Pathogenesis of pancreatic cancer: Lessons from animal models

Toxicologic Pathology

Volumn 42, Issue 1, 2014, Pages 217-228

  Murtaugh, L Charles ^a  

^a UNIVERSITY OF UTAH SCHOOL OF MEDICINE   (United States)

Author keywords

animal models; gastrointestinal system; genetically engineered mice.; pancreatic cancer

Indexed keywords

ACINAR CELL; ADVANCED CANCER; ARTICLE; CANCER DIAGNOSIS; CANCER MODEL; CANCER RISK; CARCINOGENESIS; CHEMOPROPHYLAXIS; EXOCRINE SECRETION; EXON; GENE DELETION; GENETIC DAMAGE; HIGH RISK PATIENT; HUMAN; INFLAMMATION; INTRON; MEDICAL RESEARCH; MOLECULAR MECHANICS; MOUSE MODEL; NONHUMAN; ONCOGENE; ONCOGENE K RAS; PANCREAS ADENOCARCINOMA; PHENOTYPE; PRIORITY JOURNAL; SYRIAN HAMSTER; TUMOR SUPPRESSOR GENE;

ANIMAL MODELS; GASTROINTESTINAL SYSTEM; GENETICALLY ENGINEERED MICE.; PANCREATIC CANCER;

ANIMALS; CARCINOMA, PANCREATIC DUCTAL; CRICETINAE; DISEASE MODELS, ANIMAL; HUMANS; MICE; PANCREATIC NEOPLASMS; PROTO-ONCOGENE PROTEINS P21(RAS); RISK FACTORS;

EID: 84892711349     PISSN: 01926233     EISSN: 15331601     Source Type: Journal    
DOI: 10.1177/0192623313508250     Document Type: Article

References (103)

1. Aguirre A. J., Bardeesy N., Sinha M., Lopez L., Tuveson D. A., Horner J., Redston M. S., DePinho R. A.. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 2003 ; 17: 3112-26
2. Almoguera C., Shibata D., Forrester K., Martin J., Arnheim N., Perucho M.. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988 ; 53: 549-54
3. Ardito C. M., Gruner B. M., Takeuchi K. K., Lubeseder-Martellato C., Teichmann N., Mazur P. K., Delgiorno K. E., Carpenter E. S., Halbrook C. J., Hall J. C., Pal D., Briel T., Herner A., Trajkovic-Arsic M., Sipos B., Liou G. Y., Storz P., Murray N. R., Threadgill D. W., Sibilia M., Washington M. K., Wilson C. L., Schmid R. M., Raines E. W., Crawford H. C., Siveke J. T.. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell. 2012 ; 22: 304-17
4. Bardeesy N., Aguirre A. J., Chu G. C., Cheng K. H., Lopez L. V., Hezel A. F., Feng B., Brennan C., Weissleder R., Mahmood U., Hanahan D., Redston M. S., Chin L., Depinho R. A.. Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc Natl Acad Sci USA. 2006 ; 103: 5947-52
5. Bardeesy N., Cheng K. H., Berger J. H., Chu G. C., Pahler J., Olson P., Hezel A. F., Horner J., Lauwers G. Y., Hanahan D., DePinho R. A.. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 2006 ; 20: 3130-46
6. Birt D. F., Salmasi S., Pour P. M.. Enhancement of experimental pancreatic cancer in Syrian golden hamsters by dietary fat. J Natl Cancer Inst. 1981 ; 67: 1327-32
7. Blaine S. A., Ray K. C., Anunobi R., Gannon M. A., Washington M. K., Means A. L.. Adult pancreatic acinar cells give rise to ducts but not endocrine cells in response to growth factor signaling. Development. 2010 ; 137: 2289-96
8. Bosetti C., Lucenteforte E., Silverman D. T., Petersen G., Bracci P. M., Ji B. T., Negri E., Li D., Risch H. A., Olson S. H., Gallinger S., Miller A. B., Bueno-de-Mesquita H. B., Talamini R., Polesel J., Ghadirian P., Baghurst P. A., Zatonski W., Fontham E., Bamlet W. R., Holly E. A., Bertuccio P., Gao Y. T., Hassan M., Yu H., Kurtz R. C., Cotterchio M., Su J., Maisonneuve P., Duell E. J., Boffetta P., La Vecchia C.. Cigarette smoking and pancreatic cancer: An analysis from the International Pancreatic Cancer Case-control Consortium (Panc4). Ann Oncol. 2012 ; 23: 1880-88
