in non-cancerous tissue. Different clinical stages and lymph node metastasis between groups were significantly different (P<0.05). We used siRNA and forced-expression in multiple cell lines to define the role of CEACAM6 in the regulation of proliferation of pancreatic carcinoma in vitro and in vivo. Knockdown of endogenous CEACAM6 decreased proliferation of BxPC-3 and SW1990 cells. These changes significantly reduced cyclin D1 and CDK4 protein levels. Conversely, overexpression of CEACAM6 in MIA PaCa-2 cells stimulated proliferation and increased cyclin D1 and CDK4 protein levels. Our results confirm that CEACAM6 promoted cell proliferation, and these changes were mediated by cyclin D1/CDK4. These observations contribute to our understanding of the important roles of CEACAM6 in pancreatic carcinoma development and progression and could be a promising molecular target for the development of new diagnostic and therapeutic strategies of pancreatic carcinoma.

Abstract PL04-01: Metabolic approaches to cancer prevention

Abstract It is well known that macronutrient intake and exercise influence cancer risk (1). They also have important metabolic effects because they determine energy balance at the whole organism level. There is accumulating evidence that the association between obesity and cancer risk may be attributable to the endocrine-metabolic consequences of chronic positive energy balance. Examples of candidate mediators of the effect of excess energy intake on risk of cancer are increased insulin levels and decreased adiponectin levels (2,3). Mechanistically, by increasing PI3K pathway activation (due to hyperinsulinemia) or decreasing AMPK activation (due to decreased adiponectin (4)) in various renewing epithelial cell populations at risk for transformation, these hormonal changes favor cell survival and proliferation over apoptosis. This increases the probability of survival of a clone bearing an oncogenic mutation, which in turn increases risk of subsequent ‘hits’ leading to full transformation. Recent population studies demonstrating these associations will be reviewed. Importantly, the effect of energy balance on cancer risk varies substantially with cancer type: for example, obesity is strongly associated with endometrial but not lung cancer, consistent with the view that optimizing metabolic risk factors may be insufficient to reduce cancer incidence in settings where carcinogen exposure is high. Furthermore, unexpected interactions between metabolic risk factors and prevention strategies have been observed: the prostate cancer prevention trial, for example, demonstrated that insulin secretion rate as reflected by c-peptide level is an important risk factor for high grade disease, but that this c-peptide-associated risk is specifically attenuated by finasteride (5). While there is considerable evidence that the hormonal consequences of positive energy balance lead to increased risk for many cancers, the possibility that high circulating levels of specific nutrient molecules may predispose to carcinogenesis or neoplastic progression is now receiving attention, and there is early evidence that branched chain amino acids (BCAA) may be important in this regard (6,7). BCAAs favor activation of mTOR, which increases proliferation as well as rate of oxidative phosphorylation (8), which in turn may increase oxidative DNA damage. Future laboratory and clinical research may identify key serum hormonal and metabolic analytes that are altered by effective prevention measures (and may even be the mediators of their effects), and these may serve as useful surrogate endpoints in clinical trials of proposed pharmacologic cancer prevention strategies, including metformin (9), as well as lifestyle and nutritional interventions. (1) Pollak M. Do cancer cells care if their host is hungry? Cell Metab. 2009 9(5):401-3 (2) Bao Y et al. A prospective study of plasma adiponectin and pancreatic cancer risk in five US cohorts. J Natl Cancer Inst. 2013;105(2):95-103 (3) Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012;12(3):159-69 (4) Zakikhani M et al. The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase. Cancer Prev Res. 2008 1(5):369-75 (5) Neuhouser ML et al. Finasteride modifies the relation between serum C-peptide and prostate cancer risk: results from the Prostate Cancer Prevention Trial. Cancer Prev. Res. 2010 3(3):279-89 (6) Mayer J et al. Elevated BCAA are an early event in pancreatic carcinoma development. Nature Med., in press (7) Liu KA et al. Leucine supplementation differentially enhances pancreatic cancer growth in lean and overweight mice. Cancer Metab. 2014 31;2(1):6. (8) Morita M et al. mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation. Cell Metab. 2013;18(5):698-711. (9) Pollak M. Repurposing biguanides to target energy metabolism for cancer treatment. Nature Med. 2014 Jun;20(6):591-3. Citation Format: Michael N. Pollak. Metabolic approaches to cancer prevention. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr PL04-01.

