Pancreatic Precursor Lesions Research Articles

Eflornithine (DFMO) prevents progression of pancreatic cancer by modulating ornithine decarboxylase signaling.

Ornithine decarboxylase (ODC) is the key rate-limiting enzyme in the polyamine synthesis pathway and it is overexpressed in a variety of cancers. We found that polyamine synthesis and modulation of ODC signaling occurs at early stages of pancreatic precursor lesions and increases as the tumor progresses in Kras-activated p48(Cre/+)-LSL-Kras(G12D/+) mice. Interest in use of the ODC inhibitor eflornithine (DFMO) as a cancer chemopreventive agent has increased in recent years since ODC was shown to be transactivated by the c-myc oncogene and to cooperate with the ras oncogene in malignant transformation of epithelial tissues. We tested the effects of DFMO on pancreatic intraepithelial neoplasias (PanIN) and their progression to pancreatic ductal adenocarcinoma (PDAC) in genetically engineered Kras mice. The Kras(G12D/+) mice fed DFMO at 0.1% and 0.2% in the diet showed a significant inhibition (P < 0.0001) of PDAC incidence compared with mice fed control diet. Pancreatic tumor weights were decreased by 31% to 43% (P < 0.03-0.001) with both doses of DFMO. DFMO at 0.1% and 0.2% caused a significant suppression (27% and 31%; P < 0.02-0.004) of PanIN 3 lesions (carcinoma in situ). DFMO-treated pancreas exhibited modulated ODC pathway components along with decreased proliferation and increased expression of p21/p27 as compared with pancreatic tissues derived from mice fed control diet. In summary, our preclinical data indicate that DFMO has potential for chemoprevention of pancreatic cancer and should be evaluated in other PDAC models and in combination with other drugs in anticipation of future clinical trials.

The role of PAM4 in the management of pancreatic cancer: diagnosis, radioimmunodetection, and radioimmunotherapy.

PAM4, a new monoclonal antibody (MAb) known as clivatuzumab, is highly reactive with pancreatic cancer and precursor lesions. It is absent from the normal tissues and has limited reactivity with nonpancreatic cancer. The detailed characteristic of the PAM4 epitope is unknown but recent studies have shown that it is dependent on MUC1 glycosylation status. The limited PAM4 expression pattern makes it an attractive candidate for management of pancreatic adenocarcinoma. In addition, PAM4 is a serum biomarker for diagnosis of pancreatic cancer. Several different radiolabeled immunodiagnostic and immunotherapeutic agents of PAM4 have been developed and some are being evaluated in preclinical and/or clinical studies. The review will focus on PAM4 and its potential utility for the diagnosis, radioimmunodetection, and radioimmunotherapy of pancreatic cancer.

The microRNA-218 and ROBO-1 signaling axis correlates with the lymphatic metastasis of pancreatic cancer

Pancreatic cancer is known for its poor prognosis and early lymphatic metastasis is a notable characteristic. microRNAs (miRNAs) have been shown to be involved in the initiation and progression of pancreatic cancer. We, therefore, established a screening strategy to find miRNAs related to the lymphatic metastasis of pancreatic cancer and explored the target genes of miRNAs. miRNA array profiles were analyzed in tissue samples [pancreatic ductal adenocarcinoma (PDAC) and matched adjacent benign tissues (MAT)] and cell lines (BxPC-3-LN and BxPC-3). Combined analysis of profiling data from tissue samples and cell lines was used to identify miRNAs related to the lymphatic metastasis of pancreatic cancer. The expression levels of miRNAs were confirmed by real‑time reverse transcription PCR (RT-PCR) in tissue samples and cell lines. The correlation between miRNAs and clinicopathological characteristics was investigated. The expression features of miRNAs in pancreatic cancer, precursor lesions and metastatic lymph nodes were characterized by in situ hybridization (ISH). Predicted target genes of miRNAs were validated by RT-PCR and the protein levels of target genes were revealed by western blotting. Seventy and 63 miRNAs were differentially expressed in pancreatic cancer and BxPC-3-LN, compared to MAT and BxPC-3, respectively. Combined microarray analysis found 4 co-differentially expressed miRNAs (miRNA-663, miRNA-145, miRNA-218 and let-7) related to the lymphatic metastasis of pancreatic cancer. miRNA-218 was significantly downregulated in BxPC-3-LN (fold-change>10) and the expression levels of miRNA-218 were confirmed by RT-PCR. The group with lymph node metastasis and the elder group (age>64) showed lower expression of miRNA-218 (P=0.003 and 0.002), compared to patients without lymph nodes metastasis and patients in the younger group (age≤64), respectively. The expression of miRNA‑218 showed a decreasing trend from normal acinar/ductal epithelium, intraductal papillary mucinous neoplasm (IPMN), pancreatic cancer to metastatic lymph nodes by ISH. Among 8 predicted target genes of miRNA-218, rodent bone (ROBO-1) was confirmed to be upregulated in both mRNA and protein levels in pancreatic cancer. In conclusion, we established a screening strategy based on microarray results and found miRNA-218 to be a notable gene related to lymphatic metastasis of pancreatic cancer. Downregulation of miRNA-218 and upregulation of ROBO-1 were first demonstrated in pancreatic cancer. The miRNA-218 and ROBO-1 signaling axis may contribute to the lymphatic metastasis of pancreatic cancer.