9. Brembeck F. H., Schreiber F. S., Deramaudt T. B., Craig L., Rhoades B., Swain G., Grippo P., Stoffers D. A., Silberg D. G., Rustgi A. K.. The mutant K-ras oncogene causes pancreatic periductal lymphocytic infiltration and gastric mucous neck cell hyperplasia in transgenic mice. Cancer Res. 2003 ; 63: 2005-9
10. Canto M. I., Harinck F., Hruban R. H., Offerhaus G. J., Poley J. W., Kamel I., Nio Y., Schulick R. S., Bassi C., Kluijt I., Levy M. J., Chak A., Fockens P., Goggins M., Bruno M.. International Cancer of the Pancreas Screening (CAPS) consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. 2013 ; 62: 339-47
11. Carriere C., Gore A. J., Norris A. M., Gunn J. R., Young A. L., Longnecker D. S., Korc M.. Deletion of Rb accelerates pancreatic carcinogenesis by oncogenic Kras and impairs senescence in premalignant lesions. Gastroenterology. 2011 ; 141: 1091-101
12. Carriere C., Young A. L., Gunn J. R., Longnecker D. S., Korc M.. Acute pancreatitis markedly accelerates pancreatic cancer progression in mice expressing oncogenic Kras. Biochem Biophys Res Commun. 2009 ; 382: 561-65
13. Clark C. E., Hingorani S. R., Mick R., Combs C., Tuveson D. A., Vonderheide R. H.. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 2007 ; 67: 9518-27
14. Cleveland M. H., Sawyer J. M., Afelik S., Jensen J., Leach S. D.. Exocrine ontogenies: On the development of pancreatic acinar, ductal and centroacinar cells. Semin Cell Dev Biol. 2012 ; 23: 711-19
15. Collins M. A., Bednar F., Zhang Y., Brisset J. C., Galban S., Galban C. J., Rakshit S., Flannagan K. S., Adsay N. V., Pasca di Magliano M.. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest. 2012 ; 122: 639-53
16. Collisson E. A., Sadanandam A., Olson P., Gibb W. J., Truitt M., Gu S., Cooc J., Weinkle J., Kim G. E., Jakkula L., Feiler H. S., Ko A. H., Olshen A. B., Danenberg K. L., Tempero M. A., Spellman P. T., Hanahan D., Gray J. W.. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med. 2011 ; 17: 500-3
17. Cook N., Olive K. P., Frese K., Tuveson D. A.. K-Ras-driven pancreatic cancer mouse model for anticancer inhibitor analyses. Methods Enzymol. 2008 ; 439: 73-85
18. Cruz-Monserrate Z., Abd-Elgaliel W. R., Grote T., Deng D., Ji B., Arumugam T., Wang H., Tung C. H., Logsdon C. D.. Detection of pancreatic cancer tumours and precursor lesions by cathepsin E activity in mouse models. Gut. 2012 ; 61: 1315-22
19. Daniluk J., Liu Y., Deng D., Chu J., Huang H., Gaiser S., Cruz-Monserrate Z., Wang H., Ji B., Logsdon C. D.. An NF-kappaB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice. J Clin Invest. 2012 ; 122: 1519-28
20. De La O J. P., Emerson L. L., Goodman J. L., Froebe S. C., Illum B. E., Curtis A. B., Murtaugh L. C. Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc Natl Acad Sci U S A. 2008 ; 105: 18907-12
21. De La O J. P., Murtaugh L. C. Notch and Kras in pancreatic cancer: At the crossroads of mutation, differentiation and signaling. Cell Cycle. 2009 ; 8: 1860-64
22. Desai B. M., Oliver-Krasinski J., De Leon D. D., Farzad C., Hong N., Leach S. D., Stoffers D. A.. Preexisting pancreatic acinar cells contribute to acinar cell, but not islet beta cell, regeneration. J Clin Invest. 2007 ; 117: 971-77
23. Dor Y., Brown J., Martinez O. I., Melton D. A.. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature. 2004 ; 429: 41-46
