Chronic Pancreatitis and Pancreatic Cancer

Chapter

Abstract

Pancreatic cancer is one of the deadliest diseases and the current therapeutic maneuvers have little impact on disease course and outcome. While understanding the cellular and molecular mechanisms underlying pancreatic cancer pathogenesis has long been one of the major focuses of cancer research, recent studies have unprecedentedly uncovered molecular and cellular bases for the sequential transformation from normal pancreatic epithelium to invasive pancreatic cancer. However, targeted therapy against genetic events accompanying this roadmap failed to generate benefits in clinic. Recent studies have identified that chronic inflammation in microenvironment is one of the critical factors initiating and driving pancreatic carcinogenesis. Targeted manipulation of certain components in tumor microenvironment has shown therapeutic promises in clinic. In this review, we will summarize current knowledge on the roles of inflammation and chronic pancreatitis in pancreatic cancer initiation and progression, and its clinic significance in early detection and intervention of pancreatic cancer.

Notes

Acknowledgment

Funding: Supported in part by grants R01-CA129956, R01-CA148954, R01CA152309 and R01CA172233, and R01CA195651; and grant No.81402017 from NSFC of China.

Conflicts of Interest: The authors disclose no conflicts.

References

  1. Akakura N, et al. Constitutive expression of hypoxia-inducible factor-1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Res. 2001;61:6548–54.PubMedGoogle Scholar
  2. Asaumi H, Watanabe S, Taguchi M, Tashiro M, Otsuki M. Externally applied pressure activates pancreatic stellate cells through the generation of intracellular reactive oxygen species. Am J Physiol Gastrointest Liver Physiol. 2007;293:G972–8.CrossRefPubMedGoogle Scholar
  3. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357:539–45.CrossRefPubMedGoogle Scholar
  4. Ballehaninna UK, Chamberlain RS. Serum CA 19-9 as a biomarker for pancreatic cancer—a comprehensive review. Indian J Surg Oncol. 2011;2:88–100.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bansal P, Sonnenberg A. Pancreatitis is a risk factor for pancreatic cancer. Gastroenterology. 1995;109:247–51.CrossRefPubMedGoogle Scholar
  6. Bardeesy N, DePinho RA. Pancreatic cancer biology and genetics. Nat Rev Cancer. 2002;2:897–909.CrossRefPubMedGoogle Scholar
  7. Beatty GL, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331:1612–6.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Berezikov E. Evolution of microRNA diversity and regulation in animals. Nat Rev Genet. 2011;12:846–60.CrossRefPubMedGoogle Scholar
  9. Bielas JH, Loeb KR, Rubin BP, True LD, Loeb LA. Human cancers express a mutator phenotype. Proc Natl Acad Sci U S A. 2006;103:18238–42.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Brugge WR, Lauwers GY, Sahani D, Fernandez-del Castillo C, Warshaw AL. Cystic neoplasms of the pancreas. N Engl J Med. 2004;351:1218–26.CrossRefPubMedGoogle Scholar
  11. Campbell AS, Albo D, Kimsey TF, White SL, Wang TN. Macrophage inflammatory protein-3alpha promotes pancreatic cancer cell invasion. J Surg Res. 2005;123:96–101.CrossRefPubMedGoogle Scholar
  12. Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8:729–40.CrossRefPubMedGoogle Scholar
  13. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Cavestro GM, Comparato G, Nouvenne A, Sianesi M, Di Mario F. The race from chronic pancreatitis to pancreatic cancer. JOP. 2003;4:165–8.PubMedGoogle Scholar
  15. Chan A, et al. Validation of biomarkers that complement CA19.9 in detecting early pancreatic cancer. Clin Cancer Res. 2014;20:5787–95.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;30:1073–81.CrossRefPubMedGoogle Scholar
  17. Cooks T, Harris CC, Oren M. Caught in the cross fire: p53 in inflammation. Carcinogenesis. 2014;35:1680–90.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Costello E, Greenhalf W, Neoptolemos JP. New biomarkers and targets in pancreatic cancer and their application to treatment. Nat Rev Gastroenterol Hepatol. 2012;9:435–44.CrossRefPubMedGoogle Scholar
  19. Cote GA, Smith J, Sherman S, Kelly K. Technologies for imaging the normal and diseased pancreas. Gastroenterology. 2013;144:1262–71.e1.Google Scholar