A transposon-based tumor resection model of pancreatic ductal adenocarcinoma (PDAC) with extrahepatic distant metastases

A transposon-based tumor resection model of pancreatic ductal adenocarcinoma (PDAC) with extrahepatic distant metastases

Abstract 1076: Chemoprevention of pancreatic cancer by targeting Kras mutations for apoptosis.

Abstract Pancreatic cancer is often diagnosed at an advanced stage and has a poor prognosis. The overall survival rate is less than 4% at 5 years with most patients dying within one year. Therefore, more effective approaches to treat advanced pancreatic cancer and chemopreventive strategies are in urgent need. Recent reports of early dissemination in pancreatic cancer stress the need for early intervention. Activating mutations of the KRAS oncogene are possibly the single most common genetic abnormality in pancreatic cancer, present in ∼90%-95% of cases. In addition to its role in cancer progression, mutations of the KRAS gene are one of the earliest genetic abnormalities observed in pancreatic cancer, supporting its role as an initiating event for pancreatic cancer formation. Therefore, mutant KRAS gene or its gene product represents an obvious target for the prevention of pancreatic cancer. Unfortunately, direct inhibition of KRAS or its downstream effectors has been largely ineffective in treating pancreatic cancer in clinical trials. The ideas are to find an innovative approach to target KRAS. We recently proposed a new cancer chemoprevention approach SITEP (short-term intermittent therapy to eliminate premalignancy) to target the “drivers” of tumorigenesis to overcome the challenges in cancer chemoprevention. We demonstrated that a two-drug combination of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and a small molecule mimic of the mitochondrial protein Smac /DIABLO (Smac), through a synthetic lethal interaction, specifically targets mutant KRAS expressing premalignant cells for apoptosis without harming normal cells. We further showed that short-term, intermittent in vivo treatment with TRAIL and Smac mimic induced apoptosis in tumor cells and reduced tumor burden in a murine model of Kras-induced lung cancer. In this study, we examined whether targeting KRAS mutant cells for apoptosis in pancreatic precursor lesions (e.g., PanINs) by TRAIL and Smac mimic would be an effective approach for pancreatic cancer chemoprevention. We showed that constitutive expression of mutant KRAS led to the activation of downstream signaling events in the immortalized human pancreatic normal epithelial (HPNE) cells, including phosphorylation of ERK and AKT. TRAIL and Smac mimic treatment showed that control cells are resistant to either TRAIL, or Smac mimic, or TRAIL and Smac mimic combination, and expression of KRAS mutant sensitized cells to the combination of TRAIL and Smac mimic. Short term treatment of Pdx1-Kras mice showed that TRAIL and Smac mimic induced significant apoptosis in abnormal pancreatic ductal cells and reduced number of PanINs. We conclude that targeting oncogenic KRAS signaling pathways in precursor lesions by TRAIL and Smac mimic may prove useful in developing chemoprevention against pancreatic cancer. Citation Format: Oksana Zagorodna, Shaoyi Huang, Huamin Wang, Xiangwei Wu. Chemoprevention of pancreatic cancer by targeting Kras mutations for apoptosis. [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 1076. doi:10.1158/1538-7445.AM2013-1076