Abstract 1362: Nuclear morphometry measures progressive atypia in the development of pancreatic carcinoma

Abstract Pancreatic lesions that are not clearly benign are often treated as malignant despite uncertainty in the true diagnosis due to the nearly universally fatal nature of pancreatic carcinoma (PC). Nuclear morphometry is a technique to quantify nuclear features too complex for the human eye to discern. We hypothesized that nuclear atypia can be quantified with morphometry in order to distinguish between chronic pancreatitis, IPMN, and PC. We retrospectively analyzed 14 specimens of chronic pancreatitis, 16 IPMN lesions, and 19 PC lesions. Clinicopathologic data were obtained. Nuclear morphometry determined overall atypia based on the average nuclear abnormality of 95 distinct nuclear features (a nuclear signature). For PC lesions, 5 nuclear features defined a classification score (CS) representing the proportion of aggressive nuclei in a given PC lesion. Statistical significance was determined with ANOVA and the Kruskal-Wallis test. The average age for all patients was 63 ± 15 years while 62% were male; there were no differences between the 3 groups. The follow up was approximately 4 years in all groups as well. The average nuclear atypia of chronic pancreatitis was 0.80, 0.99 for IPMN, and 1.08 for PC (P = 0.02). Importantly, based on 5 nuclear features, the CS for PC lesions that recurred was 87% while it was only 56% for those PC lesions that did recur (P = 0.04). The research describes a precise, accurate, and objective method to distinguish IPMN from PC. The CS and overall atypia score provides a method to not only objectively describe a given lesion, but it importantly describes where in the progression from benign to malignant lesion an unknown lesion exists. Clinically, this may be of great utility in risk stratifying unknown pancreatic lesions at the time of diagnosis or tissue biopsy. Citation Format: Evan S. Glazer, Kimberly A. Hill, Hao (Helen) Zhang, Peter Bartels, Joseph Watkins, David S. Alberts, Robert S. Krouse. Nuclear morphometry measures progressive atypia in the development of pancreatic carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1362. doi:10.1158/1538-7445.AM2014-1362

Su1501 Morphological Changes of Intraductal Papillary Mucinous Neoplasm of the Pancreas Are Not Enough for Indicators of the Development of Pancreatic Carcinoma During Follow Up

G A A b st ra ct s receiver operator characteristics curve. The factors associated with malignant IPMNs were determined by logistic regression analysis for BD-IPMN and MD-IPMN separately. Diagnostic accuracy of the determined predictors of malignancy was calculated. Results: Total 241 patients consisted of 202 BD-IPMN and 39 MD-IPMN were included. Cutoff values of cyst size, MPD diameter, and nodule size were determined for BD-IPMN as 30 mm, 6 mm, and 10 mm, respectively, whereas for MD-IPMN as 24 mm, 12 mm and 10 mm, respectively. For BD-IPMN, nodule size ≥10 mm (OR=176.97, p<0.0001) and positive cytology (OR127.14, p<0.0001) were significantly associated with malignant IPMN (Table 1). For MD-IPMN, nodule size ≥10 mm (OR=16.07, p=0.002) and positive cytology (OR=160.00, p<0.0001) were significantly associated with malignant IPMN. Sensitivity, specificity, and overall diagnostic accuracy of nodule size ≥10 mm alone were 59%, 98%, 90%, respectively, and positive cytology alone were 83%, 96%, 94%, respectively (Table 2). In combination of nodule size ≥10 mm and/or positive cytology, sensitivity, specificity, and overall diagnostic accuracy were 96%, 95%, and 95%, respectively. Conclusions: The common predictors, nodule size ≥10 mm and positive cytology, were demonstrated to be appropriate for both BD-IPMN and MD-IPMN. In combination of nodule size ≥10 mm and/or positive cytology as predictors of malignancy, diagnostic accuracy was shown to be excellent. Table 1. Factors associated with malignant IPMN determined by logistic regression analysis.

