Inflammation, autophagy, and obesity: Common features in the pathogenesis of pancreatitis and pancreatic cancer

Gastroenterology

Volumn 144, Issue 6, 2013, Pages

  Gukovsky, Ilya ^a,b   Li, Ning ^c   Todoric, Jelena ^c,d   Gukovskaya, Anna ^a,b   Karin, Michael ^c  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

^d MEDICAL UNIVERSITY OF VIENNA   (Austria)

Author keywords

Cytokines; K Ras; Neutrophil; Pancreatic Acinar Cell; Pancreatic Ductal Adenocarcinoma

Indexed keywords

CELL ADHESION MOLECULE; HIGH MOBILITY GROUP B1 PROTEIN; INFLAMMASOME; INTERLEUKIN 10; INTERLEUKIN 1BETA; INTERLEUKIN 22; INTERLEUKIN 6; INTERLEUKIN 8; MACROPHAGE MIGRATION INHIBITION FACTOR; NEUTRALIZING ANTIBODY; REACTIVE OXYGEN METABOLITE; TOLL LIKE RECEPTOR 4; TRANSCRIPTION FACTOR AP 1; TRANSCRIPTION FACTOR NFAT; TUMOR NECROSIS FACTOR ALPHA;

ACINAR CELL; AUTOPHAGY; CANCER RISK; CELL DEATH; CELL INFILTRATION; CYTOKINE STORM; CYTOTOXIC T LYMPHOCYTE; DISEASE COURSE; DISEASE SEVERITY; GENE DELETION; GENETIC MANIPULATION; HUMAN; IMMUNOCOMPETENT CELL; INFLAMMATION; LYMPHOCYTE; MONOCYTE; NONHUMAN; OBESITY; OXIDATIVE STRESS; PANCREAS CANCER; PANCREAS INJURY; PANCREATITIS; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; TRANSCRIPTION INITIATION;

EID: 84876796439     PISSN: 00165085     EISSN: 15280012     Source Type: Journal    
DOI: 10.1053/j.gastro.2013.02.007     Document Type: Article

References (200)

1. A. Mantovani, M.A. Cassatella, C. Costantini Neutrophils in the activation and regulation of innate and adaptive immunity Nat Rev Immunol 11 2011 519 531
2. C. Nathan, A. Ding Nonresolving inflammation Cell 140 2010 871 882
3. O. Soehnlein, L. Lindbom Phagocyte partnership during the onset and resolution of inflammation Nat Rev Immunol 10 2010 427 439
4. S.T. Smale Selective transcription in response to an inflammatory stimulus Cell 140 2010 833 844
5. S. Baumgart, V. Ellenrieder, M.E. Fernandez-Zapico Oncogenic transcription factors: cornerstones of inflammation-linked pancreatic carcinogenesis Gut 62 2013 310 316
6. T. Strowig, J. Henao-Mejia, E. Elinav Inflammasomes in health and disease Nature 481 2012 278 286
7. R. Hoque, A.F. Malik, F. Gorelick Sterile inflammatory response in acute pancreatitis Pancreas 41 2012 353 357
8. A. Buter, C.W. Imrie, C.R. Carter Dynamic nature of early organ dysfunction determines outcome in acute pancreatitis Br J Surg 89 2002 298 302
9. R. Mofidi, M.D. Duff, S.J. Wigmore Association between early systemic inflammatory response, severity of multiorgan dysfunction and death in acute pancreatitis Br J Surg 93 2006 738 744
10. S.J. Pandol, A.K. Saluja, C.W. Imrie Acute pancreatitis: bench to the bedside [erratum appears in Gastroenterology 2007;133:1056] Gastroenterology 132 2007 1127 1151
11. V.K. Singh, B.U. Wu, T.L. Bollen Early systemic inflammatory response syndrome is associated with severe acute pancreatitis Clin Gastroenterol Hepatol 7 2009 1247 1251
12. H.G. Leser, V. Gross, C. Scheibenbogen Elevation of serum interleukin-6 concentration precedes acute-phase response and reflects severity in acute pancreatitis Gastroenterology 101 1991 782 785
13. J. Norman The role of cytokines in the pathogenesis of acute pancreatitis Am J Surg 175 1998 76 83
14. A.S. Gukovskaya, I. Gukovsky, V. Zaninovic Pancreatic acinar cells produce, release, and respond to tumor necrosis factor-alpha Role in regulating cell death and pancreatitis J Clin Invest 100 1997 1853 1862
15. T. Grady, P. Liang, S.A. Ernst Chemokine gene expression in rat pancreatic acinar cells is an early event associated with acute pancreatitis Gastroenterology 113 1997 1966 1975
16. L.S. Orlichenko, J. Behari, T.H. Yeh Transcriptional regulation of CXC-ELR chemokines KC and MIP-2 in mouse pancreatic acini Am J Physiol Gastrointest Liver Physiol 299 2010 G867 G876
17. I. Gukovsky, A.S. Gukovskaya, T.A. Blinman Early NF-kappaB activation is associated with hormone-induced pancreatitis Am J Physiol Gastrointest Liver Physiol 275 1998 G1402 G1414