  20. Crnogorac-Jurcevic T, et al. Proteomic analysis of chronic pancreatitis and pancreatic adenocarcinoma. Gastroenterology. 2005;129:1454–63.CrossRefPubMedGoogle Scholar
  21. Cuzzocrea S, et al. Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute pancreatitis induced by cerulein. Intensive Care Med. 2004;30:951–6.CrossRefPubMedGoogle Scholar
  22. Diao L, Chen YG. PTEN, a general negative regulator of cyclin D expression. Cell Res. 2007;17:291–2.CrossRefPubMedGoogle Scholar
  23. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature. 1997;388:548–54.CrossRefPubMedGoogle Scholar
  24. Elinav E, et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer. 2013;13:759–71.CrossRefPubMedGoogle Scholar
  25. Elnemr A, et al. PPARgamma ligand (thiazolidinedione) induces growth arrest and differentiation markers of human pancreatic cancer cells. Int J Oncol. 2000;17:1157–64.PubMedGoogle Scholar
  26. Farrow B, Evers BM. Inflammation and the development of pancreatic cancer. Surg Oncol. 2002;10:153–69.CrossRefPubMedGoogle Scholar
  27. Fleisher AS, et al. Microsatellite instability in inflammatory bowel disease-associated neoplastic lesions is associated with hypermethylation and diminished expression of the DNA mismatch repair gene, hMLH1. Cancer Res. 2000;60:4864–8.PubMedGoogle Scholar
  28. Friess H, Guo XZ, Nan BC, Kleeff J, Buchler MW. Growth factors and cytokines in pancreatic carcinogenesis. Ann N Y Acad Sci. 1999;880:110–21.CrossRefPubMedGoogle Scholar
  29. Gansauge S, et al. Genetic alterations in chronic pancreatitis: evidence for early occurrence of p53 but not K-ras mutations. Br J Surg. 1998;85:337–40.CrossRefPubMedGoogle Scholar
  30. Gidekel Friedlander SY, et al. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell. 2009;16:379–89.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Glass CK, Saijo K. Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat Rev Immunol. 2010;10:365–76.CrossRefPubMedGoogle Scholar
  32. Goggins M. Molecular markers of early pancreatic cancer. J Clin Oncol. 2005;23:4524–31.CrossRefPubMedGoogle Scholar
  33. Guerra C, 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.CrossRefPubMedGoogle Scholar
  34. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.CrossRefPubMedGoogle Scholar
  35. Hashimoto K, Ethridge RT, Saito H, Rajaraman S, Evers BM. The PPARgamma ligand, 15d-PGJ2, attenuates the severity of cerulein-induced acute pancreatitis. Pancreas. 2003;27:58–66.CrossRefPubMedGoogle Scholar
  36. Hengstler JG, et al. Mutation analysis of the cationic trypsinogen gene in patients with pancreatic cancer. Anticancer Res. 2000;20:2967–74.PubMedGoogle Scholar
  37. Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605–17.CrossRefPubMedGoogle Scholar
  38. Hingorani SR, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003;4:437–50.CrossRefPubMedGoogle Scholar
  39. Huang H, et al. Activation of nuclear factor-kappaB in acinar cells increases the severity of pancreatitis in mice. Gastroenterology. 2013;144:202–10.CrossRefPubMedGoogle Scholar
  40. Itzkowitz SH, Yio X. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol. 2004;287:G7–17.CrossRefPubMedGoogle Scholar
  41. Jackson L, Evers BM. Chronic inflammation and pathogenesis of GI and pancreatic cancers. Cancer Treat Res. 2006;130:39–65.CrossRefPubMedGoogle Scholar
  42. Jackson AL, Loeb LA. The contribution of endogenous sources of DNA damage to the multiple mutations in cancer. Mutat Res. 2001;477:7–21.CrossRefPubMedGoogle Scholar
  43. Jacobs EJ, et al. Aspirin use and pancreatic cancer mortality in a large United States cohort. J Natl Cancer Inst. 2004;96:524–8.CrossRefPubMedGoogle Scholar
  44. Jaiswal M, LaRusso NF, Gores GJ. Nitric oxide in gastrointestinal epithelial cell carcinogenesis: linking inflammation to oncogenesis. Am J Physiol Gastrointest Liver Physiol. 2001;281:G626–34.PubMedGoogle Scholar
  45. Jaster R, et al. Peroxisome proliferator-activated receptor gamma overexpression inhibits pro-fibrogenic activities of immortalised rat pancreatic stellate cells. J Cell Mol Med. 2005;9:670–82.CrossRefPubMedGoogle Scholar
  46. Jones S, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801–6.CrossRefPubMedPubMedCentralGoogle Scholar