Pancreatic carcinoma development: new etiological and pathogenetic evidence

Pancreatic adenocarcinoma (PAC) is a very aggressive cancer with a poor prognosis. To date, the causes and pathogenetic mechanisms involved in the development of this malignancy remain largely unknown. Therefore, additional studies are required to improve our knowledge of the events that occur during the process of pancreatic carcinogenesis. The purpose of this article is to describe the most recent evidence, concerning the possible risk factors and mechanisms that may contribute to determine the development of PAC, as well as models, such as the tensegrity model, that may explain this complex process. Available studies suggest that approximately 15-20% of human malignancies are somehow associated with chronic infection. Some epidemiological research has shown that some infectious agents represent risk factors for PAC. In particular, several reports showed that the infection caused by some micro-organisms, including helicobacter pylori and some bacterial species of oral microbiota, as well as by viral agents, such as human immunodeficiency virus (HIV), and hepatitis B (HBV) and C (HCV) viruses, is associated with an increased probability of developing PAC. For the first time, observational studies and meta-analyses have suggested that HBV and HCV, two hepatotropic viruses with oncogenic properties, may be also risk factors for PAC. However, the small number of available reports, nearly all performed in Asian populations, limits their validity to these ethnic groups. Therefore, additional studies focusing on populations of different geographical areas and enrolling larger series of patients are required to confirm this association. Furthermore, an accurate description and a better understanding of the events and of the pathogenetic mechanisms involved in the process of pancreatic carcinogenesis, as proposed by the tensegrity model, might be a useful approach to effectively deal with this pathology.

Abstract 190: Sulindac inhibits pancreatic carcinogenesis in LSL-KrasG12D-LSL-Trp53R172H-Pdx-1-Cre mice by suppressing aldo-keto reductase family 1B10 (AKR1B10).

Abstract Sulindac inhibits carcinogenesis via the mechanism that appears beyond cyclooxygenase inhibition. Recently sulindac has been identified as competitive inhibitors of aldo-keto reductase family 1B10 (AKR1B10). AKR1B10 is involved in the process of carbonyls, farnesyl and geranylgeranyl as well as retinal metabolisms, and these metabolic activities are important to carcinogenesis. However, there is no evidence on if inhibition of pancreatic carcinogenesis by sulindac is via inhibition of AKR1B10 and protein prenylation (i.e., Kras protein). To determine the effect of sulindac on pancreatic carcinogenesis in LSL-KrasG12D-LSL-Trp53R172H-Pdx-1-Cre mice, five-week-old mice were fed with either AIN-93M diet or AIN-93M diet contained 200ppm sulindac (n=20 mice/group). Kaplan-Meier survival analysis with Log-Rank test was performed to analyze the effect of sulindac on animal survival from the development of pancreatic carcinoma. The results showed that average animal survival in LSL-KrasG12D-LSL-Trp53R172H-Pdx-1-Cre mice was 143.7 ± 8.8 days; and with the sulindac 200ppm treatment, animal survival significantly increased to 168.0 ± 8.8 days (p&amp;lt;0.005). Extensively histopathological analyses revealed that 90% of mice developed malignant pancreatic carcinomas, of which 10% invasive pancreatic adenocarcinoma had metastasis to liver and lymph nodes. With 200ppm sulindac treatment, incidence of pancreatic cancer and its metastasis were significantly reduced to 56% and 0%, respectively (P&amp;lt;0.01). Immunchemical analysis showed that sulindac treatment significantly decreased Ki-67-labeled cell proliferation, increased caspase-3-labeled cell apoptosis, and suppressed phosphorylated ERK1/2. In vitro mouse pancreatic carcinoma cells derived from the LSL-KrasG12D/+-LSL-Trp53R172/+-Pdx-1-Cre mice were further treated with sulindac and revealed that sulindac inhibited AKR1B10 enzyme activity, suppressed Kras and HDJ2 protein prenylation, and further inhibited phosphylation of C-raf, ERK1/2 and MEK1/2. Similar to sulindac treatment, siRNA-silencing AKR1B10 expression resulted in a significant reduction of Kras protein prenylation and its downstream signals. Our results demonstrate that sulindac inhibits pancreatic carcinogenesis, mainly via inhibition of kras protein prenylation and its activated signals by targeting AKR1B10. (supported NCI R01 CA164041) Citation Format: Jie Liao, Yeon Tae Chung, Haonan Li, Wanying Zhang, Guang-Yu Yang. Sulindac inhibits pancreatic carcinogenesis in LSL-KrasG12D-LSL-Trp53R172H-Pdx-1-Cre mice by suppressing aldo-keto reductase family 1B10 (AKR1B10). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 190. doi:10.1158/1538-7445.AM2013-190

