Animal Modeling of Pancreatitis-to-Cancer Progression

Reference work entry

Abstract

Inflammatory diseases are the most common conditions of the exocrine pancreas. Chronic pancreatitis is often the result of recurrent bouts of acute pancreatitis and is a risk factor for pancreatic cancer. There has been a long interest in modeling the pathophysiological relationship between chronic pancreatitis and cancer and the recent development of genetic mouse models of pancreatic diseases has accelerated the discovery of mechanistic insights. The current paradigm proposes that the inability of normal pancreatic cells to recover from injury establishes a biological landscape that promotes cancer development. Multiple types of mechanisms concur in this process, in which both epithelial and nonepithelial cells participate, leading to persistent inability of epithelial cells to restore their differentiation programs. Developmental pathways involved in pancreatic differentiation are subverted to maintain cellular phenotypes that promote signaling from mutant KRAS, preneoplasia, and neoplasia. Downstream from KRAS, and in parallel with it, tyrosine kinase receptors, the MAPK, PI3K, NF-KB, and STAT pathways, and the mechanisms that control senescence and autophagy, contribute to the emergence of transformed clones. These signaling pathways, whose activity is modulated through complex cross-talks between epithelial, mesenchymal, and inflammatory cells, play crucial roles in the pancreatitis-to-cancer progression and provide opportunities for intervention in high-risk patients.