Loss of Raf-1 kinase inhibitor protein (RKIP) is strongly associated with high-grade tumor budding and correlates with an aggressive phenotype in pancreatic ductal adenocarcinoma (PDAC)

BackgroundRaf-1 kinase inhibitor protein (RKIP) has emerged as a significant metastatic suppressor in a variety of human cancers and is known to inhibit Ras/Raf/MEK/ERK signaling. By suppressing the activation of the NFkB/SNAIL circuit, RKIP can regulate the induction of epithelial-mesenchymal transition (EMT). The aim of this study was to evaluate RKIP expression and to determine its association with clinicopathological features, including EMT in form of tumor budding in pancreatic ductal adenocarcinoma (PDAC).MethodsStaining for RKIP was performed on a multipunch Tissue Microarray (TMA) of 114 well-characterized PDACs with clinico-pathological, follow-up and adjuvant therapy information. RKIP-expression was assessed separately in the main tumor body and in the tumor buds. Another 3 TMAs containing normal pancreatic tissue, precursor lesions (Pancreatic Intraepithelial Neoplasia, PanINs) and matched lymph node metastases were stained in parallel. Cut-off values were calculated by receiver operating characteristic (ROC) curve analysis.ResultsWe found a significant progressive loss of RKIP expression between normal pancreatic ductal epithelia (average: 74%), precursor lesions (PanINs; average: 37%), PDAC (average 20%) and lymph node metastases (average 8%, p < 0.0001). RKIP expression was significantly lower in tumor buds (average: 6%) compared to the main tumor body (average 20%; p < 0.005). RKIP loss in the tumor body was marginally associated with advanced T-stage (p = 0.0599) as well as high-grade peritumoral (p = 0.0048) and intratumoral budding (p = 0.0373). RKIP loss in the buds showed a clear association with advanced T stage (p = 0.0089).ConclusionsThe progressive loss of RKIP seems to play a major role in the neoplastic transformation of pancreas, correlates with aggressive features in PDAC and is associated with the presence of EMT in form of tumor budding.

AGR2 Is a Novel Surface Antigen That Promotes the Dissemination of Pancreatic Cancer Cells through Regulation of Cathepsins B and D

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers largely due to disseminated disease at the time of presentation. Here, we investigated the role and mechanism of action of the metastasis-associated protein anterior gradient 2 (AGR2) in the pathogenesis of pancreatic cancer. AGR2 was induced in all sporadic and familial pancreatic intraepithelial precursor lesions (PanIN), PDACs, circulating tumor cells, and metastases studied. Confocal microscopy and flow cytometric analyses indicated that AGR2 localized to the endoplasmic reticulum (ER) and the external surface of tumor cells. Furthermore, induction of AGR2 in tumor cells regulated the expression of several ER chaperones (PDI, CALU, RCN1), proteins of the ubiquitin-proteasome degradation pathway (HIP2, PSMB2, PSMA3, PSMC3, and PSMB4), and lysosomal proteases [cathepsin B (CTSB) and cathepsin D (CTSD)], in addition to promoting the secretion of the precursor form pro-CTSD. Importantly, the invasiveness of pancreatic cancer cells was proportional to the level of AGR2 expression. Functional downstream targets of the proinvasive activity of AGR2 included CTSB and CTSD in vitro, and AGR2, CTSB, and CTSD were essential for the dissemination of pancreatic cancer cells in vivo. Taken together, the results suggest that AGR2 promotes dissemination of pancreatic cancer and that its cell surface targeting may permit new strategies for early detection as well as therapeutic management.