18. E. Vaquero, I. Gukovsky, V. Zaninovic Localized pancreatic NF-kappaB activation and inflammatory response in taurocholate-induced pancreatitis Am J Physiol Gastrointest Liver Physiol 280 2001 G1197 G1208
19. M. Bhatia, M. Brady, S. Shokuhi Inflammatory mediators in acute pancreatitis J Pathol 190 2000 117 125
20. A.K. Saluja, M.M. Lerch, P.A. Phillips Why does pancreatic overstimulation cause pancreatitis? Annu Rev Physiol 69 2007 249 269
21. K. Saeki, T. Kanai, M. Nakano CCL2-induced migration and SOCS3-mediated activation of macrophages are involved in cerulein-induced pancreatitis in mice Gastroenterology 142 2012 1010 1020.e9
22. G. Perides, E.R. Weiss, E.S. Michael TNF-alpha-dependent regulation of acute pancreatitis severity by Ly-6C(hi) monocytes in mice J Biol Chem 286 2011 13327 13335
23. A.S. Bedrosian, A.H. Nguyen, M. Hackman Dendritic cells promote pancreatic viability in mice with acute pancreatitis Gastroenterology 141 2011 1915 1926.e1-14
24. R. Hoque, M. Sohail, A. Malik TLR9 and the NLRP3 inflammasome link acinar cell death with inflammation in acute pancreatitis Gastroenterology 141 2011 358 369
25. A. Demols, O. Le Moine, F. Desalle CD4(+)T cells play an important role in acute experimental pancreatitis in mice Gastroenterology 118 2000 582 590
26. A. Vonlaufen, M.V. Apte, B.A. Imhof The role of inflammatory and parenchymal cells in acute pancreatitis J Pathol 213 2007 239 248
27. M.K. Shanmugam, M. Bhatia The role of pro-inflammatory molecules and pharmacological agents in acute pancreatitis and sepsis Inflamm Allergy Drug Targets 9 2010 20 31
28. J.L. Frossard, P. Morel, C.M. Pastor Why clinical trials might succeed in acute pancreatitis when they failed in septic shock JOP 4 2003 11 16
29. E. Aoun, J. Chen, D. Reighard Diagnostic accuracy of interleukin-6 and interleukin-8 in predicting severe acute pancreatitis: a meta-analysis Pancreatology 9 2009 777 785
30. Z. Dambrauskas, N. Giese, A. Gulbinas Different profiles of cytokine expression during mild and severe acute pancreatitis World J Gastroenterol 16 2010 1845 1853
31. A.U. Steinle, H. Weidenbach, M. Wagner NF-kappaB/Rel activation in cerulein pancreatitis Gastroenterology 116 1999 420 430
32. X. Chen, B. Ji, B. Han NF-kappaB activation in pancreas induces pancreatic and systemic inflammatory response Gastroenterology 122 2002 448 457
33. D. Altavilla, C. Famulari, M. Passaniti Attenuated cerulein-induced pancreatitis in nuclear factor-kappaB-deficient mice Lab Invest 83 2003 1723 1732
34. Z. Rakonczay Jr, P. Hegyi, T. Takacs The role of NF-kappaB activation in the pathogenesis of acute pancreatitis Gut 57 2008 259 267
35. P. Neuhofer, S. Liang, H. Einwachter Deletion of IkappaBalpha activates RelA to reduce acute pancreatitis in mice through up-regulation of Spi2A Gastroenterology 144 2013 192 201
36. H. Huang, Y. Liu, J. Daniluk Activation of nuclear factor-kappaB in acinar cells increases the severity of pancreatitis in mice Gastroenterology 144 2013 202 210
37. I. Gukovsky, A. Gukovskaya Nuclear factor-kappaB in pancreatitis: jack-of-all-trades, but which one is more important? Gastroenterology 144 2013 26 29
38. D. Awla, A.V. Zetterqvist, A. Abdulla NFATc3 regulates trypsinogen activation, neutrophil recruitment, and tissue damage in acute pancreatitis in mice Gastroenterology 143 2012 1352 1360
39. B. Han, C.D. Logsdon CCK stimulates mob-1 expression and NF-kappaB activation via protein kinase C and intracellular Ca(2+) Am J Physiol Cell Physiol 278 2000 C344 C351
40. Y. Tando, H. Algul, M. Wagner Caerulein-induced NF-kappaB/Rel activation requires both Ca2+ and protein kinase C as messengers Am J Physiol Gastrointest Liver Physiol 277 1999 G678 G686
41. A. Satoh, A.S. Gukovskaya, J.M. Nieto PKC-delta and -epsilon regulate NF-kappaB activation induced by cholecystokinin and TNF-alpha in pancreatic acinar cells Am J Physiol Gastrointest Liver Physiol 287 2004 G582 G591
42. A. Satoh, A.S. Gukovskaya, J.R. Reeve Jr Ethanol sensitizes NF-kappaB activation in pancreatic acinar cells through effects on protein kinase C-epsilon Am J Physiol Gastrointest Liver Physiol 291 2006 G432 G438