Keywords

Pancreatitis Pancreatic cancer Caerulein Acino-ductal metaplasia 

List of Abbreviations

ADM

Acinar-to-ductal metaplasia

AP

Acute pancreatitis

CCK

Cholecystokinin

CCKR

CCK receptor

CDE

Choline-deficient, ethionine-supplemented diet

CFTR

Cystic fibrosis transmembrane conductance regulator

CP

Chronic pancreatitis

ECM

Extracellular matrix

EGF

Epidermal growth factor

ER

Endoplasmic reticulum

EUS-FNA

Endoscopic ultrasound-guided fine needle aspiration

GEMM

Genetically engineered mouse models

IPMN

Intraductal papillary mucinous neoplasm

JAK

Janus-activated kinase

LPS

Lipopolysaccharide

PanIN

Pancreatic intraepithelial neoplasia

PDAC

Pancreatic ductal adenocarcinoma

PDL

Pancreatic duct ligation

PSC

Pancreatic stellate cells

TGF-β

Transforming growth factor beta

TNF-α

Tumor necrosis factor alpha

WT

Wild type

References

  1. 1.
    Sheth SG, Conwell DL, Whitcomb DC, Alsante M, Anderson MA, Barkin J, et al. Academic Pancreas Centers of Excellence: guidance from a multidisciplinary chronic pancreatitis working group at PancreasFest. Pancreatology. 2017;17:419–30.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Raimondi S, Lowenfels AB, Morselli-Labate AM, Maisonneuve P, Pezzilli R. Pancreatic cancer in chronic pancreatitis; aetiology, incidence, and early detection. Best Pract Res Clin Gastroenterol. 2010;24:349–58.CrossRefPubMedGoogle Scholar
  3. 3.
    Capurso G, Boccia S, Salvia R, Del Chiaro M, Frulloni L, Arcidiacono PG, et al. Risk factors for intraductal papillary mucinous neoplasm (IPMN) of the pancreas: a multicentre case-control study. Am J Gastroenterol. 2013;108:1003–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Lowenfels AB, Maisonneuve P, DiMagno EP, Elitsur Y, Gates LK Jr, Perrault J, et al. Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J Natl Cancer Inst. 1997;89(6):442.PubMedCrossRefGoogle Scholar
  5. 5.
    Pandol SJ, Saluja AK, Imrie CW, Banks PA. Acute pancreatitis: bench to the bedside. Gastroenterology. 2007;132:1127–51.PubMedCrossRefGoogle Scholar
  6. 6.
    Nevalainen TJ, Seppa A. Acute pancreatitis caused by closed duodenal loop in the rat. Scand J Gastroenterol. 1975;10:521–7.PubMedGoogle Scholar
  7. 7.
    Lerch MM, Saluja AK, Runzi M, Dawra R, Saluja M, Steer ML. Pancreatic duct obstruction triggers acute necrotizing pancreatitis in the opossum. Gastroenterology. 1993;104:853–61.PubMedCrossRefGoogle Scholar
  8. 8.
    Ohshio G, Saluja A, Steer ML. Effects of short-term pancreatic duct obstruction in rats. Gastroenterology. 1991;100:196–202.PubMedCrossRefGoogle Scholar
  9. 9.
    Le T, Eisses JF, Lemon KL, Ozolek JA, Pociask DA, Orabi AI, et al. Intraductal infusion of taurocholate followed by distal common bile duct ligation leads to a severe necrotic model of pancreatitis in mice. Pancreas. 2015;44:493–9.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Yamasaki M, Takeyama Y, Shinkai M, Ohyanagi H. Pancreatic and bile duct obstruction exacerbates rat caerulein-induced pancreatitis: a new experimental model of acute hemorrhagic pancreatitis. J Gastroenterol. 2006;41:352–60.PubMedCrossRefGoogle Scholar
  11. 11.
    Aho HJ, Koskensalo SM, Nevalainen TJ. Experimental pancreatitis in the rat. Sodium taurocholate-induced acute haemorrhagic pancreatitis. Scand J Gastroenterol. 1980;15:411–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Laukkarinen JM, Van Acker GJ, Weiss ER, Steer ML, Perides G. A mouse model of acute biliary pancreatitis induced by retrograde pancreatic duct infusion of Na-taurocholate. Gut. 2007;56:1590–8.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Wittel UA, Wiech T, Chakraborty S, Boss B, Lauch R, Batra SK, et al. Taurocholate-induced pancreatitis: a model of severe necrotizing pancreatitis in mice. Pancreas. 2008;36:e9–21.PubMedCrossRefGoogle Scholar
  14. 14.
    Owyang C, Logsdon CD. New insights into neurohormonal regulation of pancreatic secretion. Gastroenterology. 2004;127:957–69.PubMedCrossRefGoogle Scholar
  15. 15.
    Huang SC, DH Y, Wank SA, Mantey S, Gardner JD, Jensen RT. Importance of sulfation of gastrin or cholecystokinin (CCK) on affinity for gastrin and CCK receptors. Peptides. 1989;10:785–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Jensen RT, Wank SA, Rowley WH, Sato S, Gardner JD. Interaction of CCK with pancreatic acinar cells. Trends Pharmacol Sci. 1989;10:418–23.PubMedCrossRefGoogle Scholar
  17. 17.
    Carriere C, Young AL, Gunn JR, Longnecker DS, Korc M. Acute pancreatitis markedly accelerates pancreatic cancer progression in mice expressing oncogenic Kras. Biochem Biophys Res Commun. 2009;382:561–5.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Jensen JN, Cameron E, Garay MV, Starkey TW, Gianani R, Jensen J. Recapitulation of elements of embryonic development in adult mouse pancreatic regeneration. Gastroenterology. 2005;128:728–41.PubMedCrossRefGoogle Scholar
