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1.
Clin Cancer Res ; 21(8): 1944-50, 2015 Apr 15.
Article in English | MEDLINE | ID: mdl-25623214

ABSTRACT

PURPOSE: The median survival following surgical resection of pancreatic ductal adenocarcinoma (PDAC) is currently <20 months. However, survival ≥10 years is achieved by a small subset of patients who are defined as very long-term survivors (VLTS). The goal of this study was to determine whether specific genetic alterations in resected PDACs determined very long-term survival. EXPERIMENTAL DESIGN: We sequenced the exomes of eight PDACs from patients who survived ≥10 years. On the basis of the results of the exomic analysis, targeted sequencing of selected genes was performed in a series of 27 additional PDACs from VLTSs. RESULTS: KRAS mutations were identified in 33 of 35 cancers (94%) from VLTSs and represented the most prevalent alteration in our cohort. TP53, SMAD4, and CDKN2A mutations occurred in 69%, 26%, and 17%, respectively. Mutations in RNF43, which have been previously associated with intraductal papillary mucinous neoplasms, were identified in four of the 35 cancers (11%). Taken together, our data show no difference in somatic mutations in carcinomas from VLTSs compared with available data from PDACs unselected for survival. Comparison of clinicopathologic features between VLTSs and a matching control group demonstrated that younger age, earlier stage, well/moderate grade of differentiation, and negative resection margins were associated with VLTS. However, more advanced stage, poor grade, or nodal disease did not preclude long-term survival. CONCLUSIONS: Our results suggest that in most patients, somatic mutations in commonly mutated genes are unlikely to be the primary determinant of very long-term survival following surgical resection of PDAC.


Subject(s)
Mutation , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/mortality , Adult , Aged , Aged, 80 and over , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/mortality , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/surgery , Case-Control Studies , Exome , Female , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Mutation Rate , Neoplasm Grading , Neoplasm Staging , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/surgery , Pancreatic Neoplasms/therapy , Prognosis , Tumor Burden
2.
Lab Invest ; 95(1): 43-55, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25347153

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a dismal prognosis. However, while most patients die within the first year of diagnosis, very rarely, a few patients can survive for >10 years. Better understanding the molecular characteristics of the pancreatic adenocarcinomas from these very-long-term survivors (VLTS) may provide clues for personalized medicine and improve current pancreatic cancer treatment. To extend our previous investigation, we examined the proteomes of individual pancreas tumor tissues from a group of VLTS patients (survival ≥10 years) and short-term survival patients (STS, survival <14 months). With a given analytical sensitivity, the protein profile of each pancreatic tumor tissue was compared to reveal the proteome alterations that may be associated with pancreatic cancer survival. Pathway analysis of the differential proteins identified suggested that MYC, IGF1R and p53 were the top three upstream regulators for the STS-associated proteins, and VEGFA, APOE and TGFß-1 were the top three upstream regulators for the VLTS-associated proteins. Immunohistochemistry analysis using an independent cohort of 145 PDAC confirmed that the higher abundance of ribosomal protein S8 (RPS8) and prolargin (PRELP) were correlated with STS and VLTS, respectively. Multivariate Cox analysis indicated that 'High-RPS8 and Low-PRELP' was significantly associated with shorter survival time (HR=2.69, 95% CI 1.46-4.92, P=0.001). In addition, galectin-1, a previously identified protein with its abundance aversely associated with pancreatic cancer survival, was further evaluated for its significance in cancer-associated fibroblasts. Knockdown of galectin-1 in pancreatic cancer-associated fibroblasts dramatically reduced cell migration and invasion. The results from our study suggested that PRELP, LGALS1 and RPS8 might be significant prognostic factors, and RPS8 and LGALS1 could be potential therapeutic targets to improve pancreatic cancer survival if further validated.