24. Duell E. J., Lucenteforte E., Olson S. H., Bracci P. M., Li D., Risch H. A., Silverman D. T., Ji B. T., Gallinger S., Holly E. A., Fontham E. H., Maisonneuve P., Bueno-de-Mesquita H. B., Ghadirian P., Kurtz R. C., Ludwig E., Yu H., Lowenfels A. B., Seminara D., Petersen G. M., La Vecchia C., Boffetta P.. Pancreatitis and pancreatic cancer risk: A pooled analysis in the International Pancreatic Cancer Case-control Consortium (PanC4). Ann Oncol. 2012 ; 23: 2964-70
25. Ekholm R., Zelander T., Edlund Y.. The ultrastructural organization of the rat exocrine pancreas. II. Centroacinar cells, intercalary and intralobular ducts. J Ultrastruct Res. 1962 ; 7: 73-83
26. Elashoff M., Matveyenko A. V., Gier B., Elashoff R., Butler P. C.. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011 ; 141: 150-56
27. Eser S., Messer M., Eser P., von Werder A., Seidler B., Bajbouj M., Vogelmann R., Meining A., von Burstin J., Algul H., Pagel P., Schnieke A. E., Esposito I., Schmid R. M., Schneider G., Saur D. In vivo diagnosis of murine pancreatic intraepithelial neoplasia and early-stage pancreatic cancer by molecular imaging. Proc Natl Acad Sci U S A. 2011 ; 108: 9945-50
28. Eser S., Reiff N., Messer M., Seidler B., Gottschalk K., Dobler M., Hieber M., Arbeiter A., Klein S., Kong B., Michalski C. W., Schlitter A. M., Esposito I., Kind A. J., Rad L., Schnieke A. E., Baccarini M., Alessi D. R., Rad R., Schmid R. M., Schneider G., Saur D.. Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell. 2013 ; 23: 406-20
29. Faca V. M., Song K. S., Wang H., Zhang Q., Krasnoselsky A. L., Newcomb L. F., Plentz R. R., Gurumurthy S., Redston M. S., Pitteri S. J., Pereira-Faca S. R., Ireton R. C., Katayama H., Glukhova V., Phanstiel D., Brenner D. E., Anderson M. A., Misek D., Scholler N., Urban N. D., Barnett M. J., Edelstein C., Goodman G. E., Thornquist M. D., McIntosh M. W., DePinho R. A., Bardeesy N., Hanash S. M.. A mouse to human search for plasma proteome changes associated with pancreatic tumor development. PLoS Med. 2008 ; 5: e123
30. Flandez M., Cendrowski J., Canamero M., Salas A., Del Pozo N., Schoonjans K., Real F. X. Nr5a2 heterozygosity sensitises to, and cooperates with, inflammation in KRasG12V-driven pancreatic tumourigenesis. Gut. 2013 ;:
31. Fukuda A., Wang S. C., Morris J. P. T., Folias A. E., Liou A., Kim G. E., Akira S., Boucher K. M., Firpo M. A., Mulvihill S. J., Hebrok M.. Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell. 2011 ; 19: 441-55
32. Funahashi H., Satake M., Dawson D., Huynh N. A., Reber H. A., Hines O. J., Eibl G.. Delayed progression of pancreatic intraepithelial neoplasia in a conditional Kras(G12D) mouse model by a selective cyclooxygenase-2 inhibitor. Cancer Res. 2007 ; 67: 7068-71
33. Gale E. A.. GLP-1-based therapies and the exocrine pancreas: More light, or just more heat?. Diabetes. 2012 ; 61: 986-88
34. Gier B., Matveyenko A. V., Kirakossian D., Dawson D., Dry S. M., Butler P. C. Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras(G12D) mouse model. Diabetes. 2012 ; 61: 1250-62
35. Granger A., Kushner J. A.. Cellular origins of beta-cell regeneration: A legacy view of historical controversies. J Intern Med. 2009 ; 266: 325-38
36. Greer J. B., Whitcomb D. C.. Inflammation and pancreatic cancer: An evidence-based review. Curr Opin Pharmacol. 2009 ; 9: 411-18
37. Grippo P. J., Nowlin P. S., Demeure M. J., Longnecker D. S., Sandgren E. P.. Preinvasive pancreatic neoplasia of ductal phenotype induced by acinar cell targeting of mutant Kras in transgenic mice. Cancer Res. 2003 ; 63: 2016-19