  19. 19.
    Fendrich V, Esni F, Garay MV, Feldmann G, Habbe N, Jensen JN, et al. Hedgehog signaling is required for effective regeneration of exocrine pancreas. Gastroenterology. 2008;135:621–31.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Okamura D, Starr ME, Lee EY, Stromberg AJ, Evers BM, Saito H. Age-dependent vulnerability to experimental acute pancreatitis is associated with increased systemic inflammation and thrombosis. Aging Cell. 2012;11:760–9.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Sahin-Toth M. Genetic risk in chronic pancreatitis: the misfolding-dependent pathway. Curr Opin Gastroenterol. 2017;33(5):390.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Mizunuma T, Kawamura S, Kishino Y. Effects of injecting excess arginine on rat pancreas. J Nutr. 1984;114:467–71.PubMedCrossRefGoogle Scholar
  23. 23.
    Cui HF, Bai ZL. Protective effects of transplanted and mobilized bone marrow stem cells on mice with severe acute pancreatitis. World J Gastroenterol. 2003;9:2274–7.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Rao KN, Eagon PK, Okamura K, Van Thiel DH, Gavaler JS, Kelly RH, et al. Acute hemorrhagic pancreatic necrosis in mice. Induction in male mice treated with estradiol. Am J Pathol. 1982;109:8–14.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Pandol SJ, Periskic S, Gukovsky I, Zaninovic V, Jung Y, Zong Y, et al. Ethanol diet increases the sensitivity of rats to pancreatitis induced by cholecystokinin octapeptide. Gastroenterology. 1999;117:706–16.PubMedCrossRefGoogle Scholar
  26. 26.
    Quon MG, Kugelmas M, Wisner JR Jr, Chandrasoma P, Valenzuela JE. Chronic alcohol consumption intensifies caerulein-induced acute pancreatitis in the rat. Int J Pancreatol. 1992;12:31–9.PubMedGoogle Scholar
  27. 27.
    Yadav D, Whitcomb DC. The role of alcohol and smoking in pancreatitis. Nat Rev Gastroenterol Hepatol. 2010;7:131–45.PubMedCrossRefGoogle Scholar
  28. 28.
    Yamamoto M, Otani M, Otsuki M. A new model of chronic pancreatitis in rats. Am J Physiol Gastrointest Liver Physiol. 2006;291:G700–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Guerra C, Collado M, Navas C, Schuhmacher AJ, Hernandez-Porras I, Canamero M, et al. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell. 2011;19:728–39.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Elsasser HP, Haake T, Grimmig M, Adler G, Kern HF. Repetitive cerulein-induced pancreatitis and pancreatic fibrosis in the rat. Pancreas. 1992;7:385–90.PubMedCrossRefGoogle Scholar
  31. 31.
    Neuschwander-Tetri BA, Bridle KR, Wells LD, Marcu M, Ramm GA. Repetitive acute pancreatic injury in the mouse induces procollagen alpha1(I) expression colocalized to pancreatic stellate cells. Lab Investig. 2000;80:143–50.PubMedCrossRefGoogle Scholar
  32. 32.
    Neuschwander-Tetri BA, Burton FR, Presti ME, Britton RS, Janney CG, Garvin PR, et al. Repetitive self-limited acute pancreatitis induces pancreatic fibrogenesis in the mouse. Dig Dis Sci. 2000;45:665–74.PubMedCrossRefGoogle Scholar
  33. 33.
    Ohashi S, Nishio A, Nakamura H, Asada M, Tamaki H, Kawasaki K, et al. Overexpression of redox-active protein thioredoxin-1 prevents development of chronic pancreatitis in mice. Antioxid Redox Signal. 2006;8:1835–45.PubMedCrossRefGoogle Scholar
  34. 34.
    Vaquero E, Molero X, Tian X, Salas A, Malagelada JR. Myofibroblast proliferation, fibrosis, and defective pancreatic repair induced by cyclosporin in rats. Gut. 1999;45:269–77.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Weaver C, Bishop AE, Polak JM. Pancreatic changes elicited by chronic administration of excess L-arginine. Exp Mol Pathol. 1994;60:71–87.PubMedCrossRefGoogle Scholar
  36. 36.
    Ida S, Ohmuraya M, Hirota M, Ozaki N, Hiramatsu S, Uehara H, et al. Chronic pancreatitis in mice by treatment with choline-deficient ethionine-supplemented diet. Exp Anim. 2010;59:421–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Li J, Guo M, Hu B, Liu R, Wang R, Tang C. Does chronic ethanol intake cause chronic pancreatitis?: evidence and mechanism. Pancreas. 2008;37:189–95.PubMedCrossRefGoogle Scholar
  38. 38.
    Lieber CS, DeCarli LM. Alcoholic liver injury: experimental models in rats and baboons. Adv Exp Med Biol. 1975;59:379–93.PubMedCrossRefGoogle Scholar
  39. 39.