  47. Kalthoff H, Roeder C, Brockhaus M, Thiele HG, Schmiegel W. Tumor necrosis factor (TNF) up-regulates the expression of p75 but not p55 TNF receptors, and both receptors mediate, independently of each other, up-regulation of transforming growth factor alpha and epidermal growth factor receptor mRNA. J Biol Chem. 1993;268:2762–6.PubMedGoogle Scholar
  48. Kang H, et al. Downregulation of microRNA-362-3p and microRNA-329 promotes tumor progression in human breast cancer. Cell Death Differ. 2016;23(3):484–95.CrossRefPubMedGoogle Scholar
  49. Keiles S, Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006;33:221–7.CrossRefPubMedGoogle Scholar
  50. Klimstra DS, Longnecker DS. K-ras mutations in pancreatic ductal proliferative lesions. Am J Pathol. 1994;145:1547–50.PubMedPubMedCentralGoogle Scholar
  51. Kong X, et al. Detection of differentially expressed microRNAs in serum of pancreatic ductal adenocarcinoma patients: miR-196a could be a potential marker for poor prognosis. Dig Dis Sci. 2011;56:602–9.CrossRefPubMedGoogle Scholar
  52. Kong X, Li L, Li Z, Xie K. Targeted destruction of the orchestration of the pancreatic stroma and tumor cells in pancreatic cancer cases: molecular basis for therapeutic implications. Cytokine Growth Factor Rev. 2012;23:343–56.CrossRefPubMedPubMedCentralGoogle Scholar
  53. Kozomara A, Griffiths-Jones S. miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 2014;42:D68–73.CrossRefPubMedGoogle Scholar
  54. Li L, et al. Down-regulation of microRNA-494 via loss of SMAD4 increases FOXM1 and beta-catenin signaling in pancreatic ductal adenocarcinoma cells. Gastroenterology. 2014;147:485–97.e18.Google Scholar
  55. Liao Z, et al. Guidelines: diagnosis and therapy for chronic pancreatitis. J Interv Gastroenterol. 2013;3:133–6.Google Scholar
  56. Lowenfels AB, et al. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med. 1993;328:1433–7.CrossRefPubMedGoogle Scholar
  57. Lowenfels AB, et al. Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J Natl Cancer Inst. 1997;89:442–6.CrossRefPubMedGoogle Scholar
  58. Lu H, Ouyang W, Huang C. Inflammation, a key event in cancer development. Mol Cancer Res. 2006;4:221–33.CrossRefPubMedGoogle Scholar
  59. Maire F, et al. Differential diagnosis between chronic pancreatitis and pancreatic cancer: value of the detection of KRAS2 mutations in circulating DNA. Br J Cancer. 2002;87:551–4.CrossRefPubMedPubMedCentralGoogle Scholar
  60. Maitra A, Hruban RH. Pancreatic cancer. Annu Rev Pathol. 2008;3:157–88.CrossRefPubMedPubMedCentralGoogle Scholar
  61. Maitra A, Fukushima N, Takaori K, Hruban RH. Precursors to invasive pancreatic cancer. Adv Anat Pathol. 2005;12:81–91.CrossRefPubMedGoogle Scholar
  62. Malats N, et al. Cystic fibrosis transmembrane regulator (CFTR) DeltaF508 mutation and 5T allele in patients with chronic pancreatitis and exocrine pancreatic cancer. PANKRAS II Study Group. Gut. 2001;48:70–4.CrossRefPubMedPubMedCentralGoogle Scholar
  63. Malka D, et al. Risk of pancreatic adenocarcinoma in chronic pancreatitis. Gut. 2002;51:849–52.CrossRefPubMedPubMedCentralGoogle Scholar
  64. Mazur PK, Herner A, Neff F, Siveke JT. Current methods in mouse models of pancreatic cancer. Methods Mol Biol. 2015;1267:185–215.CrossRefPubMedGoogle Scholar
  65. Mazzieri R, et al. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell. 2011;19:512–26.CrossRefPubMedGoogle Scholar
  66. McDade TP, Perugini RA, Vittimberga FJ Jr, Carrigan RC, Callery MP. Salicylates inhibit NF-kappaB activation and enhance TNF-alpha-induced apoptosis in human pancreatic cancer cells. J Surg Res. 1999;83:56–61.CrossRefPubMedGoogle Scholar
  67. McKay CJ, Glen P, McMillan DC. Chronic inflammation and pancreatic cancer. Best Pract Res Clin Gastroenterol. 2008;22:65–73.CrossRefPubMedGoogle Scholar
  68. Mitchem JB, et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 2013;73:1128–41.CrossRefPubMedGoogle Scholar
  69. Morcos NY, Zakhary NI, Said MM, Tadros MM. Postoperative simple biochemical markers for prediction of bone metastases in Egyptian breast cancer patients. Ecancermedicalscience. 2013;7:305.PubMedPubMedCentralGoogle Scholar