43. E.C. Thrower, J. Yuan, A. Usmani A novel protein kinase D inhibitor attenuates early events of experimental pancreatitis in isolated rat acini Am J Physiol Gastrointest Liver Physiol 300 2011 G120 G129
44. R. Sharif, R. Dawra, K. Wasiluk Impact of toll-like receptor 4 on the severity of acute pancreatitis and pancreatitis-associated lung injury in mice Gut 58 2009 813 819
45. D. Awla, A. Abdulla, S. Regner TLR4 but not TLR2 regulates inflammation and tissue damage in acute pancreatitis induced by retrograde infusion of taurocholate Inflamm Res 60 2011 1093 1098
46. W. Denham, J. Yang, G. Fink Gene targeting demonstrates additive detrimental effects of interleukin 1 and tumor necrosis factor during pancreatitis Gastroenterology 113 1997 1741 1746
47. J.L. Frossard, A. Saluja, L. Bhagat The role of intercellular adhesion molecule 1 and neutrophils in acute pancreatitis and pancreatitis-associated lung injury Gastroenterology 116 1999 694 701
48. M. Sendler, A. Dummer, F.U. Weiss Tumour necrosis factor α secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice Gut 62 2013 430 439
49. D. Awla, A. Abdulla, I. Syk Neutrophil-derived matrix metalloproteinase-9 is a potent activator of trypsinogen in acinar cells in acute pancreatitis J Leukoc Biol 91 2012 711 719
50. J.L. Frossard, S. Lenglet, F. Montecucco Role of CCL-2, CCR-2 and CCR-4 in cerulein-induced acute pancreatitis and pancreatitis-associated lung injury J Clin Pathol 64 2011 387 393
51. Y. Sakai, A. Masamune, A. Satoh Macrophage migration inhibitory factor is a critical mediator of severe acute pancreatitis Gastroenterology 124 2003 725 736
52. V. Zaninovic, A.S. Gukovskaya, I. Gukovsky Cerulein upregulates ICAM-1 in pancreatic acinar cells, which mediates neutrophil adhesion to these cells Am J Physiol Gastrointest Liver Physiol 279 2000 G666 G676
53. H. Hartman, A. Abdulla, D. Awla P-selectin mediates neutrophil rolling and recruitment in acute pancreatitis Br J Surg 99 2012 246 255
54. D. Sandoval, A. Gukovskaya, P. Reavey The role of neutrophils and platelet-activating factor in mediating experimental pancreatitis Gastroenterology 111 1996 1081 1091
55. A.S. Gukovskaya, E. Vaquero, V. Zaninovic Neutrophils and NADPH oxidase mediate intrapancreatic trypsin activation in murine experimental acute pancreatitis Gastroenterology 122 2002 974 984
56. A. Abdulla, D. Awla, H. Thorlacius Role of neutrophils in the activation of trypsinogen in severe acute pancreatitis J Leukoc Biol 90 2011 975 982
57. D. Awla, A. Abdulla, S. Zhang Lymphocyte function antigen-1 regulates neutrophil recruitment and tissue damage in acute pancreatitis Br J Pharmacol 163 2011 413 423
58. W. Hartwig, M. Klafs, M. Kirschfink Interaction of complement and leukocytes in severe acute pancreatitis: potential for therapeutic intervention Am J Physiol Gastrointest Liver Physiol 291 2006 G844 G850
59. J. Werner, W. Hartwig, T. Hackert Multidrug strategies are effective in the treatment of severe experimental pancreatitis Surgery 151 2012 372 381
60. F. Marrache, S.P. Tu, G. Bhagat Overexpression of interleukin-1beta in the murine pancreas results in chronic pancreatitis Gastroenterology 135 2008 1277 1287
61. C. Moreno, C. Nicaise, T. Gustot Chemokine receptor CCR5 deficiency exacerbates cerulein-induced acute pancreatitis in mice Am J Physiol Gastrointest Liver Physiol 291 2006 G1089 G1099
62. G.E. White, A.J. Iqbal, D.R. Greaves CC chemokine receptors and chronic inflammation-therapeutic opportunities and pharmacological challenges Pharmacol Rev 65 2013 47 89
63. A. Demols, J.L. Van Laethem, E. Quertinmont Endogenous interleukin-10 modulates fibrosis and regeneration in experimental chronic pancreatitis Am J Physiol Gastrointest Liver Physiol 282 2002 G1105 G1112
64. D. Feng, O. Park, S. Radaeva Interleukin-22 ameliorates cerulein-induced pancreatitis in mice by inhibiting the autophagic pathway Int J Biol Sci 8 2012 249 257