    Ponnappa BC, Marciniak R, Schneider T, Hoek JB, Rubin E. Ethanol consumption and susceptibility of the pancreas to cerulein-induced pancreatitis. Pancreas. 1997;14:150–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Vonlaufen A, Phillips PA, Xu Z, Zhang X, Yang L, Pirola RC, et al. Withdrawal of alcohol promotes regression while continued alcohol intake promotes persistence of LPS-induced pancreatic injury in alcohol-fed rats. Gut. 2011;60:238–46.PubMedCrossRefGoogle Scholar
  41. 41.
    Kono H, Nakagami M, Rusyn I, Connor HD, Stefanovic B, Brenner DA, et al. Development of an animal model of chronic alcohol-induced pancreatitis in the rat. Am J Physiol Gastrointest Liver Physiol. 2001;280:G1178–86.PubMedCrossRefGoogle Scholar
  42. 42.
    Neglia JP, FitzSimmons SC, Maisonneuve P, Schoni MH, Schoni-Affolter F, Corey M, et al. The risk of cancer among patients with cystic fibrosis. Cystic Fibrosis and Cancer Study group. N Engl J Med. 1995;332:494–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Dimagno MJ, Lee SH, Hao Y, Zhou SY, McKenna BJ, Owyang C. A proinflammatory, antiapoptotic phenotype underlies the susceptibility to acute pancreatitis in cystic fibrosis transmembrane regulator (−/−) mice. Gastroenterology. 2005;129:665–81.PubMedCrossRefGoogle Scholar
  44. 44.
    Meyerholz DK, Stoltz DA, Pezzulo AA, Welsh MJ. Pathology of gastrointestinal organs in a porcine model of cystic fibrosis. Am J Pathol. 2010;176:1377–89.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Braganza JM, Lee SH, McCloy RF, McMahon MJ. Chronic pancreatitis. Lancet. 2011;377:1184–97.PubMedCrossRefGoogle Scholar
  46. 46.
    Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet. 1996;14:141–5.PubMedCrossRefGoogle Scholar
  47. 47.
    Archer H, Jura N, Keller J, Jacobson M, Bar-Sagi D. A mouse model of hereditary pancreatitis generated by transgenic expression of R122H trypsinogen. Gastroenterology. 2006;131:1844–55.PubMedCrossRefGoogle Scholar
  48. 48.
    Selig L, Sack U, Gaiser S, Kloppel G, Savkovic V, Mossner J, et al. Characterisation of a transgenic mouse expressing R122H human cationic trypsinogen. BMC Gastroenterol. 2006;6:30.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Ellis I, Lerch MM, Whitcomb DC, Consensus Committees of the European Registry of Hereditary Pancreatic Diseases MM-CPSGIAoP. Genetic testing for hereditary pancreatitis: guidelines for indications, counselling, consent and privacy issues. Pancreatology. 2001;1:405–15.PubMedCrossRefGoogle Scholar
  50. 50.
    Ohmuraya M, Hirota M, Araki M, Mizushima N, Matsui M, Mizumoto T, et al. Autophagic cell death of pancreatic acinar cells in serine protease inhibitor Kazal type 3-deficient mice. Gastroenterology. 2005;129:696–705.PubMedCrossRefGoogle Scholar
  51. 51.
    Marrache F, SP T, Bhagat G, Pendyala S, Osterreicher CH, Gordon S, et al. Overexpression of interleukin-1beta in the murine pancreas results in chronic pancreatitis. Gastroenterology. 2008;135:1277–87.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Huang H, Liu Y, Daniluk J, Gaiser S, Chu J, Wang H, et al. Activation of nuclear factor-kappaB in acinar cells increases the severity of pancreatitis in mice. Gastroenterology. 2013;144:202–10.PubMedCrossRefGoogle Scholar
  53. 53.
    Neuhofer P, Liang S, Einwachter H, Schwerdtfeger C, Wartmann T, Treiber M, et al. Deletion of IkappaBalpha activates RelA to reduce acute pancreatitis in mice through up-regulation of Spi2A. Gastroenterology. 2013;144:192–201.PubMedCrossRefGoogle Scholar
  54. 54.
    Sindhu RS, Parvathy G, Fysal K, Jacob MK, Geetha S, Krishna B, et al. Clinical profile of PanIN lesions in tropical chronic pancreatitis. Indian J Gastroenterol. 2015;34:436–41.PubMedCrossRefGoogle Scholar
  55. 55.
    Swidnicka-Siergiejko AK, Gomez-Chou SB, Cruz-Monserrate Z, Deng D, Liu Y, Huang H, et al. Chronic inflammation initiates multiple forms of K-Ras-independent mouse pancreatic cancer in the absence of TP53. Oncogene. 2017;36:3149–58.PubMedCrossRefGoogle Scholar
  56. 56.
    Gerdes B, Ramaswamy A, Kersting M, Ernst M, Lang S, Schuermann M, et al. p16(INK4a) alterations in chronic pancreatitis-indicator for high-risk lesions for pancreatic cancer. Surgery. 2001;129:490–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Pfeffer RB, Stasior O, Hinton JW. The clinical picture of the sequential development of acute hemorrhagic pancreatitis in the dog. Surg Forum. 1957;8:248–51.PubMedGoogle Scholar
  58. 58.
    Ji B, Bi Y, Simeone D, Mortensen RM, Logsdon CD. Human pancreatic acinar cells lack functional responses to cholecystokinin and gastrin. Gastroenterology. 2001;121:1380–90.PubMedCrossRefGoogle Scholar
  59. 59.