PpENKGene Methylation Status in the Development of Pancreatic Carcinoma

Objective. To explore the association of hypermethylation of the proenkephalin gene (ppENK) with pancreatic carcinoma and to identify the effects of a demethylating agent on pancreatic cell lines. Method. Human pancreatic cancer tissues and five pancreatic carcinoma cell lines, as well as normal pancreatic tissue, were used. ppENK methylation status was detected by MS-PCR (methylation-specific PCR). Results. Methylation of ppENK was detected in 90.3% (28/31) of the human pancreatic carcinoma tissues but was not seen in normal pancreatic tissue. There was no correlation between the extent of methylation of ppENK and the clinicopathological features of the pancreatic carcinomas. Methylated ppENK was detected in all the pancreatic cancer cell lines and was associated with loss of mRNA expression in the pancreatic carcinoma cell lines and normal pancreatic tissue. After treatment with 5-aza-dC, methylated ppENK was not detected and the inhibition of ppENK mRNA expression was reversed. Conclusions. Inhibition of ppENK expression by a change in its methylation status plays an important role in pancreatic carcinogenesis. ppENK methylation is thus an important molecular event that distinguishes pancreatic carcinoma tissue from normal pancreatic tissue. Effects on cell growth, apoptosis, and the cell cycle may contribute to changes of ppENK methylation status.

Human Retinoblastoma Binding Protein 9, a Serine Hydrolase Implicated in Pancreatic Cancers

Human retinoblastoma binding protein 9 (RBBP9) is an interacting partner of the retinoblastoma susceptibility protein (Rb). RBBP9 is a tumor-associated protein required for pancreatic neoplasia, affects cell cycle control, and is involved in the TGF-β signalling pathway. Sequence analysis suggests that RBBP9 belongs to the α/β hydrolase superfamily of enzymes. The serine hydrolase activity of RBBP9 is required for development of pancreatic carcinomas in part by inhibiting TGF-β antiproliferative signaling through suppressing Smad2/3 phosphorylation. The crystal structure of human RBBP9 confirms the α/β hydrolase fold, with a six-stranded parallel β-sheet flanked by α helixes. The structure of RBBP9 resembles that of the YdeN protein from Bacillus subtilis, which is suggested to have carboxylesterase activity. RBBP9 contains a Ser75-His165-Asp138 catalytic triad, situated in a prominent pocket on the surface of the protein. The side chains of the LxCxE sequence motif that is important for interaction with Rb is mostly buried in the structure. Structure- function studies of RBBP9 suggest possible routes for novel cancer drug discovery programs.

Pancreatic cancer bears overexpression of neurotensin and neurotensin receptor subtype-1 and SR 48692 counteracts neurotensin induced cell proliferation in human pancreatic ductal carcinoma cell line PANC-1