65. Y. Koike, T. Kanai, K. Saeki MyD88-dependent interleukin-10 production from regulatory CD11b(+)Gr-1(high) cells suppresses development of acute cerulein pancreatitis in mice Immunol Lett 148 2012 172 177
66. J. Xue, D.T. Nguyen, A. Habtezion Aryl hydrocarbon receptor regulates pancreatic IL-22 production and protects mice from acute pancreatitis Gastroenterology 143 2012 1670 1680
67. W.E. Naugler, M. Karin The wolf in sheep's clothing: the role of interleukin-6 in immunity, inflammation and cancer Trends Mol Med 14 2008 109 119
68. S.A. Jones, J. Scheller, S. Rose-John Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling J Clin Invest 121 2011 3375 3383
69. J. Scheller, A. Chalaris, D. Schmidt-Arras The pro- and anti-inflammatory properties of the cytokine interleukin-6 Biochim Biophys Acta 1813 2011 878 888
70. K.C. Chao, K.F. Chao, C.C. Chuang Blockade of interleukin 6 accelerates acinar cell apoptosis and attenuates experimental acute pancreatitis in vivo Br J Surg 93 2006 332 338
71. S. Cuzzocrea, E. Mazzon, L. Dugo Absence of endogenous interleukin-6 enhances the inflammatory response during acute pancreatitis induced by cerulein in mice Cytokine 18 2002 274 285
72. H. Witt, M.V. Apte, V. Keim Chronic pancreatitis: challenges and advances in pathogenesis, genetics, diagnosis, and therapy Gastroenterology 132 2007 1557 1573
73. G. Sparmann, S. Behrend, J. Merkord Cytokine mRNA levels and lymphocyte infiltration in pancreatic tissue during experimental chronic pancreatitis induced by dibutyltin dichloride Dig Dis Sci 46 2001 1647 1656
74. S. Hense, G. Sparmann, H. Weber Immunologic characterization of acute pancreatitis in rats induced by dibutyltin dichloride (DBTC) Pancreas 27 2003 e6 e12
75. Y. Sakaguchi, M. Inaba, M. Tsuda The Wistar Bonn Kobori rat, a unique animal model for autoimmune pancreatitis with extrapancreatic exocrinopathy Clin Exp Immunol 152 2008 1 12
76. H. Schmitz-Winnenthal, D.H. Pietsch, S. Schimmack Chronic pancreatitis is associated with disease-specific regulatory T-cell responses Gastroenterology 138 2010 1178 1188
77. R.E. Hunger, C. Mueller, K. Z'Graggen Cytotoxic cells are activated in cellular infiltrates of alcoholic chronic pancreatitis Gastroenterology 112 1997 1656 1663
78. A.M. Kaiser, A.K. Saluja, A. Sengupta Relationship between severity, necrosis, and apoptosis in five models of experimental acute pancreatitis Am J Physiol Cell Physiol 269 1995 C1295 C1304
79. M. Bhatia Apoptosis versus necrosis in acute pancreatitis Am J Physiol Gastrointest Liver Physiol 286 2004 G189 G196
80. O.A. Mareninova, K.F. Sung, P. Hong Cell death in pancreatitis: caspases protect from necrotizing pancreatitis J Biol Chem 281 2006 3370 3381
81. Y. Nakamura, J.H. Do, J. Yuan Inflammatory cells regulate p53 and caspases in acute pancreatitis Am J Physiol Gastrointest Liver Physiol 298 2010 G92 G100
82. A.A. Aghdassi, J. Mayerle, S. Christochowitz Animal models for investigating chronic pancreatitis Fibrogenesis Tissue Repair 4 2011 26
83. R. Pezzilli, R. Ceciliato, B. Barakat Immune-manipulation of the inflammatory response in acute pancreatitis What can be expected? JOP 5 2004 115 121
84. U.C. Bang, S. Semb, C. Nojgaard Pharmacological approach to acute pancreatitis World J Gastroenterol 14 2008 2968 2976
85. M.L. Kylanpaa, H. Repo, P.A. Puolakkainen Inflammation and immunosuppression in severe acute pancreatitis World J Gastroenterol 16 2010 2867 2872
86. H. Algul, M. Treiber, M. Lesina Pancreas-specific RelA/p65 truncation increases susceptibility of acini to inflammation-associated cell death following cerulein pancreatitis J Clin Invest 117 2007 1490 1501
87. B. Baumann, M. Wagner, T. Aleksic Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo J Clin Invest 117 2007 1502 1513
88. M. Zhou, B. Chen, H. Sun The protective effects of Lipoxin A4 during the early phase of severe acute pancreatitis in rats Scand J Gastroenterol 46 2011 211 219
89. C.N. Serhan, S. Krishnamoorthy, A. Recchiuti Novel anti-inflammatory-pro- resolving mediators and their receptors Curr Top Med Chem 11 2011 629 647