    Talukdar R, Sareen A, Zhu H, Yuan Z, Dixit A, Cheema H, et al. Release of cathepsin B in cytosol causes cell death in acute pancreatitis. Gastroenterology 2016;151:747–58, e5.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Molero X, Vaquero EC, Flandez M, Gonzalez AM, Ortiz MA, Cibrian-Uhalte E, et al. Gene expression dynamics after murine pancreatitis unveils novel roles for Hnf1alpha in acinar cell homeostasis. Gut. 2012;61:1187–96.PubMedCrossRefGoogle Scholar
  61. 61.
    Takacs T, Czako L, Morschl E, Laszlo F, Tiszlavicz L, Rakonczay Z Jr, et al. The role of nitric oxide in edema formation in L-arginine-induced acute pancreatitis. Pancreas. 2002;25:277–82.PubMedCrossRefGoogle Scholar
  62. 62.
    Czako L, Takacs T, Varga IS, Tiszlavicz L, Hai DQ, Hegyi P, et al. Involvement of oxygen-derived free radicals in L-arginine-induced acute pancreatitis. Dig Dis Sci. 1998;43:1770–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Samuel I, Chaudhary A, Fisher RA, Joehl RJ. Exacerbation of acute pancreatitis by combined cholinergic stimulation and duct obstruction. Am J Surg. 2005;190:721–4.PubMedCrossRefGoogle Scholar
  64. 64.
    Treiber M, Neuhofer P, Anetsberger E, Einwachter H, Lesina M, Rickmann M, et al. Myeloid, but not pancreatic, RelA/p65 is required for fibrosis in a mouse model of chronic pancreatitis. Gastroenterology. 2011;141:1473–85, 85 e1–7.CrossRefGoogle Scholar
  65. 65.
    Guerra C, Schuhmacher AJ, Canamero M, Grippo PJ, Verdaguer L, Perez-Gallego L, et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell. 2007;11:291–302.PubMedCrossRefGoogle Scholar
  66. 66.
    Muller-Decker K, Furstenberger G, Annan N, Kucher D, Pohl-Arnold A, Steinbauer B, et al. Preinvasive duct-derived neoplasms in pancreas of keratin 5-promoter cyclooxygenase-2 transgenic mice. Gastroenterology. 2006;130:2165–78.PubMedCrossRefGoogle Scholar
  67. 67.
    Gukovsky I, Gukovskaya AS, Blinman TA, Zaninovic V, Pandol SJ. Early NF-kappaB activation is associated with hormone-induced pancreatitis. Am J Phys. 1998;275:G1402–14.Google Scholar
  68. 68.
    Li N, Wu X, Holzer RG, Lee JH, Todoric J, Park EJ, et al. Loss of acinar cell IKKalpha triggers spontaneous pancreatitis in mice. J Clin Invest. 2013;123:2231–43.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Diakopoulos KN, Lesina M, Wormann S, Song L, Aichler M, Schild L, et al. Impaired autophagy induces chronic atrophic pancreatitis in mice via sex- and nutrition-dependent processes. Gastroenterology 2015;148:626–38, e17.PubMedCrossRefGoogle Scholar
  70. 70.
    Antonucci L, Fagman JB, Kim JY, Todoric J, Gukovsky I, Mackey M, et al. Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress. Proc Natl Acad Sci U S A. 2015;112:E6166–74.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Baumgart M, Werther M, Bockholt A, Scheurer M, Ruschoff J, Dietmaier W, et al. Genomic instability at both the base pair level and the chromosomal level is detectable in earliest PanIN lesions in tissues of chronic pancreatitis. Pancreas. 2010;39:1093–103.PubMedCrossRefGoogle Scholar
  72. 72.
    Matsubayashi H, Canto M, Sato N, Klein A, Abe T, Yamashita K, et al. DNA methylation alterations in the pancreatic juice of patients with suspected pancreatic disease. Cancer Res. 2006;66:1208–17.PubMedCrossRefGoogle Scholar
  73. 73.
    Yan L, McFaul C, Howes N, Leslie J, Lancaster G, Wong T, et al. Molecular analysis to detect pancreatic ductal adenocarcinoma in high-risk groups. Gastroenterology. 2005;128:2124–30.PubMedCrossRefGoogle Scholar
  74. 74.
    Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362(17):1605.PubMedCrossRefGoogle Scholar
  75. 75.
    Rosty C, Geradts J, Sato N, Wilentz RE, Roberts H, Sohn T, et al. p16 inactivation in pancreatic intraepithelial neoplasias (PanINs) arising in patients with chronic pancreatitis. Am J Surg Pathol. 2003;27:1495–501.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Ying H, Dey P, Yao W, Kimmelman AC, Draetta GF, Maitra A, et al. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 2016;30:355–85.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Wu J, Matthaei H, Maitra A, Dal Molin M, Wood LD, Eshleman JR, et al. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med. 2011;3:92ra66.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Furukawa T, Kuboki Y, Tanji E, Yoshida S, Hatori T, Yamamoto M, et al. Whole-exome sequencing uncovers frequent GNAS mutations in intraductal papillary mucinous neoplasms of the pancreas. Sci Rep. 2011;1:161.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Taki K, Ohmuraya M, Tanji E, Komatsu H, Hashimoto D, Semba K, et al. GNAS(R201H) and Kras(G12D) cooperate to promote murine pancreatic tumorigenesis recapitulating human intraductal papillary mucinous neoplasm. Oncogene. 2016;35:2407–12.CrossRefPubMedGoogle Scholar