Pdx1 Expression in Pancreatic Precursor Lesions and Neoplasms

Pancreatic and duodenal homeobox (Pdx1) is a homeobox transcription factor required for the embryonic development of the pancreas. Pdx1 expression has been earlier identified in pancreatic ductal adenocarcinomas and endocrine neoplasms. This study characterizes Pdx1 protein expression in pancreatic precursor lesions and neoplasms, including pancreatic intraepithelial neoplasia (PanIN, n=32), intraductal papillary mucinous neoplasm (IPMN, n=88), mucinous cystic neoplasm (MCN, n=3), acinar cell carcinoma (ACC, n=8), pancreatic endocrine neoplasm (PEN, n=44), pancreatoblastoma (PB, n=1), solid pseudopapillary neoplasm (n=8), invasive ductal adenocarcinoma (n=67), and nondysplastic ductal epithelium. A mouse monoclonal antibody for Pdx1 was used to examine archived surgical pathology cases and tissue microarrays containing >655 tissue cores from more than 250 pancreatic specimens. Immunohistochemical labeling for Pdx1 was performed using standard methods and scored for percentage and intensity of nuclear labeling. Among non-neoplastic pancreatic tissues, Pdx1 nuclear protein was expressed in islet cells, cells of the centroacinar cell compartment, and non-neoplastic ductal epithelium. No expression of Pdx1 was seen in non-neoplastic acinar cells. Among pancreatic neoplasms, Pdx1 consistently labeled >50% of the tumor cells in 87.5% of ACC cases and 38.6% of PEN cases. Pdx1 expression was variable in invasive ductal adenocarcinoma and precursor lesions of ductal adenocarcinomas (PanIN, IPMN, and MCN). A single case of PB was examined and it showed Pdx1 in the acinar component, but no expression in squamoid nests. Solid pseudopapillary neoplasms did not express Pdx1. This study shows Pdx1 expression in precursor lesions of ductal adenocarcinomas, PEN, ACC, and a case of PB. In the immunohistochemical evaluation of neoplasms of the pancreas, Pdx1 expression is not a finding specific to PENs and ductal adenocarcinomas, but also occurs in precursor lesions (PanIN, IPMN, MCN) and other neoplasms of the pancreas.

Abstract B4: Calorie restriction prevents the development of pancreatic cancer in Kras; Pdx-1Cre mice

Abstract Pancreatic cancer progresses over many years, which offers the opportunity for early detection and prevention. Studies have identified elevated body mass index as a risk factor for pancreatic cancer. Lowering body weight by calorie restriction has long been associated with extended life expectancy and reduced tumor incidence in laboratory animals. Chronic and intermittent calorie restriction has a powerful protective effect against tumor development. This proposal addresses the hypothesis that intermittent calorie restriction will prevent the development and delay the progression of preneoplastic to neoplastic pancreatic lesions. The Kras; Pdx-1Cre mouse model provides an opportunity to study the efficacy of calorie restriction during the preinvasive state. At 8 weeks of age Kras; Pdx-1Cre mice were (1) fed ad libitum a purified diet based on the AIN93M recommendations (control), or (2) a modified AIN 93M diet in which mice were fed in one-week intervals at 50% of ad libitum intake followed by one week of feeding at 100% of ad libitum intake (intermittent group), or fed a modified AIN 93M diet at 75% of ad libitum intake. Food intake was measured daily and body weights were recorded weekly. At 44 weeks of age, mice were sacrificed and blood was obtained to measure serum insulin-like growth factor (IGF-1) and adiponectin; the pancreases were evaluated histologically for PanIn lesions and pancreatic ductal adenocarcinoma (PDA). Control mice gained more weight than restricted groups (p&amp;lt;0.05). Food intake was greater in the control group compared to the restricted groups; there were no differences in food intake between intermittent and chronic calorie restricted mice. The incidences of PanIn 2 and PanIn 3 lesions were significantly reduced in calorie-restricted mice (n = 15) (p&amp;lt; 0.001) compared to ad libitium fed mice (n = 12). Intermittent calorie restriction suppressed PanIn 2 and PanIn 3 lesions to a greater extent than chronic calorie restriction (P&amp;lt;0.01). Seventy-three percent of the ad libitum fed mice had Pan-In 2 and PanIn 3 lesions, whereas 27% and 40 % of the intermittent and chronic calorie restricted mice, respectively, had PanIn 2 and PanIn 3 lesions. PDA was identified in 27% of the ad libitum fed mice but not in the calorie-restricted groups. Serum IGF-1 concentrations of the intermittent (523±35.9 pg/ml) and chronic calorie restricted mice (407.8±33.1 pg/ml) were significantly less (P&amp;lt;0.05) than the ad libitum fed mice (590.0±33.5 pg/ml). Chronic calorie restriction reduced serum IGF-1 levels to a greater extent than intermittent restriction (P&amp;lt;0.05). Serum adiponectin concentrations increased significantly in intermittent (4.94 ± 0.293 ng/nl) and chronic (4.86 ± 0.297 ng/ml) calorie restricted mice compared with the ad libitum fed mice (3.52±0.422 ng/ml). In summary, this is the first study to show that chronic and intermittent calorie restriction delays the progression of pancreatic precursor lesions to PDA and that intermittent calorie restriction has a greater beneficial effect than chronic restriction. Citation Information: Cancer Prev Res 2011;4(10 Suppl):B4.