Subject(s)
Adenocarcinoma/metabolism , Carcinoma, Pancreatic Ductal/metabolism , Neoplasm Proteins/metabolism , Pancreatic Neoplasms/metabolism , Survival Analysis , Adenocarcinoma/surgery , Carcinoma, Pancreatic Ductal/surgery , Cell Line, Tumor , Female , Humans , Male , Middle Aged , Neoplasm Proteins/genetics , Pancreatic Neoplasms/surgery , Proteomics
3.
Cancer Biol Ther ; 13(10): 899-907, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22785208

ABSTRACT

The overall 5 year survival rate for pancreatic ductal adenocarcinoma (i.e., PDAC) is a dismal 5%, although patients that have undergone surgical resection have a somewhat better survival rate of up to 20%. Very long-term survivors of PDAC (defined as patients with ≥ 10 year survival following apparently curative resection), on the other hand, are considerably less frequent. The molecular characteristics of very long-term survivors (VLTS) are poorly understood, but might provide novel insights into prognostication for this disease. In this study, a panel of five VLTS and stage-matched short-term survivors (STS, defined as disease-specific mortality within 14 months of resection) were identified, and quantitative proteomics was applied to comparatively profile tumor tissues from both cohorts. Differentially expressed proteins were identified in cancers from VLTS vs. STS patients. Specifically, the expression of galectin-1 was 2-fold lower in VLTS compared with STS tumors. Validation studies were performed by immunohistochemistry (IHC) in two additional cohorts of resected PDAC, including: 1) an independent cohort of VLTS and 2) a panel of sporadic PDAC with a considerable range of overall survival following surgery. Immunolabeling analysis confirmed that significantly lower expression of stromal galectin-1 was associated with VLTS (p = 0.02) and also correlated with longer survival in sporadic, surgically-treated PDAC cases (hazard ratio = 4.9, p = 0.002). The results from this study provide new insights to better understand the role of galectin-1 in PDAC survival, and might be useful for rendering prognostic information, and developing more effective therapeutic strategies aimed at improving survival.


Subject(s)
Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/mortality , Galectin 1/genetics , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/mortality , Tumor Microenvironment/genetics , Carcinoma, Pancreatic Ductal/pathology , Disease Progression , Galectin 1/metabolism , Gene Expression Regulation, Neoplastic , Humans , Neoplasm Staging , Pancreatic Neoplasms/pathology , Prognosis , Stromal Cells/metabolism
4.
Cell Oncol (Dordr) ; 35(2): 119-26, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22351431

ABSTRACT

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with a 5-year survival rate of <5% and an average survival of only 6 months. Although advances have been made in understanding the pathogenesis of PDAC in the last decades, overall survival has not changed. Various clinicopathological and immunohistological variables have been associated with survival time but the exact role that these variables play in relation to survival is not clear. METHODS AND RESULTS: To examine how the variables affected survival independently, multivariate analysis was conducted in a study group of 78 pancreatic ductal adenocarcinomas. The analysis included clinicopathological parameters and protein expression examined by immunohistochemistry of p53, Smad4, Axl, ALDH, MSH2, MSH6, MLH1 and PMS2. Lymph node ratio <0.2 (p = 0.004), tumor free resection margins (p = 0.044) and Smad4 expression (p = 0.004) were the only independent prognostic variables in the multivariate analysis. Expression of the other proteins examined was not significantly related to survival. CONCLUSIONS: Discrepancies with other studies in this regard are likely due to differences in quantification of immunohistochemical staining and the lack of multivariate analysis. It underscores the importance to standardize the methods used for the application of immunohistochemistry in prognostic studies.


Subject(s)
Carcinoma, Pancreatic Ductal/diagnosis , Carcinoma, Pancreatic Ductal/pathology , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/pathology , Smad4 Protein/metabolism , Adult , Aged , Aldehyde Dehydrogenase 1 Family , Carcinoma, Pancreatic Ductal/enzymology , Female , Humans , Immunohistochemistry , Isoenzymes/metabolism , Kaplan-Meier Estimate , Lymph Nodes/pathology , Male , Middle Aged , Multivariate Analysis , Neoplasm Staging , Pancreatic Neoplasms/enzymology , Prognosis , Retinal Dehydrogenase/metabolism , Tumor Suppressor Protein p53/metabolism
5.
Hum Pathol ; 43(3): 457-61, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21992816