38. Guerra C., Mijimolle N., Dhawahir A., Dubus P., Barradas M., Serrano M., Campuzano V., Barbacid M.. Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell. 2003 ; 4: 111-20
39. Guerra C., Schuhmacher A. J., Canamero M., Grippo P. J., Verdaguer L., Perez-Gallego L., Dubus P., Sandgren E. P., Barbacid M.. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell. 2007 ; 11: 291-302
40. Habbe N., Shi G., Meguid R. A., Fendrich V., Esni F., Chen H., Feldmann G., Stoffers D. A., Konieczny S. F., Leach S. D., Maitra A.. Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. Proc Natl Acad Sci U S A. 2008 ; 105: 18913-18
41. Hingorani S. R., Petricoin E. F., Maitra A., Rajapakse V., King C., Jacobetz M. A., Ross S., Conrads T. P., Veenstra T. D., Hitt B. A., Kawaguchi Y., Johann D., Liotta L. A., Crawford H. C., Putt M. E., Jacks T., Wright C. V., Hruban R. H., Lowy A. M., Tuveson D. A.. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003 ; 4: 437-50
42. Hingorani S. R., Wang L., Multani A. S., Combs C., Deramaudt T. B., Hruban R. H., Rustgi A. K., Chang S., Tuveson D. A.. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 2005 ; 7: 469-83
43. Holmstrom S. R., Deering T., Swift G. H., Poelwijk F. J., Mangelsdorf D. J., Kliewer S. A., MacDonald R. J.. LRH-1 and PTF1-L coregulate an exocrine pancreas-specific transcriptional network for digestive function. Genes Dev. 2011 ; 25: 1674-79
44. Hruban R. H., Adsay N. V., Albores-Saavedra J., Anver M. R., Biankin A. V., Boivin G. P., Furth E. E., Furukawa T., Klein A., Klimstra D. S., Kloppel G., Lauwers G. Y., Longnecker D. S., Luttges J., Maitra A., Offerhaus G. J., Perez-Gallego L., Redston M., Tuveson D. A.. Pathology of genetically engineered mouse models of pancreatic exocrine cancer: Consensus report and recommendations. Cancer Res. 2006 ; 66: 95-106
45. Hruban R. H., Adsay N. V., Albores-Saavedra J., Compton C., Garrett E. S., Goodman S. N., Kern S. E., Klimstra D. S., Kloppel G., Longnecker D. S., Luttges J., Offerhaus G. J.. Pancreatic intraepithelial neoplasia: A new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol. 2001 ; 25: 579-86
46. Huang H., Daniluk J., Liu Y., Chu J., Li Z., Ji B., Logsdon C. D. Oncogenic K-Ras requires activation for enhanced activity. Oncogene. 2013 ;:
47. Isoda K., Young J. L., Zirlik A., MacFarlane L. A., Tsuboi N., Gerdes N., Schonbeck U., Libby P.. Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells. Arterioscler Thromb Vasc Biol. 2006 ; 26: 611-17
48. Ji B., Tsou L., Wang H., Gaiser S., Chang D. Z., Daniluk J., Bi Y., Grote T., Longnecker D. S., Logsdon C. D. Ras activity levels control the development of pancreatic diseases. Gastroenterology. 2009 ; 137: 1072 1082 e1-82 6
49. Keefe M. D., Wang H., De La O. J., Khan A., Firpo M. A., Murtaugh L. C.. Beta-catenin is selectively required for the expansion and regeneration of mature pancreatic acinar cells in mice. Dis Model Mech. 2012 ; 5: 503-14
50. Kelly K. A., Bardeesy N., Anbazhagan R., Gurumurthy S., Berger J., Alencar H., Depinho R. A., Mahmood U., Weissleder R.. Targeted nanoparticles for imaging incipient pancreatic ductal adenocarcinoma. PLoS Med. 2008 ; 5: e85