  80. 80.
    Longnecker D. Experimental pancreatic cancer: role of species, sex and diet. Bull Cancer. 1990;77:27–37.PubMedGoogle Scholar
  81. 81.
    Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003;4:437–50.CrossRefPubMedGoogle Scholar
  82. 82.
    Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 2005;7:469–83.CrossRefPubMedGoogle Scholar
  83. 83.
    Aguirre AJ, Bardeesy N, Sinha M, Lopez L, Tuveson DA, Horner J, et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 2003;17:3112–26.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Bardeesy N, Cheng KH, Berger JH, Chu GC, Pahler J, Olson P, et al. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 2006;20:3130–46.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Morris JP, Cano DA, Sekine S, Wang SC, Hebrok M. Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J Clin Invest. 2010;120:508–20.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Fukuda A, Wang SC, JPt M, Folias AE, Liou A, Kim GE, et al. Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell. 2011;19:441–55.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Carriere C, Young AL, Gunn JR, Longnecker DS, Korc M. Acute pancreatitis accelerates initiation and progression to pancreatic cancer in mice expressing oncogenic Kras in the nestin cell lineage. PLoS One. 2011;6:e27725.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Flandez M, Cendrowski J, Canamero M, Salas A, del Pozo N, Schoonjans K, et al. Nr5a2 heterozygosity sensitises to, and cooperates with, inflammation in KRas(G12V)-driven pancreatic tumourigenesis. Gut. 2014;63:647–55.PubMedCrossRefGoogle Scholar
  89. 89.
    Rijkers AP, van Eijck CH. Acute pancreatitis. N Engl J Med. 2017;376:596–7.PubMedCrossRefGoogle Scholar
  90. 90.
    Siveke JT, Lubeseder-Martellato C, Lee M, Mazur PK, Nakhai H, Radtke F, et al. Notch signaling is required for exocrine regeneration after acute pancreatitis. Gastroenterology. 2008;134:544–55.CrossRefPubMedGoogle Scholar
  91. 91.
    Kong B, Bruns P, Behler NA, Chang L, Schlitter AM, Cao J, et al. Dynamic landscape of pancreatic carcinogenesis reveals early molecular networks of malignancy. Gut. 2016.Google Scholar
  92. 92.
    Pinho AV, Rooman I, Reichert M, De Medts N, Bouwens L, Rustgi AK, et al. Adult pancreatic acinar cells dedifferentiate to an embryonic progenitor phenotype with concomitant activation of a senescence programme that is present in chronic pancreatitis. Gut. 2011;60:958–66.PubMedCrossRefGoogle Scholar
  93. 93.
    Krah NM, De La OJ, Swift GH, Hoang CQ, Willet SG, Chen Pan F, et al. The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma. elife 2015:4.Google Scholar
  94. 94.
    Martinelli P, Madriles F, Canamero M, Pau EC, Pozo ND, Guerra C, et al. The acinar regulator Gata6 suppresses KrasG12V-driven pancreatic tumorigenesis in mice. Gut. 2016;65:476–86.PubMedCrossRefGoogle Scholar
  95. 95.
    Shi G, DiRenzo D, Qu C, Barney D, Miley D, Konieczny SF. Maintenance of acinar cell organization is critical to preventing Kras-induced acinar-ductal metaplasia. Oncogene. 2013;32:1950–8.PubMedCrossRefGoogle Scholar
  96. 96.
    Kopp JL, von Figura G, Mayes E, Liu FF, Dubois CL, JPt M, et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;22:737–50.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Liu J, Akanuma N, Liu C, Naji A, Halff GA, Washburn WK, et al. TGF-beta1 promotes acinar to ductal metaplasia of human pancreatic acinar cells. Sci Rep. 2016;6:30904.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Houbracken I, de Waele E, Lardon J, Ling Z, Heimberg H, Rooman I, et al. Lineage tracing evidence for transdifferentiation of acinar to duct cells and plasticity of human pancreas. Gastroenterology. 2011;141:731–41, 41 e1–4.CrossRefGoogle Scholar
  99. 99.
    Strobel O, Dor Y, Alsina J, Stirman A, Lauwers G, Trainor A, et al. In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia. Gastroenterology. 2007;133:1999–2009.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Wollny D, Zhao S, Everlien I, Lun X, Brunken J, Brune D, et al. Single-cell analysis uncovers clonal Acinar cell heterogeneity in the adult pancreas. Dev Cell. 2016;39:289–301.PubMedCrossRefGoogle Scholar
  101. 101.
    Collado M, Serrano M. Senescence in tumours: evidence from mice and humans. Nat Rev Cancer. 2010;10:51–7.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M, et al. Tumour biology: senescence in premalignant tumours. Nature. 2005;436:642.PubMedCrossRefGoogle Scholar
  103. 103.
    Caldwell ME, DeNicola GM, Martins CP, Jacobetz MA, Maitra A, Hruban RH, et al. Cellular features of senescence during the evolution of human and murine ductal pancreatic cancer. Oncogene. 2012;31:1599–608.PubMedCrossRefGoogle Scholar