ABSTRACT

Hereditary diffuse gastric cancer is an autosomal dominant cancer syndrome characterized by highly penetrant diffuse gastric cancer. It is caused by germ line mutations in CDH1, encoding the cell-cell adhesion protein E-cadherin. Pancreatic ductal adenocarcinoma is one of the most dismal malignancies in humans. Although absent E-cadherin expression in pancreatic ductal adenocarcinoma is related to a higher tumor grade and a worse prognosis, there have been no reports of pancreatic ductal adenocarcinoma associated with hereditary diffuse gastric cancer. Here, we describe a patient with hereditary diffuse gastric cancer who was subsequently diagnosed with pancreatic ductal adenocarcinoma. To investigate if the previously identified CDH1 germ line mutation initiated pancreatic ductal adenocarcinoma development, we performed mutational and proteomic analyses. We conclude that the pancreatic ductal adenocarcinoma did not occur in the context of the germ line CDH1 mutation but rather appeared as a sporadic event. Immunohistochemistry ultimately proved to be the most valuable tool of investigation as persistent CDH1 staining in the pancreatic ductal adenocarcinoma unequivocally revealed E-cadherin expression.


Subject(s)
Adenocarcinoma/pathology , Carcinoma, Pancreatic Ductal/pathology , Pancreatic Neoplasms/pathology , Stomach Neoplasms/pathology , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Antigens, CD , Cadherins/genetics , Cadherins/metabolism , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/metabolism , DNA Mutational Analysis , Fatal Outcome , Gastrectomy , Germ-Line Mutation , Humans , Male , Middle Aged , Neoplasm Recurrence, Local , Neoplasms, Multiple Primary , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Polymorphism, Single Nucleotide , Proteomics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins p21(ras) , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , ras Proteins/genetics , ras Proteins/metabolism
6.
Neoplasia ; 13(10): 923-30, 2011 Oct.
Article in English | MEDLINE | ID: mdl-22028618

ABSTRACT

Ligand-dependent activation of the Hedgehog (Hh) signaling pathway has been implicated in both tumor initiation and metastasis of pancreatic ductal adenocarcinoma (PDAC). Prior studies in genetically engineered mouse models (GEMMs) have assessed the role of Hh signaling by cell autonomous expression of a constitutively active Gli2 within epithelial cells. On the contrary, aberrant pathway reactivation in the human exocrine pancreas occurs principally as a consequence of Sonic Hh ligand (Shh) overexpression from epithelial cells. To recapitulate the cognate pathophysiology of Hh signaling observed in the human pancreas, we examined GEMM where Hh ligand is conditionally overexpressed within the mature exocrine pancreas using a tamoxifen-inducible Elastase-Cre promoter (Ela-CreERT2;LSL-mShh). We also facilitated potential cell autonomous epithelial responsiveness to secreted Hh ligand by generating compound transgenic mice with concomitant expression of the Hh receptor Smoothened (Ela-CreERT2;LSL-mShh;LSL-mSmo). Of interest, none of these mice developed intraductal precursor lesions or PDAC during the follow-up period of up to 12 months after tamoxifen induction. Instead, all animals demonstrated marked expansion of stromal cells, consistent with the previously described epithelial-to-stromal paracrine Hh signaling. Hh responsiveness was mirrored by the expression of primary cilia within the expanded mesenchymal compartment and the absence within mature acinar cells. In the absence of cooperating mutations, Hh ligand overexpression in the mature exocrine pancreas is insufficient to induce neoplasia, even when epithelial cells coexpress the Smo receptor. This autochthonous model serves as a platform for studying epithelial stromal interactions in pancreatic carcinogenesis.