51. Khasawneh J., Schulz M. D., Walch A., Rozman J., Hrabe de Angelis M., Klingenspor M., Buck A., Schwaiger M., Saur D., Schmid R. M., Kloppel G., Sipos B., Greten F. R., Arkan M. C.. Inflammation and mitochondrial fatty acid beta-oxidation link obesity to early tumor promotion. Proc Natl Acad Sci U S A. 2009 ; 106: 3354-59
52. Konturek P. C., Dembinski A., Warzecha Z., Burnat G., Ceranowicz P., Hahn E. G., Dembinski M., Tomaszewska R., Konturek S. J.. Pioglitazone, a specific ligand of peroxisome proliferator-activated receptor-gamma, protects pancreas against acute cerulein-induced pancreatitis. World J Gastroenterol. 2005 ; 11: 6322-29
53. Kopinke D., Murtaugh L. C.. Exocrine-to-endocrine differentiation is detectable only prior to birth in the uninjured mouse pancreas. BMC Dev Biol. 2010 ; 10: 38
54. Kopp J. L., Dubois C. L., Schaffer A. E., Hao E., Shih H. P., Seymour P. A., Ma J., Sander M.. Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas. Development. 2011 ; 138: 653-65
55. Kopp J. L., von Figura G., Mayes E., Liu F. F., Dubois C. L., Morris J. P. t., Pan F. C., Akiyama H., Wright C. V., Jensen K., Hebrok M., Sander M.. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell. 2012 ; 22: 737-50
56. Kowalik A. S., Johnson C. L., Chadi S. A., Weston J. Y., Fazio E. N., Pin C. L.. Mice lacking the transcription factor Mist1 exhibit an altered stress response and increased sensitivity to caerulein-induced pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2007 ; 292: G1123-32
57. Kretzschmar K., Watt F. M.. Lineage tracing. Cell. 2012 ; 148: 33-45
58. Laurent-Puig P., Lievre A., Blons H.. Mutations and response to epidermal growth factor receptor inhibitors. Clin Cancer Res. 2009 ; 15: 1133-39
59. Lesina M., Kurkowski M. U., Ludes K., Rose-John S., Treiber M., Kloppel G., Yoshimura A., Reindl W., Sipos B., Akira S., Schmid R. M., Algul H.. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell. 2011 ; 19: 456-69
60. Li D., Duell E. J., Yu K., Risch H. A., Olson S. H., Kooperberg C., Wolpin B. M., Jiao L., Dong X., Wheeler B., Arslan A. A., Bueno-de-Mesquita H. B., Fuchs C. S., Gallinger S., Gross M., Hartge P., Hoover R. N., Holly E. A., Jacobs E. J., Klein A. P., LaCroix A., Mandelson M. T., Petersen G., Zheng W., Agalliu I., Albanes D., Boutron-Ruault M. C., Bracci P. M., Buring J. E., Canzian F., Chang K., Chanock S. J., Cotterchio M., Gaziano J. M., Giovannucci E. L., Goggins M., Hallmans G., Hankinson S. E., Hoffman Bolton J. A., Hunter D. J., Hutchinson A., Jacobs K. B., Jenab M., Khaw K. T., Kraft P., Krogh V., Kurtz R. C., McWilliams R. R., Mendelsohn J. B., Patel A. V., Rabe K. G., Riboli E., Shu X. O., Tjonneland A., Tobias G. S., Trichopoulos D., Virtamo J., Visvanathan K., Watters J., Yu H., Zeleniuch-Jacquotte A., Amundadottir L., Stolzenberg-Solomon R. Z. Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer. Carcinogenesis. 2012 ; 33: 1384-90
61. Li D., Yeung S. C., Hassan M. M., Konopleva M., Abbruzzese J. L.. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology. 2009 ; 137: 482-88
62. Maitra A., Hruban R. H.. Pancreatic cancer. Annu Rev Pathol. 2008 ; 3: 157-88
63. Maniati E., Bossard M., Cook N., Candido J. B., Emami-Shahri N., Nedospasov S. A., Balkwill F. R., Tuveson D. A., Hagemann T.. Crosstalk between the canonical NF-kappaB and Notch signaling pathways inhibits Ppargamma expression and promotes pancreatic cancer progression in mice. J Clin Invest. 2011 ; 121: 4685-99