The presence of neurotensin and neurotensin receptors has been demonstrated in human pancreatic carcinomas using autoradiography and Northern blot analysis. In vitro studies have reported that the neurotensin antagonist SR 48692 could inhibit the growth of MIA PaCa-2 cells in a neurotensin mediated fashion, and neurotensin could overcome this inhibition or stimulate proliferation. However, it is currently unknown whether such actions are exerted on PANC-1 cells. In addition, the immunolocation of neurotensin and neurotensin receptors is still unclear in human pancreatic ductal carcinoma tissues. Immunohistochemistry was applied to detect the distribution of neurotensin and neurotensin receptor subtype-1 in human pancreatic ductal carcinoma and normal pancreatic tissues. Furthermore, an in vitro study was carried out to test the pharmacological profile of neurotensin and SR 48692 in human pancreatic ductal carcinoma cell line PANC-1. Compared with normal pancreatic tissues, pancreatic ductal carcinoma tissues have higher neurotensin and neurotensin receptor subtype-1 expression rates. Pancreatic ductal carcinomas (32/40) bear the expression of both neurotensin and neurotensin receptor subtype-1. We observed that neurotensin (10⁻¹¹-10⁻⁷ M) significantly stimulated the proliferation of PANC-1 and SR 48692 (10⁻¹¹-10⁻⁷ M) alone had no effect on the growth of PANC-1 cells; however, SR 48692 (10⁻¹⁰-10⁻⁶ M) inhibited the stimulatory effect of neurotensin (10⁻⁹ M). Considering the overexpression of both neurotensin and neurotensin receptor subtype-1 in pancreatic ductal carcinomas, it could enable us to develop markers for pancreatic cancer diagnosis. As SR 48692 could inhibit neurotensin induced cell growth, neurotensin receptor subtype-1 may serve as a therapeutic target for the therapy of pancreatic carcinomas. Furthermore, our study indicates that the counteraction of neurotensin and neurotensin receptor subtype-1 regulates the genesis and development of pancreatic carcinomas.

Incidencia y características de las neoplasias quísticas pancreáticas

Cystic neoplasms (CN) of the pancreas represent 10% of cystic lesions and 1% of pancreatic tumors. Mucinous cystic neoplasm (MCN), serous cystadenoma (SC) and intraductal papillary mucinous neoplasm (IPMN) are cystic neoplasms and represent more than 90% of these types of lesion. Few series have been published on these lesions, especially in Spain. To evaluate the incidence, characteristics and survival of patients with cystic neoplasms attended in our hospital in the last 12 years. A retrospective analysis was carried out in all patients diagnosed with CN between January 1997 and December 2008. Diagnosis was made by abdominal computed tomography, pancreatic-magnetic resonance imaging and/or endoscopic ultrasonography. Sex, age, year of diagnosis, symptoms, tumoral location and size, type of surgery, pathology, and survival were evaluated. A total of 117 patients were analyzed. The mean age was 63±14 years and 56% were women. Eighty-eight patients had IPMN, 21 had SC and eight had MCN. Fifty-six per cent were diagnosed in the last 4 years, 42.7% were diagnosed as an incidental finding and 19% had a history of acute pancreatitis. The most frequent location was the pancreatic head (53%). The mean imaging size was 32mm. Surgical resection was performed in 69.2% of the patients. Twenty-three percent of the tumors were malignant, 30% were carcinoma in situ and 70% were invasive. Thirteen percent of the patients died; of these 93.3% had invasive carcinoma. Five-year survival was 94.7% in SC, 76% in IPMN and 60% in MCN. CN were mainly identified as incidental findings, although acute pancreatitis is another possible cause. The most frequent tumor in our environment is IPMN. Surgical treatment of IPMN and MCN, at the right moment, may be useful to prevent the development of pancreatic carcinoma.

Surgical Pancreatic Ductal Drainage for Chronic Pancreatitis

To assess the efficacy of surgical pancreatic ductal drainage for chronic pancreatitis, we analyzed short-term and long-term outcomes and postoperative pancreatic function. Thirty-two surgical pancreatic ductal drainages (17 Frey procedures, 15 Partington procedures) were performed for patients with pain or relapsing acute pancreatitis due to obstruction of the main pancreatic duct including pancreatolithiasis. The short-term outcomes (mortality 0%, morbidity 34%) and pain relief (89%) after surgery were acceptable. In long-term follow-up periods after surgery, two patients (6%) had relapsing acute pancreatitis and one of them required further surgical pancreatic ductal drainage. Two patients were dead of liver failure but there was no development of pancreatic carcinoma. Fifty percent of the patients developed pancreatic exocrine insufficiency. Ninety percent of the patients who had normal preoperative endocrine function did not develop diabetes mellitus. Surgical pancreatic ductal drainage was safe and excellent in pain relief and preventing acute pancreatitis. Therefore, surgical procedures should be evaluated for patients with chronic pancreatitis who are intractable by endoscopic interventions before deterioration of the pancreatic function.