Subject(s)
Hedgehog Proteins/metabolism , Pancreas/metabolism , Stromal Cells/metabolism , Acinar Cells/metabolism , Acinar Cells/pathology , Animals , Cell Proliferation , Estrogen Antagonists/pharmacology , Female , Genetic Engineering/methods , Hedgehog Proteins/genetics , Humans , Immunoblotting , Immunohistochemistry , Insulin/metabolism , Keratins/metabolism , Male , Metaplasia , Mice , Mice, Transgenic , Microscopy, Confocal , Pancreas/drug effects , Pancreas/pathology , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Smoothened Receptor , Stromal Cells/pathology , Tamoxifen/pharmacology , Tubulin/metabolism
7.
Cancer Biol Ther ; 12(7): 598-609, 2011 Oct 01.
Article in English | MEDLINE | ID: mdl-21768779

ABSTRACT

Pancreatic cancer is one of the most lethal of human malignancies, and potent therapeutic options are lacking. Inhibition of cell cycle progression through pharmacological blockade of cyclin-dependent kinases (CDK) has been suggested as a potential treatment option for human cancers with deregulated cell cycle control. Dinaciclib (SCH727965) is a novel small molecule multi-CDK inhibitor with low nanomolar potency against CDK1, CDK2, CDK5 and CDK9 that has shown favorable toxicity and efficacy in preliminary mouse experiments, and has been well tolerated in Phase I clinical trials. In the current study, the therapeutic efficacy of SCH727965 on human pancreatic cancer cells was tested using in vitro and in vivo model systems. Treatment with SCH727965 significantly reduced in vitro cell growth, motility and colony formation in soft agar of MIAPaCa-2 and Pa20C cells. These phenotypic changes were accompanied by marked reduction of phosphorylation of Retinoblastoma (Rb) and reduced activation of RalA. Single agent therapy with SCH727965 (40 mg/kg i.p. twice weekly) for 4 weeks significantly reduced subcutaneous tumor growth in 10/10 (100%) of tested low-passage human pancreatic cancer xenografts. Treatment of low passage pancreatic cancer xenografts with a combination of SCH727965 and gemcitabine was significantly more effective than either agent alone. Gene Set Enrichment Analysis identified overrepresentation of the Notch and Transforming Growth Factor-ß (TGF-ß) signaling pathways in the xenografts least responsive to SCH727965 treatment. Treatment with the cyclin-dependent kinase inhibitor SCH727965 alone or in combination is a highly promising novel experimental therapeutic strategy against pancreatic cancer.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cyclin-Dependent Kinases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Pancreatic Neoplasms/drug therapy , Pyridinium Compounds/pharmacology , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cyclic N-Oxides , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Drug Resistance, Neoplasm/genetics , Humans , Indolizines , Male , Mice , Mice, Nude , Pancreatic Neoplasms/embryology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Phosphorylation/drug effects , Pyridinium Compounds/administration & dosage , Receptors, Notch/genetics , Receptors, Notch/metabolism , Retinoblastoma Protein/metabolism , Signal Transduction , Transforming Growth Factor beta/metabolism , Xenograft Model Antitumor Assays , ral GTP-Binding Proteins/metabolism , Gemcitabine
8.
Mod Pathol ; 24(9): 1229-36, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21572398

ABSTRACT

Acinar cell carcinoma is a rare non-ductal neoplasm of the pancreas with poorly defined molecular genetic features. Recently, biallelic inactivation of LKB1 was described in an acinar cell carcinoma of a Peutz-Jeghers patient carrying a heterozygous germline LKB1 mutation, and inhibition of mTOR signaling resulted in partial remission of the tumor. To explore the potential of mTOR inhibitors in sporadic acinar cell carcinoma, the LKB1 gene was investigated in five sporadic acinar cell carcinomas by sequence analysis, methylation analysis and mRNA expression. In addition, microsatellite instability and methylation of a number of tumor suppressor genes were investigated and KRAS, TP53, CDKN1A, SMAD4 and CTNNB1 were studied by mutation analysis and immunohistochemistry. No mutations, deletions or promoter hypermethylation of LKB1 were found in any of the sporadic acinar cell carcinomas, and mRNA expression of LKB1 was not altered. Amplifications at chromosome 20q and 19p were found in 100 and 80% of the cases, respectively. In addition, hypermethylation of one or more tumor suppressor genes was found in 80% of cases. One case harbored a TP53 mutation, and expression of SMAD4 and CTNNB1 was altered in one case each. No KRAS mutations or microsatellite instability were found. To conclude, no evidence for a role for LKB1 in tumorigenesis of sporadic pancreatic acinar cell carcinoma was found. However, copy number variations and hypermethylation were found in a majority of cases. Molecular pathways involved in acinar cell carcinoma-tumorigenesis differ from those involved in ductal pancreatic neoplasms. Further studies are needed to increase our understanding of molecular pathogenesis of acinar cell carcinoma, which may eventually result in development of new therapeutic targets.