64. Means A. L., Meszoely I. M., Suzuki K., Miyamoto Y., Rustgi A. K., Coffey R. J., Wright C. V., Stoffers D. A., Leach S. D.. Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development. 2005 ; 132: 3767-76
65. Michaud D. S., Izard J., Wilhelm-Benartzi C. S., You D. H., Grote V. A., Tjonneland A., Dahm C. C., Overvad K., Jenab M., Fedirko V., Boutron-Ruault M. C., Clavel-Chapelon F., Racine A., Kaaks R., Boeing H., Foerster J., Trichopoulou A., Lagiou P., Trichopoulos D., Sacerdote C., Sieri S., Palli D., Tumino R., Panico S., Siersema P. D., Peeters P. H., Lund E., Barricarte A., Huerta J. M., Molina-Montes E., Dorronsoro M., Quiros J. R., Duell E. J., Ye W., Sund M., Lindkvist B., Johansen D., Khaw K. T., Wareham N., Travis R. C., Vineis P., Bueno-de-Mesquita H. B., Riboli E. Plasma antibodies to oral bacteria and risk of pancreatic cancer in a large European prospective cohort study. Gut. 2012 ;:
66. Morris J. P. t., Cano D. A., Sekine S., Wang S. C., Hebrok M.. Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J Clin Invest. 2010 ; 120: 508-20
67. Murtaugh L. C., Melton D. A.. Genes, signals, and lineages in pancreas development. Annu Rev Cell Dev Biol. 2003 ; 19: 71-89
68. Navas C., Hernandez-Porras I., Schuhmacher A. J., Sibilia M., Guerra C., Barbacid M.. EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell. 2012 ; 22: 318-30
69. Nitsche C., Simon P., Weiss F. U., Fluhr G., Weber E., Gartner S., Behn C. O., Kraft M., Ringel J., Aghdassi A., Mayerle J., Lerch M. M.. Environmental risk factors for chronic pancreatitis and pancreatic cancer. Dig Dis. 2011 ; 29: 235-42
70. Nyborg N. C., Molck A. M., Madsen L. W., Knudsen L. B.. The human GLP-1 analog liraglutide and the pancreas: Evidence for the absence of structural pancreatic changes in three species. Diabetes. 2012 ; 61: 1243-49
71. Olive K. P., Jacobetz M. A., Davidson C. J., Gopinathan A., McIntyre D., Honess D., Madhu B., Goldgraben M. A., Caldwell M. E., Allard D., Frese K. K., Denicola G., Feig C., Combs C., Winter S. P., Ireland-Zecchini H., Reichelt S., Howat W. J., Chang A., Dhara M., Wang L., Ruckert F., Grutzmann R., Pilarsky C., Izeradjene K., Hingorani S. R., Huang P., Davies S. E., Plunkett W., Egorin M., Hruban R. H., Whitebread N., McGovern K., Adams J., Iacobuzio-Donahue C., Griffiths J., Tuveson D. A. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009 ; 324: 1457-61
72. Pasca di Magliano M., Logsdon C. D.. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology. 2013 ; 144: 1220-29
73. Perez-Mancera P. A., Guerra C., Barbacid M., Tuveson D. A.. What we have learned about pancreatic cancer from mouse models. Gastroenterology. 2012 ; 142: 1079-92
74. Petersen G. M., Amundadottir L., Fuchs C. S., Kraft P., Stolzenberg-Solomon R. Z., Jacobs K. B., Arslan A. A., Bueno-de-Mesquita H. B., Gallinger S., Gross M., Helzlsouer K., Holly E. A., Jacobs E. J., Klein A. P., LaCroix A., Li D., Mandelson M. T., Olson S. H., Risch H. A., Zheng W., Albanes D., Bamlet W. R., Berg C. D., Boutron-Ruault M. C., Buring J. E., Bracci P. M., Canzian F., Clipp S., Cotterchio M., de Andrade M., Duell E. J., Gaziano J. M., Giovannucci E. L., Goggins M., Hallmans G., Hankinson S. E., Hassan M., Howard B., Hunter D. J., Hutchinson A., Jenab M., Kaaks R., Kooperberg C., Krogh V., Kurtz R. C., Lynch S. M., McWilliams R. R., Mendelsohn J. B., Michaud D. S., Parikh H., Patel A. V., Peeters P. H., Rajkovic A., Riboli E., Rodriguez L., Seminara D., Shu X. O., Thomas G., Tjonneland A., Tobias G. S., Trichopoulos D., Van Den Eeden S. K., Virtamo J., Wactawski-Wende J., Wang Z., Wolpin B. M., Yu H., Yu K., Zeleniuch-Jacquotte A., Fraumeni J. F., Hoover R. N., Hartge P., Chanock S. J. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet. 2010 ; 42: 224-28