90. N. Bardeesy, R.A. DePinho Pancreatic cancer biology and genetics Nat Rev Cancer 2 2002 897 909
91. A.F. Hezel, A.C. Kimmelman, B.Z. Stanger Genetics and biology of pancreatic ductal adenocarcinoma Genes Dev 20 2006 1218 1249
92. A. Maitra, R.H. Hruban Pancreatic cancer Annu Rev Pathol 3 2008 157 188
93. M. Erkan, S. Hausmann, C.W. Michalski The role of stroma in pancreatic cancer: diagnostic and therapeutic implications Nat Rev Gastroenterol Hepatol 9 2012 454 467
94. C. Feig, A. Gopinathan, A. Neesse The pancreas cancer microenvironment Clin Cancer Res 18 2012 4266 4276
95. S.I. Grivennikov, F.R. Greten, M. Karin Immunity, inflammation, and cancer Cell 140 2010 883 899
96. A. Fukuda, S.C. Wang, J.P. Morris 4th Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression Cancer Cell 19 2011 441 455
97. M. Lesina, M.U. Kurkowski, K. Ludes Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer Cancer Cell 19 2011 456 469
98. N. Li, S.I. Grivennikov, M. Karin The unholy trinity: inflammation, cytokines, and STAT3 shape the cancer microenvironment Cancer Cell 19 2011 429 431
99. J. Ling, Y. Kang, R. Zhao KrasG12D-induced IKK2/beta/NF-kappaB activation by IL-1alpha and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma Cancer Cell 21 2012 105 120
100. E. Maniati, M. Bossard, N. Cook Crosstalk between the canonical NF-kappaB and Notch signaling pathways inhibits Ppargamma expression and promotes pancreatic cancer progression in mice J Clin Invest 121 2011 4685 4699
101. C.E. Clark, S.R. Hingorani, R. Mick Dynamics of the immune reaction to pancreatic cancer from inception to invasion Cancer Res 67 2007 9518 9527
102. A.D. Cox, K.P. Olive Silencing the killers: paracrine immune suppression in pancreatic cancer Cancer Cell 21 2012 715 716
103. L.J. Bayne, G.L. Beatty, N. Jhala Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer Cancer Cell 21 2012 822 835
104. Y. Pylayeva-Gupta, K.E. Lee, C.H. Hajdu Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia Cancer Cell 21 2012 836 847
105. C. Guerra, A.J. Schuhmacher, M. Canamero Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice Cancer Cell 11 2007 291 302
106. C. Guerra, M. Collado, C. Navas Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence Cancer Cell 19 2011 728 739
107. A.D. Rhim, E.T. Mirek, N.M. Aiello EMT and dissemination precede pancreatic tumor formation Cell 148 2012 349 361
108. S.I. Grivennikov, M. Karin Inflammation and oncogenesis: a vicious connection Curr Opin Genet Dev 20 2010 65 71
109. J. Daniluk, Y. Liu, D. Deng An NF-kappaB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice J Clin Invest 122 2012 1519 1528
110. B. Levine, G. Kroemer Autophagy in the pathogenesis of disease Cell 132 2008 27 42
111. N. Mizushima Autophagy: process and function Genes Dev 21 2007 2861 2873
112. N. Mizushima, T. Yoshimori, Y. Ohsumi The role of atg proteins in autophagosome formation Annu Rev Cell Dev Biol 27 2011 107 132
113. D.J. Klionsky, F.C. Abdalla, H. Abeliovich Guidelines for the use and interpretation of assays for monitoring autophagy Autophagy 8 2012 445 544
114. B. Ravikumar, S. Sarkar, J.E. Davies Regulation of mammalian autophagy in physiology and pathophysiology Physiol Rev 90 2010 1383 1435
115. P. Saftig, J. Klumperman Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function Nat Rev Mol Cell Biol 10 2009 623 635
116. A.S. Gukovskaya, I. Gukovsky Autophagy and pancreatitis Am J Physiol Gastrointest Liver Physiol 303 2012 G993 G1003
117. G. Adler, G. Rohr, H.F. Kern Alteration of membrane fusion as a cause of acute pancreatitis in the rat Dig Dis Sci 27 1982 993 1002
118. H.J. Aho, T.J. Nevalainen, V.T. Havia Human acute pancreatitis: a light and electron microscopic study Acta Pathol Microbiol Immunol Scand A 90 1982 367 373
119. H. Helin, M. Mero, H. Markkula Pancreatic acinar ultrastructure in human acute pancreatitis Virchows Arch A Pathol Anat Histol 387 1980 259 270
120. H. Koike, M.L. Steer, J. Meldolesi Pancreatic effects of ethionine: blockade of exocytosis and appearance of crinophagy and autophagy precede cellular necrosis Am J Physiol 242 1982 G297 G307