Subject(s)
Carcinoma, Acinar Cell/genetics , Pancreatic Neoplasms/genetics , Protein Serine-Threonine Kinases/genetics , AMP-Activated Protein Kinase Kinases , DNA Methylation , DNA Mutational Analysis , DNA, Neoplasm/genetics , Gene Dosage , Humans , Immunohistochemistry , Microsatellite Instability , Multiplex Polymerase Chain Reaction
9.
Patholog Res Int ; 2011: 620601, 2011 Mar 27.
Article in English | MEDLINE | ID: mdl-21512581

ABSTRACT

Pancreatic cancer is an almost universally lethal disease and despite extensive research over the last decades, this has not changed significantly. Nevertheless, much progress has been made in understanding the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) suggesting that different therapeutic strategies based on these new insights are forthcoming. Increasing focus exists on designing the so-called targeted treatment strategies in which the genetic characteristics of a tumor guide therapy. In the past, the focus of research was on identifying the most frequently affected genes in PDAC, but with the complete sequencing of the pancreatic cancer genome the focus has shifted to defining the biological function that the altered genes play. In this paper we aimed to put the genetic alterations present in pancreatic cancer in the context of their role in signaling pathways. In addition, this paper provides an update of the recent advances made in the development of the targeted treatment approach in PDAC.

10.
Clin Cancer Res ; 17(9): 2799-806, 2011 May 01.
Article in English | MEDLINE | ID: mdl-21389100

ABSTRACT

PURPOSE: Investigate the efficacy and pharmacodynamic effects of MK-1775, a potent Wee1 inhibitor, in both monotherapy and in combination with gemcitabine (GEM) using a panel of p53-deficient and p53 wild-type human pancreatic cancer xenografts. EXPERIMENTAL DESIGN: Nine individual patient-derived pancreatic cancer xenografts (6 with p53-deficient and 3 with p53 wild-type status) from the PancXenoBank collection at Johns Hopkins were treated with MK-1775, GEM, or GEM followed 24 hour later by MK-1775, for 4 weeks. Tumor growth rate/regressions were calculated on day 28. Target modulation was assessed by Western blotting and immunohistochemistry. RESULTS: MK-1775 treatment led to the inhibition of Wee1 kinase and reduced inhibitory phosphorylation of its substrate Cdc2. MK-1775, when dosed with GEM, abrogated the checkpoint arrest to promote mitotic entry and facilitated tumor cell death as compared to control and GEM-treated tumors. MK-1775 monotherapy did not induce tumor regressions. However, the combination of GEM with MK-1775 produced robust antitumor activity and remarkably enhanced tumor regression response (4.01-fold) compared to GEM treatment in p53-deficient tumors. Tumor regrowth curves plotted after the drug treatment period suggest that the effect of the combination therapy is longer-lasting than that of GEM. None of the agents produced tumor regressions in p53 wild-type xenografts. CONCLUSIONS: These results indicate that MK-1775 selectively synergizes with GEM to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Pancreatic Ductal/drug therapy , Deoxycytidine/analogs & derivatives , Pancreatic Neoplasms/drug therapy , Pyrazoles/administration & dosage , Pyrimidines/administration & dosage , Animals , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Cell Cycle Proteins/antagonists & inhibitors , Cell Line, Tumor , Deoxycytidine/administration & dosage , Disease Progression , Drug Synergism , Female , Genes, p53 , Humans , Mice , Mice, Nude , Mutation/physiology , Neoplasms/drug therapy , Neoplasms/pathology , Nuclear Proteins/antagonists & inhibitors , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Pyrimidinones , Tumor Burden/drug effects , Xenograft Model Antitumor Assays , Gemcitabine
11.
Mol Cancer Ther ; 9(8): 2255-64, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20647339