75. Petersen G. M., de Andrade M., Goggins M., Hruban R. H., Bondy M., Korczak J. F., Gallinger S., Lynch H. T., Syngal S., Rabe K. G., Seminara D., Klein A. P.. Pancreatic cancer genetic epidemiology consortium. Cancer Epidemiol Biomarkers Prev. 2006 ; 15: 704-10
76. Poruk K. E., Firpo M. A., Adler D. G., Mulvihill S. J.. Screening for pancreatic cancer: Why, how, and who?. Ann Surg. 2013 ; 257: 17-26
77. Pour P., Althoff J., Kruger F. W., Mohr U.. A potent pancreatic carcinogen in Syrian hamsters: N-nitrosobis(2-oxopropyl)amine. J Natl Cancer Inst. 1977 ; 58: 1449-53
78. Pour P. M.. Histogenesis of exocrine pancreatic cancer in the hamster model. Environ Health Perspect. 1984 ; 56: 229-43
79. Pour P. M., Takahashi M., Donnelly T., Stepan K.. Modification of pancreatic carcinogenesis in the hamster model. IX. Effect of pancreatitis. J Natl Cancer Inst. 1983 ; 71: 607-13
80. Provenzano P. P., Cuevas C., Chang A. E., Goel V. K., Von Hoff D. D., Hingorani S. R.. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012 ; 21: 418-29
81. Rhim A. D., Mirek E. T., Aiello N. M., Maitra A., Bailey J. M., McAllister F., Reichert M., Beatty G. L., Rustgi A. K., Vonderheide R. H., Leach S. D., Stanger B. Z.. EMT and dissemination precede pancreatic tumor formation. Cell. 2012 ; 148: 349-61
82. Sandgren E. P., Quaife C. J., Paulovich A. G., Palmiter R. D., Brinster R. L.. Pancreatic tumor pathogenesis reflects the causative genetic lesion. Proc Natl Acad Sci U S A. 1991 ; 88: 93-97
83. Schneider G., Siveke J. T., Eckel F., Schmid R. M.. Pancreatic cancer: Basic and clinical aspects. Gastroenterology. 2005 ; 128: 1606-25
84. Schneider M. B., Matsuzaki H., Haorah J., Ulrich A., Standop J., Ding X. Z., Adrian T. E., Pour P. M.. Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology. 2001 ; 120: 1263-70
85. Serrano M., Lin A. W., McCurrach M. E., Beach D., Lowe S. W.. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997 ; 88: 593-602
86. Shi G., DiRenzo D., Qu C., Barney D., Miley D., Konieczny S. F.. Maintenance of acinar cell organization is critical to preventing Kras-induced acinar-ductal metaplasia. Oncogene. 2013 ; 32: 1950-58
87. Siegel R., Naishadham D., Jemal A.. Cancer statistics, 2013. CA Cancer J Clin. 2013 ; 63: 11-30
88. Singh M., Lima A., Molina R., Hamilton P., Clermont A. C., Devasthali V., Thompson J. D., Cheng J. H., Bou Reslan H., Ho C. C., Cao T. C., Lee C. V., Nannini M. A., Fuh G., Carano R. A., Koeppen H., Yu R. X., Forrest W. F., Plowman G. D., Johnson L. Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models. Nat Biotechnol. 2010 ; 28: 585-93
89. Skoulidis F., Cassidy L. D., Pisupati V., Jonasson J. G., Bjarnason H., Eyfjord J. E., Karreth F. A., Lim M., Barber L. M., Clatworthy S. A., Davies S. E., Olive K. P., Tuveson D. A., Venkitaraman A. R.. Germline Brca2 heterozygosity promotes Kras(G12D)-driven carcinogenesis in a murine model of familial pancreatic cancer. Cancer Cell. 2010 ; 18: 499-509