121. C. Niederau, J.H. Grendell Intracellular vacuoles in experimental acute pancreatitis in rats and mice are an acidified compartment J Clin Invest 81 1988 229 236
122. S. Willemer, G. Kloppel, H.F. Kern Immunocytochemical and morphometric analysis of acinar zymogen granules in human acute pancreatitis Virchows Arch A Pathol Anat Histopathol 415 1989 115 123
123. O.A. Mareninova, K. Hermann, S.W. French Impaired autophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitis J Clin Invest 119 2009 3340 3355
124. D. Grasso, A. Ropolo, A. Lo Re Zymophagy, a novel selective autophagy pathway mediated by VMP1-USP9x-p62, prevents pancreatic cell death J Biol Chem 286 2011 8308 8324
125. F. Fortunato, H. Burgers, F. Bergmann Impaired autolysosome formation correlates with Lamp-2 depletion: role of apoptosis, autophagy, and necrosis in pancreatitis Gastroenterology 137 2009 350 360 360.e1-5
126. D. Hashimoto, M. Ohmuraya, M. Hirota Involvement of autophagy in trypsinogen activation within the pancreatic acinar cells J Cell Biol 181 2008 1065 1072
127. M. Komatsu, S. Kageyama, Y. Ichimura p62/SQSTM1/A170: physiology and pathology Pharmacol Res 66 2012 457 462
128. J. Moscat, M.T. Diaz-Meco p62: a versatile multitasker takes on cancer Trends Biochem Sci 37 2012 230 236
129. I. Gukovsky, S.J. Pandol, O.A. Mareninova Impaired autophagy and organellar dysfunction in pancreatitis J Gastroenterol Hepatol 27 Suppl 2 2012 27 32
130. I. Gukovsky, S.J. Pandol, A.S. Gukovskaya Organellar dysfunction in the pathogenesis of pancreatitis Antioxid Redox Signal 15 2011 2699 2710
131. M. Alirezaei, C.T. Flynn, J.L. Whitton Interactions between enteroviruses and autophagy in vivo Autophagy 8 2012 973 975
132. M. Boonen, E. van Meel, V. Oorschot Vacuolization of mucolipidosis type II mouse exocrine gland cells represents accumulation of autolysosomes Mol Biol Cell 22 2011 1135 1147
133. M. Ohmuraya, M. Hirota, M. Araki Autophagic cell death of pancreatic acinar cells in serine protease inhibitor Kazal type 3-deficient mice Gastroenterology 129 2005 696 705
134. J.M. Romac, M. Ohmuraya, C. Bittner Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype Am J Physiol Gastrointest Liver Physiol 298 2010 G518 G524
135. N. Li, X. Wu, R.G. Holzer Loss of acinar cell Ikka triggers spontaneous pancreatitis in mice J Clin Invest 2013 April 8 Epub ahead of print
136. W. Halangk, M.M. Lerch, B. Brandt-Nedelev Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis J Clin Invest 106 2000 773 781
137. T. Wartmann, J. Mayerle, T. Kahne Cathepsin L inactivates human trypsinogen, whereas cathepsin L-deletion reduces the severity of pancreatitis in mice Gastroenterology 138 2010 726 737
138. M. Aghajan, N. Li, M. Karin Obesity, autophagy and the pathogenesis of liver and pancreatic cancers J Gastroenterol Hepatol 27 Suppl 2 2012 10 14
139. A.C. Kimmelman The dynamic nature of autophagy in cancer Genes Dev 25 2011 1999 2010
140. E. White Deconvoluting the context-dependent role for autophagy in cancer Nature reviews Cancer 12 2012 401 410
141. S. Yang, X. Wang, G. Contino Pancreatic cancers require autophagy for tumor growth Genes Dev 25 2011 717 729
142. S. Yang, A.C. Kimmelman A critical role for autophagy in pancreatic cancer Autophagy 7 2011 912 913
143. J.Y. Guo, H.Y. Chen, R. Mathew Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis Genes Dev 25 2011 460 470
144. H. Ying, A.C. Kimmelman, C.A. Lyssiotis Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism Cell 149 2012 656 670
145. R. Lock, S. Roy, C.M. Kenific Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation Mol Biol Cell 22 2011 165 178
146. J.H. Kim, H.Y. Kim, Y.K. Lee Involvement of mitophagy in oncogenic K-Ras-induced transformation: overcoming a cellular energy deficit from glucose deficiency Autophagy 7 2011 1187 1198
147. G. Bellot, R. Garcia-Medina, P. Gounon Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains Mol Cell Biol 29 2009 2570 2581