  70. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  71. Mueller E, et al. Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. Proc Natl Acad Sci U S A. 2000;97:10990–5.CrossRefPubMedPubMedCentralGoogle Scholar
  72. Neesse A, et al. Stromal biology and therapy in pancreatic cancer. Gut. 2011;60:861–8.CrossRefPubMedGoogle Scholar
  73. Olive KP, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324:1457–61.CrossRefPubMedPubMedCentralGoogle Scholar
  74. Pan X, et al. Nuclear factor-kappaB p65/relA silencing induces apoptosis and increases gemcitabine effectiveness in a subset of pancreatic cancer cells. Clin Cancer Res. 2008;14:8143–51.CrossRefPubMedPubMedCentralGoogle Scholar
  75. Rachagani S, et al. Clinical implications of miRNAs in the pathogenesis, diagnosis and therapy of pancreatic cancer. Adv Drug Deliv Rev. 2015;81:16–33.CrossRefPubMedGoogle Scholar
  76. Raimondi S, Maisonneuve P, Lowenfels AB. Epidemiology of pancreatic cancer: an overview. Nat Rev Gastroenterol Hepatol. 2009;6:699–708.CrossRefPubMedGoogle Scholar
  77. Reding T, et al. A selective COX-2 inhibitor suppresses chronic pancreatitis in an animal model (WBN/Kob rats): significant reduction of macrophage infiltration and fibrosis. Gut. 2006;55:1165–73.CrossRefPubMedPubMedCentralGoogle Scholar
  78. Rozenblum E, et al. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res. 1997;57:1731–4.PubMedGoogle Scholar
  79. Sakorafas GH, Tsiotou AG. Pancreatic cancer in patients with chronic pancreatitis: a challenge from a surgical perspective. Cancer Treat Rev. 1999;25:207–17.CrossRefPubMedGoogle Scholar
  80. Schernhammer ES, et al. A prospective study of aspirin use and the risk of pancreatic cancer in women. J Natl Cancer Inst. 2004;96:22–8.CrossRefPubMedGoogle Scholar
  81. Schneider A, Whitcomb DC. Hereditary pancreatitis: a model for inflammatory diseases of the pancreas. Best Pract Res Clin Gastroenterol. 2002;16:347–63.CrossRefPubMedGoogle Scholar
  82. Schultz NA, et al. MicroRNA biomarkers in whole blood for detection of pancreatic cancer. JAMA. 2014;311:392–404.CrossRefPubMedGoogle Scholar
  83. Shi C, Merchant N, Newsome G, Goldenberg DM, Gold DV. Differentiation of pancreatic ductal adenocarcinoma from chronic pancreatitis by PAM4 immunohistochemistry. Arch Pathol Lab Med. 2014;138:220–8.CrossRefPubMedPubMedCentralGoogle Scholar
  84. Shimizu K, et al. Thiazolidinedione derivatives as novel therapeutic agents to prevent the development of chronic pancreatitis. Pancreas. 2002;24:184–90.CrossRefPubMedGoogle Scholar
  85. Suzuki J, et al. Novel IkB kinase inhibitors for treatment of nuclear factor-kB-related diseases. Expert Opin Investig Drugs. 2011;20:395–405.CrossRefPubMedGoogle Scholar
  86. Uomo I, Miraglia S, Pastorello M. Inflammation and pancreatic ductal adenocarcinoma: a potential scenario for novel drug targets. JOP. 2010;11:199–202.PubMedGoogle Scholar
  87. Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378:607–20.CrossRefPubMedPubMedCentralGoogle Scholar
  88. Vogelstein B, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319:525–32.CrossRefPubMedGoogle Scholar
  89. Wang LW, et al. Prevalence and clinical features of chronic pancreatitis in China: a retrospective multicenter analysis over 10 years. Pancreas. 2009;38:248–54.CrossRefPubMedGoogle Scholar
  90. Wiseman H, Halliwell B. Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem J. 1996;313(Pt 1):17–29.CrossRefPubMedPubMedCentralGoogle Scholar
  91. Xie D, Xie K. Pancreatic cancer stromal biology and therapy. Genes Dis. 2015;2:133–43.CrossRefPubMedPubMedCentralGoogle Scholar
  92. Yu JH, Kim H. Oxidative stress and cytokines in the pathogenesis of pancreatic cancer. J Cancer Prev. 2014;19:97–102.CrossRefPubMedPubMedCentralGoogle Scholar
  93. Zagury D, Burny A, Gallo RC. Toward a new generation of vaccines: the anti-cytokine therapeutic vaccines. Proc Natl Acad Sci U S A. 2001;98:8024–9.CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Nature Singapore Pte Ltd. and Shanghai Scientific and Technical Publishers 2017

Authors and Affiliations

  1. 1.Department of GastroenterologyShanghai Changhai HospitalShanghaiChina
  2. 2.Departments of Gastroenterology, Hepatology and Nutrition, Unit 1644The University of Texas MD Anderson Cancer CenterHoustonUSA

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