MicroRNA expression profiles in pancreatic cystic tumors.

e14579 Background: Short non-coding microRNAs (miRNAs) play a role in post-transcriptional gene regulation and can contribute to cancer development and progression. Expression profiles can distinguish between normal pancreas, chronic pancreatitis and pancreatic adenocarcinoma (PDAC) and may be able to correlate with disease progression from non-invasive precursor lesions to PDAC. We aimed to investigate the global miRNA expression profiles in pancreatic benign-cystic-tumours (BCT) compared with PDAC and carcinoma-ex-IPMN (CEI). Methods: Microarray analysis was conducted on 43 formalin-fixed paraffin-embedded (FFPE) pancreatic tumour surgical resection samples. These included 20 BCT, 9 CEI and 14 PDACs. The total RNA including the miRNA was isolated from the FFPE slides. Samples were analyzed with the Geniom Realtime Analyzer (febit gmbh, Germany) using the Geniom Biochip MPEA Homo sapiens. The probes are specific for all major mature miRNAs and miRNA* sequences in Sanger miRBase (version 13.0). Differential expression analysis was performed. We compared: BCT vs. CEI; BCT vs. PDAC, and CEI vs. PDAC. Certain miRNAs of interest were further investigated using quantitative real-time reverse-transcriptase polymerase chain reaction (RT- PCR). Results: There was a poor correlation in the intensity values between the BCT and PDAC groups. This led us to identify 20 significantly deregulated miRNAs in PDAC when compared to BCT. There were another 54 miRNAs found to be deregulated when we compared BCT to CEI and CEI to PDAC. Benign tumour subgroups were also analysed. Conclusions: There appear to be unique miRNA expression profiles in pancreatic cystic tumours and precursor lesions. In addition, 20 miRNAs have been identified which may be specific to PDAC. We aim to identify miRNAs for use as clinical biomarkers. No significant financial relationships to disclose.

β-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice

Cellular plasticity in adult organs is involved in both regeneration and carcinogenesis. WT mouse acinar cells rapidly regenerate following injury that mimics acute pancreatitis, a process characterized by transient reactivation of pathways involved in embryonic pancreatic development. In contrast, such injury promotes the development of pancreatic ductal adenocarcinoma (PDA) precursor lesions in mice expressing a constitutively active form of the GTPase, Kras, in the exocrine pancreas. The molecular environment that mediates acinar regeneration versus the development of PDA precursor lesions is poorly understood. Here, we used genetically engineered mice to demonstrate that mutant Kras promotes acinar-to-ductal metaplasia (ADM) and pancreatic cancer precursor lesion formation by blocking acinar regeneration following acute pancreatitis. Our results indicate that beta-catenin is required for efficient acinar regeneration. In addition, canonical beta-catenin signaling, a pathway known to regulate embryonic acinar development, is activated following acute pancreatitis. This regeneration-associated activation of beta-catenin signaling was not observed during the initiation of Kras-induced acinar-to-ductal reprogramming. Furthermore, stabilized beta-catenin signaling antagonized the ability of Kras to reprogram acini into PDA preneoplastic precursors. Therefore, these results suggest that beta-catenin signaling is a critical determinant of acinar plasticity and that it is inhibited during Kras-induced fate decisions that specify PDA precursors, highlighting the importance of temporal regulation of embryonic signaling pathways in the development of neoplastic cell fates.