148. I. Papandreou, A.L. Lim, K. Laderoute Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L Cell Death Differ 15 2008 1572 1581
149. V. Rausch, L. Liu, A. Apel Autophagy mediates survival of pancreatic tumour-initiating cells in a hypoxic microenvironment J Pathol 227 2012 325 335
150. K. Degenhardt, R. Mathew, B. Beaudoin Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis Cancer Cell 10 2006 51 64
151. A. Kuraishy, M. Karin, S.I. Grivennikov Tumor promotion via injury- and death-induced inflammation Immunity 35 2011 467 477
152. M. Baumgart, M. Werther, A. Bockholt Genomic instability at both the base pair level and the chromosomal level is detectable in earliest PanIN lesions in tissues of chronic pancreatitis Pancreas 39 2010 1093 1103
153. Y. Inami, S. Waguri, A. Sakamoto Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells J Cell Biol 193 2011 275 284
154. A. Takamura, M. Komatsu, T. Hara Autophagy-deficient mice develop multiple liver tumors Genes Dev 25 2011 795 800
155. U.K. Bhanot, P. Moller Mechanisms of parenchymal injury and signaling pathways in ectatic ducts of chronic pancreatitis: implications for pancreatic carcinogenesis Lab Invest 89 2009 489 497
156. M. Komatsu, S. Waguri, M. Koike Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice Cell 131 2007 1149 1163
157. M. Komatsu, H. Kurokawa, S. Waguri The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1 Nat Cell Biol 12 2010 213 223
158. G.M. DeNicola, F.A. Karreth, T.J. Humpton Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis Nature 475 2011 106 109
159. V. Deretic Autophagy: an emerging immunological paradigm J Immunol 189 2012 15 20
160. D.R. Green, L. Galluzzi, G. Kroemer Mitochondria and the autophagy-inflammation-cell death axis in organismal aging Science 333 2011 1109 1112
161. C.S. Shi, K. Shenderov, N.N. Huang Activation of autophagy by inflammatory signals limits IL-1beta production by targeting ubiquitinated inflammasomes for destruction Nat Immunol 13 2012 255 263
162. G.S. Hotamisligil, E. Erbay Nutrient sensing and inflammation in metabolic diseases Nat Rev Immunol 8 2008 923 934
163. O. Osborn, J.M. Olefsky The cellular and signaling networks linking the immune system and metabolism in disease Nat Med 18 2012 363 374
164. S.P. Weisberg, D. McCann, M. Desai Obesity is associated with macrophage accumulation in adipose tissue J Clin Invest 112 2003 1796 1808
165. A.R. Johnson, J.J. Milner, L. Makowski The inflammation highway: metabolism accelerates inflammatory traffic in obesity Immunol Rev 249 2012 218 238
166. R. Stienstra, J.A. van Diepen, C.J. Tack Inflammasome is a central player in the induction of obesity and insulin resistance Proc Natl Acad Sci U S A 108 2011 15324 15329
167. S.Z. Hasnain, R. Lourie, I. Das The interplay between endoplasmic reticulum stress and inflammation Immunol Cell Biol 90 2012 260 270
168. L. Yang, P. Li, S. Fu Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance Cell Metab 11 2010 467 478
169. E.J. Anderson, M.E. Lustig, K.E. Boyle Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans J Clin Invest 119 2009 573 581
170. J.L. Frossard, P. Lescuyer, C.M. Pastor Experimental evidence of obesity as a risk factor for severe acute pancreatitis World J Gastroenterol 15 2009 5260 5265
171. S. Navina, C. Acharya, J.P. DeLany Lipotoxicity causes multisystem organ failure and exacerbates acute pancreatitis in obesity Sci Transl Med 3 2011 107ra110
172. M. Pini, J.A. Sennello, R.J. Cabay Effect of diet-induced obesity on acute pancreatitis induced by administration of interleukin-12 plus interleukin-18 in mice Obesity (Silver Spring) 18 2010 476 481
173. J.A. Sennello, R. Fayad, M. Pini Interleukin-18, together with interleukin-12, induces severe acute pancreatitis in obese but not in nonobese leptin-deficient mice Proc Natl Acad Sci U S A 105 2008 8085 8090
174. N.J. Zyromski, A. Mathur, H.A. Pitt A murine model of obesity implicates the adipokine milieu in the pathogenesis of severe acute pancreatitis Am J Physiol Gastrointest Liver Physiol 295 2008 G552 G558