90. Solar M., Cardalda C., Houbracken I., Martin M., Maestro M. A., De Medts N., Xu X., Grau V., Heimberg H., Bouwens L., Ferrer J.. Pancreatic exocrine duct cells give rise to insulin-producing beta cells during embryogenesis but not after birth. Dev Cell. 2009 ; 17: 849-60
91. Strobel O., Dor Y., Alsina J., Stirman A., Lauwers G., Trainor A., Castillo C. F., Warshaw A. L., Thayer S. P. In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia. Gastroenterology. 2007 ; 133: 1999-2009
92. Takahashi M., Furukawa F., Toyoda K., Sato H., Hasegawa R., Imaida K., Hayashi Y.. Effects of various prostaglandin synthesis inhibitors on pancreatic carcinogenesis in hamsters after initiation with N-nitrosobis(2-oxopropyl)amine. Carcinogenesis. 1990 ; 11: 393-95
93. Takahashi M., Hori M., Mutoh M., Wakabayashi K., Nakagama H.. Experimental animal models of pancreatic carcinogenesis for prevention studies and their relevance to human disease. Cancers. 2011 ; 3: 582-602
94. Takeuchi Y., Takahashi M., Sakano K., Mutoh M., Niho N., Yamamoto M., Sato H., Sugimura T., Wakabayashi K.. Suppression of N-nitrosobis(2-oxopropyl) amine-induced pancreatic carcinogenesis in hamsters by pioglitazone, a ligand of peroxisome proliferator-activated receptor gamma. Carcinogenesis. 2007 ; 28: 1692-96
95. Tuveson D. A., Shaw A. T., Willis N. A., Silver D. P., Jackson E. L., Chang S., Mercer K. L., Grochow R., Hock H., Crowley D., Hingorani S. R., Zaks T., King C., Jacobetz M. A., Wang L., Bronson R. T., Orkin S. H., DePinho R. A., Jacks T.. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell. 2004 ; 5: 375-87
96. van Miltenburg M. H., Jonkers J.. Using genetically engineered mouse models to validate candidate cancer genes and test new therapeutic approaches. Curr Opin Genet Dev. 2012 ; 22: 21-27
97. van Westerloo D. J., Florquin S., de Boer A. M., Daalhuisen J., de Vos A. F., Bruno M. J., van der Poll T.. Therapeutic effects of troglitazone in experimental chronic pancreatitis in mice. Am J Pathol. 2005 ; 166: 721-28
98. von Figura G., Morris J. P. T., Wright C. V., Hebrok M. Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation. Gut. 2013 ;:
99. Yachida S., Jones S., Bozic I., Antal T., Leary R., Fu B., Kamiyama M., Hruban R. H., Eshleman J. R., Nowak M. A., Velculescu V. E., Kinzler K. W., Vogelstein B., Iacobuzio-Donahue C. A.. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010 ; 467: 1114-17
100. Ying H., Kimmelman A. C., Lyssiotis C. A., Hua S., Chu G. C., Fletcher-Sananikone E., Locasale J. W., Son J., Zhang H., Coloff J. L., Yan H., Wang W., Chen S., Viale A., Zheng H., Paik J. H., Lim C., Guimaraes A. R., Martin E. S., Chang J., Hezel A. F., Perry S. R., Hu J., Gan B., Xiao Y., Asara J. M., Weissleder R., Wang Y. A., Chin L., Cantley L. C., DePinho R. A. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell. 2012 ; 149: 656-70
101. Yoshimoto M., Tsutsumi M., Iki K., Sasaki Y., Tsujiuchi T., Sugimura T., Wakabayashi K., Konishi Y.. Carcinogenicity of heterocyclic amines for the pancreatic duct epithelium in hamsters. Cancer Lett. 1999 ; 143: 235-39
102. Zhu L., Shi G., Schmidt C. M., Hruban R. H., Konieczny S. F.. Acinar cells contribute to the molecular heterogeneity of pancreatic intraepithelial neoplasia. Am J Pathol. 2007 ; 171: 263-73
103. Zoumpourlis V., Solakidi S., Papathoma A., Papaevangeliou D.. Alterations in signal transduction pathways implicated in tumour progression during multistage mouse skin carcinogenesis. Carcinogenesis. 2003 ; 24: 1159-65