The Expression Pattern of PDX-1, SHH, Patched and Gli-1 Is Associated with Pathological and Clinical Features in Human Pancreatic Cancer

Background and Aims: Pancreatic cancer cells have been shown to possess stem-cell-like properties, especially by reactivating embryonic transcription factors involved in tissue differentiation. We therefore investigated if and to what extent developmental genes of the human pancreas are expressed in pancreatic ductal adenocarcinomas and precursor lesions, pancreatic intraepithelial neoplasia (PanIN), and if this correlates or predicts response to treatment and overall survival. Material and Methods: Invasive ductal adenocarcinomas of the pancreas [UICC pT3pN0 (n = 13) vs. pT3pN1 (n = 25)] and tumors after neoadjuvant chemotherapy [5-fluorouracil (FU)/folic-acid and gemcitabine; UICC ypNO (n = 7) vs. ypN1 (n = 6)] resected between 1997 and 2003 were characterized histochemically and immunohistochemically [pancreas duodenum homeobox 1 (PDX-1), Sonic hedgehog protein (SHH), Patched (Ptc) and Gli-1]. Gene distribution was compared with morphological patterns of the pancreatic carcinoma and PanIN as well as with peritumorous reactions of normal pancreas. Results: The overall expression of PDX-1, SHH, Ptc and Gli-1 was low, but showed a distinctive and topographic linkage inside pancreatic carcinomas as well as inside PanlNs. Additionally, a topographic and significant association of these markers with nodal status (PDX-1, Ptc, Gli-1), tumor size (PDX-1, Gli-1) and R status (PDX-1) was found. After stratification with the strongest outcome predictor, grading, survival analysis revealed that Ptc expression in grade 2 and PDX-1 expression in grade 3 carcinomas are independent survival factors. Conclusions: Markers of pancreas development are reexpressed in invasive ductal adenocarcinomas and their expression is essentially associated with general clinical and pathological features such as survival Or nodal Status.

Reduction of pp32 expression in poorly differentiated pancreatic ductal adenocarcinomas and intraductal papillary mucinous neoplasms with moderate dysplasia

Nuclear phosphoprotein 32 (pp32) inhibits K-ras induced transformation in experimental models. pp32 mRNA expression correlates with differentiation status in breast and prostate cancers. In this study, we evaluated pp32 protein expression in relation to the differentiation status of pancreatic ductal adenocarcinomas and precursor lesions of the pancreatic cancers. pp32 expression showed strong nuclear staining in normal pancreatic acini and ducts. The intensity of this staining was maintained in pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms with mild dysplasia, well-differentiated adenocarcinomas, and in a subset of moderately differentiated adenocarcinomas. pp32 staining was absent or reduced in poorly differentiated tumors and in intraductal papillary mucinous neoplasms with moderate dysplasia. We validated pp32 expression by a second technique, immunoblot analysis of lysates from resected pancreatic ductal adenocarcinomas and pancreatic cancer cell lines. The well-differentiated pancreatic cancer cell line HPAC expressed high amounts of pp32, as compared to the poorly differentiated pancreatic cancer cell lines MiaPaCa2, Pl19, and Pl21 cells. Artificial introduction of pp32 expression into a poorly differentiated cell line, MiaPaCa2, caused an increase in G1 arrest compared to control cells. On the basis of this study and previous functional work that shows pp32 can inhibit K-ras transformation, we propose that reduction in pp32 expression levels may be a critical event in the progression of pancreatic tumorigenesis in an aggressive subset of pancreatic ductal adenocarcinomas.