175. N. Franco-Pons, S. Gea-Sorli, D. Closa Release of inflammatory mediators by adipose tissue during acute pancreatitis J Pathol 221 2010 175 182
176. M. Wiseman The second World Cancer Research Fund/American Institute for Cancer Research expert report Food, nutrition, physical activity, and the prevention of cancer: a global perspective Proc Nutr Soc 67 2008 253 256
177. G.C. Chu, A.C. Kimmelman, A.F. Hezel Stromal biology of pancreatic cancer J Cell Biochem 101 2007 887 907
178. A. Neesse, P. Michl, K.K. Frese Stromal biology and therapy in pancreatic cancer Gut 60 2011 861 868
179. M.L. Curti, P. Jacob, M.C. Borges Studies of gene variants related to inflammation, oxidative stress, dyslipidemia, and obesity: implications for a nutrigenetic approach J Obes 2011 2011 497401
180. N. Miron, M.M. Miron, V.G. Milea Proinflammatory cytokines: an insight into pancreatic oncogenesis Roum Arch Microbiol Immunol 69 2010 183 189
181. J. Khasawneh, M.D. Schulz, A. Walch Inflammation and mitochondrial fatty acid beta-oxidation link obesity to early tumor promotion Proc Natl Acad Sci U S A 106 2009 3354 3359
182. B. Sun, M. Karin Obesity, inflammation, and liver cancer J Hepat 56 2012 704 713
183. B. Vandanmagsar, Y.H. Youm, A. Ravussin The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance Nat Med 17 2011 179 188
184. E.J. Park, J.H. Lee, G.Y. Yu Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression Cell 140 2010 197 208
185. H.C. Crawford, C.R. Scoggins, M.K. Washington Matrix metalloproteinase-7 is expressed by pancreatic cancer precursors and regulates acinar-to-ductal metaplasia in exocrine pancreas J Clin Invest 109 2002 1437 1444
186. H. Yamamoto, F. Itoh, S. Iku Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human pancreatic adenocarcinomas: clinicopathologic and prognostic significance of matrilysin expression J Clin Oncol 19 2001 1118 1127
187. E.E. Calle, R. Kaaks Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms Nat Rev Cancer 4 2004 579 591
188. D.A. Altomare, S. Tanno, A. De Rienzo Frequent activation of AKT2 kinase in human pancreatic carcinomas J Cell Biochem 87 2002 470 476
189. C.M. Taniguchi, B. Emanuelli, C.R. Kahn Critical nodes in signalling pathways: insights into insulin action Nat Rev Mol Cell Biol 7 2006 85 96
190. S.D. Hursting, N.A. Berger Energy balance, host-related factors, and cancer progression J Clin Oncol 28 2010 4058 4065
191. D. Cirillo, A.M. Rachiglio, R. la Montagna Leptin signaling in breast cancer: an overview J Cell Biochem 105 2008 956 964
192. J.I. Fenton, S.D. Hursting, S.N. Perkins Interleukin-6 production induced by leptin treatment promotes cell proliferation in an Apc (Min/+) colon epithelial cell line Carcinogenesis 27 2006 1507 1515
193. M. Dalamaga, I. Migdalis, J.L. Fargnoli Pancreatic cancer expresses adiponectin receptors and is associated with hypoleptinemia and hyperadiponectinemia: a case-control study Cancer Causes Control 20 2009 625 633
194. M.C. Chang, Y.T. Chang, T.C. Su Adiponectin as a potential differential marker to distinguish pancreatic cancer and chronic pancreatitis Pancreas 35 2007 16 21
195. R.Z. Stolzenberg-Solomon, S. Weinstein, M. Pollak Prediagnostic adiponectin concentrations and pancreatic cancer risk in male smokers Am J Epidemiol 168 2008 1047 1055
196. A.L. McCleary-Wheeler, G.A. Lomberk, F.U. Weiss Insights into the epigenetic mechanisms controlling pancreatic carcinogenesis Cancer Lett 328 2013 212 221
197. U. Burk, J. Schubert, U. Wellner A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells EMBO Rep 9 2008 582 589
198. S. Ali, A. Ahmad, S. Banerjee Gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin or its analogue CDF Cancer Res 70 2010 3606 3617
199. E.B. Wendlandt, J.W. Graff, T.L. Gioannini The role of microRNAs miR-200b and miR-200c in TLR4 signaling and NF-kappaB activation Innate Immun 18 2012 846 855
200. D.V. Chartoumpekis, A. Zaravinos, P.G. Ziros Differential expression of microRNAs in adipose tissue after long-term high-fat diet-induced obesity in mice PLoS One 7 2012 e34872