  104. 104.
    Notta F, Chan-Seng-Yue M, Lemire M, Li Y, Wilson GW, Connor AA, et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature. 2016;538:378–82.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Apte M, Pirola RC, Wilson JS. Pancreatic stellate cell: physiologic role, role in fibrosis and cancer. Curr Opin Gastroenterol. 2015;31:416–23.PubMedCrossRefGoogle Scholar
  106. 106.
    Apte MV, Pirola RC, Wilson JS. Pancreatic stellate cells: a starring role in normal and diseased pancreas. Front Physiol. 2012;3:344.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Andoh A, Takaya H, Saotome T, Shimada M, Hata K, Araki Y, et al. Cytokine regulation of chemokine (IL-8, MCP-1, and RANTES) gene expression in human pancreatic periacinar myofibroblasts. Gastroenterology. 2000;119:211–9.PubMedCrossRefGoogle Scholar
  108. 108.
    Masamune A, Kikuta K, Watanabe T, Satoh K, Satoh A, Shimosegawa T. Pancreatic stellate cells express toll-like receptors. J Gastroenterol. 2008;43:352–62.PubMedCrossRefGoogle Scholar
  109. 109.
    Jesnowski R, Furst D, Ringel J, Chen Y, Schrodel A, Kleeff J, et al. Immortalization of pancreatic stellate cells as an in vitro model of pancreatic fibrosis: deactivation is induced by matrigel and N-acetylcysteine. Lab Investig. 2005;85:1276–91.PubMedCrossRefGoogle Scholar
  110. 110.
    Sherman MH, RT Y, Engle DD, Ding N, Atkins AR, Tiriac H, et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell. 2014;159:80–93.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Rakonczay Z Jr, Hegyi P, Takacs T, McCarroll J, Saluja AK. The role of NF-kappaB activation in the pathogenesis of acute pancreatitis. Gut. 2008;57:259–67.PubMedCrossRefGoogle Scholar
  112. 112.
    Hoque R, Malik AF, Gorelick F, Mehal WZ. Sterile inflammatory response in acute pancreatitis. Pancreas. 2012;41:353–7.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Schmitz-Winnenthal H, Pietsch DH, Schimmack S, Bonertz A, Udonta F, Ge Y, et al. Chronic pancreatitis is associated with disease-specific regulatory T-cell responses. Gastroenterology. 2010;138:1178–88.PubMedCrossRefGoogle Scholar
  114. 114.
    Hense S, Sparmann G, Weber H, Liebe S, Emmrich J. Immunologic characterization of acute pancreatitis in rats induced by dibutyltin dichloride (DBTC). Pancreas. 2003;27:e6–12.PubMedCrossRefGoogle Scholar
  115. 115.
    Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA. The pancreas cancer microenvironment. Clin Cancer Res. 2012;18:4266–76.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Kloppel G, et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell. 2011;19:456–69.PubMedCrossRefGoogle Scholar
  117. 117.
    Ling J, Kang Y, Zhao R, Xia Q, Lee DF, Chang Z, et al. KrasG12D-induced IKK2/beta/NF-kappaB activation by IL-1alpha and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21:105–20.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Logsdon CD, Lu W. The significance of Ras activity in pancreatic cancer initiation. Int J Biol Sci. 2016;12:338–46.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Huang H, Daniluk J, Liu Y, Chu J, Li Z, Ji B, et al. Oncogenic K-Ras requires activation for enhanced activity. Oncogene. 2014;33:532–5.PubMedCrossRefGoogle Scholar
  120. 120.
    Collins MA, Bednar F, Zhang Y, Brisset JC, Galban S, Galban CJ, et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest. 2012;122:639–53.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Collins MA, Yan W, Sebolt-Leopold JS, Pasca di Magliano M. MAPK signaling is required for dedifferentiation of acinar cells and development of pancreatic intraepithelial neoplasia in mice. Gastroenterology. 2014;146:822–34, e7.PubMedGoogle Scholar
  122. 122.
    Halbrook CJ, Wen HJ, Ruggeri JM, Takeuchi KK, Zhang Y, di Magliano MP, et al. Mitogen-activated protein kinase kinase activity maintains acinar-to-ductal metaplasia and is required for organ regeneration in pancreatitis. Cell Mol Gastroenterol Hepatol. 2017;3:99–118.PubMedCrossRefGoogle Scholar
  123. 123.
    Davies CC, Harvey E, McMahon RF, Finegan KG, Connor F, Davis RJ, et al. Impaired JNK signaling cooperates with KrasG12D expression to accelerate pancreatic ductal adenocarcinoma. Cancer Res. 2014;74:3344–56.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Liou GY, Doppler H, Braun UB, Panayiotou R, Scotti Buzhardt M, Radisky DC, et al. Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia. Nat Commun. 2015;6:6200.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Wodziak D, Dong A, Basin MF, Lowe AW. Anterior gradient 2 (AGR2) induced epidermal growth factor receptor (EGFR) signaling is essential for murine pancreatitis-associated tissue regeneration. PLoS One. 2016;11:e0164968.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Sandgren EP, Luetteke NC, Palmiter RD, Brinster RL, Lee DC. Overexpression of TGF alpha in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell. 1990;61:1121–35.PubMedCrossRefGoogle Scholar