Pancreatic Expression database: a generic model for the organization, integration and mining of complex cancer datasets

BackgroundPancreatic cancer is the 5th leading cause of cancer death in both males and females. In recent years, a wealth of gene and protein expression studies have been published broadening our understanding of pancreatic cancer biology. Due to the explosive growth in publicly available data from multiple different sources it is becoming increasingly difficult for individual researchers to integrate these into their current research programmes. The Pancreatic Expression database, a generic web-based system, is aiming to close this gap by providing the research community with an open access tool, not only to mine currently available pancreatic cancer data sets but also to include their own data in the database.DescriptionCurrently, the database holds 32 datasets comprising 7636 gene expression measurements extracted from 20 different published gene or protein expression studies from various pancreatic cancer types, pancreatic precursor lesions (PanINs) and chronic pancreatitis. The pancreatic data are stored in a data management system based on the BioMart technology alongside the human genome gene and protein annotations, sequence, homologue, SNP and antibody data. Interrogation of the database can be achieved through both a web-based query interface and through web services using combined criteria from pancreatic (disease stages, regulation, differential expression, expression, platform technology, publication) and/or public data (antibodies, genomic region, gene-related accessions, ontology, expression patterns, multi-species comparisons, protein data, SNPs). Thus, our database enables connections between otherwise disparate data sources and allows relatively simple navigation between all data types and annotations.ConclusionThe database structure and content provides a powerful and high-speed data-mining tool for cancer research. It can be used for target discovery i.e. of biomarkers from body fluids, identification and analysis of genes associated with the progression of cancer, cross-platform meta-analysis, SNP selection for pancreatic cancer association studies, cancer gene promoter analysis as well as mining cancer ontology information. The data model is generic and can be easily extended and applied to other types of cancer. The database is available online with no restrictions for the scientific community at .

Multifocal neoplastic precursor lesions associated with lobular atrophy of the pancreas in patients having a strong family history of pancreatic cancer.

We screened 116 patients with a strong family history of pancreatic cancer using a combination of endoscopic ultrasound and computed tomography. Ten of these patients underwent surgical resection at our institution, providing an opportunity to define the morphology of pancreatic precursor lesions in patients with a strong family history of pancreatic cancer. Eight of the 10 pancreata were available and these were entirely submitted for histologic examination. The number of pancreatic intraepithelial neoplasia (PanIN) lesions and intraductal papillary mucinous neoplasms (IPMNs) were compared with age-matched controls. Parenchymal changes were defined. Selected precursor neoplasms from 6 pancreata were microdissected and analyzed for KRAS gene mutations. PanINs were significantly more common in the 8 cases (mean of 10.7% of the duct profiles, range 1.0% to 27.3%) than in the controls (mean 1.9%, range 0% to 9.2%, P<0.01). Different KRAS gene mutations were identified in separately microdissected precursor lesions in 2 of 6 cases. IPMNs were identified in 4 of the 8 cases, including 2 pancreata each having 2 distinct IPMNs. Both the IPMNs and the PanINs, even the low-grade PanIN-1 lesions, were associated with lobular parenchymal atrophy. Some individuals with a strong family history of pancreatic cancer develop multifocal, noninvasive epithelial precursor lesions of the pancreas. PanINs and IPMNs produce obstructive lobular atrophy, and this atrophy is likely the source of the chronic pancreatitis-like changes seen in these patients. The multifocal nature of familial pancreatic neoplasia suggests that surveillance of these patients is warranted after partial pancreatectomy.

Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study

Now that more than two decades have passed since the first reports of intraductal papillary-mucinous neoplasms (IPMNs), it has become clear that IPMN consists of a spectrum of neoplasms with both morphological and immunohistochemical variations. At a meeting of international experts on pancreatic precursor lesions held in 2003, it was agreed that a consensus classification of IPMN subtypes should be established to enable a more detailed analysis of the clinicopathological significance of the variations. Based on our experience and on information from the literature, we selected representative histological examples of IPMNs and defined a consensus nomenclature and criteria for classifying variants as distinctive IPMN subtypes including gastric type, intestinal type, pancreatobiliary type, and oncocytic type. These definitions can be used for further analyses of the clinicopathological significance of the variations of IPMN.

Bi-allelic inactivation of the BRCA2 gene occurs after K-ras mutations in pancreatic precursor lesions from patients with germiline BRCA2 mutations

Bi-allelic inactivation of the BRCA2 gene occurs after K-ras mutations in pancreatic precursor lesions from patients with germiline BRCA2 mutations