ABSTRACT

Curcumin or diferuloylmethane is a yellow polyphenol extracted from the rhizome of turmeric (Curcuma longa). A large volume (several hundreds) of published reports has established the anticancer and chemopreventative properties of curcumin in preclinical models of every known major cancer type. Nevertheless, the clinical translation of curcumin has been significantly hampered due to its poor systemic bioavailability, which mandates that patients consume up to 8 to 10 g of the free drug orally each day to achieve detectable levels in circulation. We have engineered a polymeric nanoparticle encapsulated curcumin formulation (NanoCurc) that shows remarkably higher systemic bioavailability in plasma and tissues compared with free curcumin upon parenteral administration. In xenograft models of human pancreatic cancer established in athymic mice, administration of parenteral NanoCurc significantly inhibits primary tumor growth in both subcutaneous and orthotopic settings. The combination of parenteral NanoCurc with gemcitabine results in enhanced tumor growth inhibition versus either single agent, suggesting an additive therapeutic influence in vivo. Furthermore, this combination completely abrogates systemic metastases in orthotopic pancreatic cancer xenograft models. Tumor growth inhibition is accompanied by significant reduction in activation of nuclear factor-kappaB, as well as significant reduction in expression of matrix metalloproteinase-9 and cyclin D1, in xenografts treated with NanoCurc and gemcitabine. NanoCurc is a promising new formulation that is able to overcome a major impediment for the clinical translation of curcumin to cancer patients by improving systemic bioavailability, and by extension, therapeutic efficacy.


Subject(s)
Curcumin/administration & dosage , Curcumin/therapeutic use , Nanoparticles/administration & dosage , Neoplasm Metastasis/prevention & control , Pancreatic Neoplasms/drug therapy , Polymers/administration & dosage , Xenograft Model Antitumor Assays , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biological Availability , Cell Line, Tumor , Cell Proliferation/drug effects , Curcumin/pharmacology , Cyclin D1/metabolism , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Disease Models, Animal , Down-Regulation/drug effects , Drug Synergism , Humans , Matrix Metalloproteinase 9/metabolism , Mice , NF-kappa B/metabolism , Neoplasm Metastasis/pathology , Pancreatic Neoplasms/enzymology , Pancreatic Neoplasms/pathology , Subcutaneous Tissue/drug effects , Gemcitabine
12.
Arch Pathol Lab Med ; 133(3): 375-81, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19260743

ABSTRACT

CONTEXT: Pancreatic cancer has a poor prognosis with a 5-year survival of less than 5%. Early detection is at present the only way to improve this outlook. This review focuses on the recent advances in our understanding of pancreatic carcinogenesis, the scientific evidence for a multistaged tumor progression, and the role genetically engineered mouse models can play in recapitulating the natural course and biology of human disease. OBJECTIVES: To illustrate the stepwise tumor progression of pancreatic cancer and genetic alterations within the different stages of progression and to review the findings made with genetically engineered mouse models concerning pancreatic carcinogenesis. DATA SOURCES: A review of recent literature on pancreatic tumorigenesis and genetically engineered mouse models. CONCLUSIONS: Pancreatic cancer develops through stepwise tumor progression in which preinvasive stages, called pancreatic intraepithelial neoplasia, precede invasive pancreatic cancer. Genetic alterations in oncogenes and tumor suppressor genes underlying pancreatic cancer are also found in pancreatic intraepithelial neoplasia. These mutations accumulate during progression through the consecutive stages of pancreatic intraepithelial neoplasia lesions. Also in genetically engineered mouse models of pancreatic ductal adenocarcinoma, tumorigenesis occurs through stepwise progression via consecutive mouse pancreatic intraepithelial neoplasia, and these models provide important tools for clinical applications. Nevertheless differences between mice and men still remain.


Subject(s)
Adenocarcinoma/genetics , Carcinoma in Situ/genetics , Pancreatic Neoplasms/genetics , Adenocarcinoma/diagnosis , Animals , Carcinoma in Situ/diagnosis , Disease Models, Animal , Disease Progression , Humans , Mice , Mice, Transgenic , Pancreatic Neoplasms/diagnosis , Prognosis
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