  127. 127.
    Miyamoto Y, Maitra A, Ghosh B, Zechner U, Argani P, Iacobuzio-Donahue CA, et al. Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell. 2003;3:565–76.CrossRefPubMedGoogle Scholar
  128. 128.
    Ardito CM, Gruner BM, Takeuchi KK, Lubeseder-Martellato C, Teichmann N, Mazur PK, et al. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell. 2012;22:304–17.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Chen NM, Singh G, Koenig A, Liou GY, Storz P, Zhang JS, et al. NFATc1 links EGFR signaling to induction of Sox9 transcription and acinar-ductal transdifferentiation in the pancreas. Gastroenterology. 2015;148:1024–34, e9.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Prevot PP, Simion A, Grimont A, Colletti M, Khalaileh A, Van den Steen G, et al. Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia. Gut. 2012;61:1723–32.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Baer R, Cintas C, Dufresne M, Cassant-Sourdy S, Schonhuber N, Planque L, et al. Pancreatic cell plasticity and cancer initiation induced by oncogenic Kras is completely dependent on wild-type PI 3-kinase p110alpha. Genes Dev. 2014;28:2621–35.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Wu CY, Carpenter ES, Takeuchi KK, Halbrook CJ, Peverley LV, Bien H, et al. PI3K regulation of RAC1 is required for KRAS-induced pancreatic tumorigenesis in mice. Gastroenterology 2014;147:1405–16, e7.PubMedCentralCrossRefGoogle Scholar
  133. 133.
    Heid I, Lubeseder-Martellato C, Sipos B, Mazur PK, Lesina M, Schmid RM, et al. Early requirement of Rac1 in a mouse model of pancreatic cancer. Gastroenterology. 2011;141:719–30, 30 e1–7.CrossRefGoogle Scholar
  134. 134.
    Lubeseder-Martellato C, Alexandrow K, Hidalgo-Sastre A, Heid I, Boos SL, Briel T, et al. Oncogenic KRas-induced increase in fluid-phase endocytosis is dependent on N-WASP and is required for the formation of pancreatic preneoplastic lesions. EBioMedicine. 2017;15:90–9.PubMedCrossRefGoogle Scholar
  135. 135.
    Folch-Puy E, Granell S, Dagorn JC, Iovanna JL, Closa D. Pancreatitis-associated protein I suppresses NF-kappa B activation through a JAK/STAT-mediated mechanism in epithelial cells. J Immunol. 2006;176:3774–9.PubMedCrossRefGoogle Scholar
  136. 136.
    Miyatsuka T, Kaneto H, Shiraiwa T, Matsuoka TA, Yamamoto K, Kato K, et al. Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation. Genes Dev. 2006;20:1435–40.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    JH Y, Kim KH, Kim H. Suppression of IL-1beta expression by the Jak 2 inhibitor AG490 in cerulein-stimulated pancreatic acinar cells. Biochem Pharmacol. 2006;72:1555–62.CrossRefGoogle Scholar
  138. 138.
    Loncle C, Bonjoch L, Folch-Puy E, Lopez-Millan MB, Lac S, Molejon MI, et al. IL17 functions through the novel REG3beta-JAK2-STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancer. Cancer Res. 2015;75:4852–62.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Baumgart S, Chen NM, Siveke JT, Konig A, Zhang JS, Singh SK, et al. Inflammation-induced NFATc1-STAT3 transcription complex promotes pancreatic cancer initiation by KrasG12D. Cancer Discov. 2014;4:688–701.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Gruber R, Panayiotou R, Nye E, Spencer-Dene B, Stamp G, Behrens A. YAP1 and TAZ control pancreatic cancer initiation in mice by direct up-regulation of JAK-STAT3 signaling. Gastroenterology. 2016;151:526–39.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Daniluk J, Liu Y, Deng D, Chu J, Huang H, Gaiser S, et al. An NF-kappaB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice. J Clin Invest. 2012;122:1519–28.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Philip B, Roland CL, Daniluk J, Liu Y, Chatterjee D, Gomez SB, et al. A high-fat diet activates oncogenic Kras and COX2 to induce development of pancreatic ductal adenocarcinoma in mice. Gastroenterology. 2013;145:1449–58.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Cancer Progression and Metastasis Group, Institute for Cancer ResearchMedical University WienViennaAustria
  2. 2.Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre, CNIOMadridSpain
  3. 3.Departament de Ciències Experimentals i de la SalutUniversitat Pompeu FabraBarcelonaSpain
  4. 4.CIBERONCMadridSpain

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