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.
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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.
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.
Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357:539–45.
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.
Bansal P, Sonnenberg A. Pancreatitis is a risk factor for pancreatic cancer. Gastroenterology. 1995;109:247–51.
Bardeesy N, DePinho RA. Pancreatic cancer biology and genetics. Nat Rev Cancer. 2002;2:897–909.
Beatty GL, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331:1612–6.
Berezikov E. Evolution of microRNA diversity and regulation in animals. Nat Rev Genet. 2011;12:846–60.
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.
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.
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.
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.
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.
Cavestro GM, Comparato G, Nouvenne A, Sianesi M, Di Mario F. The race from chronic pancreatitis to pancreatic cancer. JOP. 2003;4:165–8.
Chan A, et al. Validation of biomarkers that complement CA19.9 in detecting early pancreatic cancer. Clin Cancer Res. 2014;20:5787–95.
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.
Cooks T, Harris CC, Oren M. Caught in the cross fire: p53 in inflammation. Carcinogenesis. 2014;35:1680–90.
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.
Cote GA, Smith J, Sherman S, Kelly K. Technologies for imaging the normal and diseased pancreas. Gastroenterology. 2013;144:1262–71.e1.
Crnogorac-Jurcevic T, et al. Proteomic analysis of chronic pancreatitis and pancreatic adenocarcinoma. Gastroenterology. 2005;129:1454–63.
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.
Diao L, Chen YG. PTEN, a general negative regulator of cyclin D expression. Cell Res. 2007;17:291–2.
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.
Elinav E, et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer. 2013;13:759–71.
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.
Farrow B, Evers BM. Inflammation and the development of pancreatic cancer. Surg Oncol. 2002;10:153–69.
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.
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.
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.
Gidekel Friedlander SY, et al. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell. 2009;16:379–89.
Glass CK, Saijo K. Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat Rev Immunol. 2010;10:365–76.
Goggins M. Molecular markers of early pancreatic cancer. J Clin Oncol. 2005;23:4524–31.
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.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
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.
Hengstler JG, et al. Mutation analysis of the cationic trypsinogen gene in patients with pancreatic cancer. Anticancer Res. 2000;20:2967–74.
Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605–17.
Hingorani SR, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003;4:437–50.
Huang H, et al. Activation of nuclear factor-kappaB in acinar cells increases the severity of pancreatitis in mice. Gastroenterology. 2013;144:202–10.
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.
Jackson L, Evers BM. Chronic inflammation and pathogenesis of GI and pancreatic cancers. Cancer Treat Res. 2006;130:39–65.
Jackson AL, Loeb LA. The contribution of endogenous sources of DNA damage to the multiple mutations in cancer. Mutat Res. 2001;477:7–21.
Jacobs EJ, et al. Aspirin use and pancreatic cancer mortality in a large United States cohort. J Natl Cancer Inst. 2004;96:524–8.
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.
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.
Jones S, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801–6.
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.
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.
Keiles S, Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006;33:221–7.
Klimstra DS, Longnecker DS. K-ras mutations in pancreatic ductal proliferative lesions. Am J Pathol. 1994;145:1547–50.
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.
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.
Kozomara A, Griffiths-Jones S. miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 2014;42:D68–73.
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.
Liao Z, et al. Guidelines: diagnosis and therapy for chronic pancreatitis. J Interv Gastroenterol. 2013;3:133–6.
Lowenfels AB, et al. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med. 1993;328:1433–7.
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.
Lu H, Ouyang W, Huang C. Inflammation, a key event in cancer development. Mol Cancer Res. 2006;4:221–33.
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.
Maitra A, Hruban RH. Pancreatic cancer. Annu Rev Pathol. 2008;3:157–88.
Maitra A, Fukushima N, Takaori K, Hruban RH. Precursors to invasive pancreatic cancer. Adv Anat Pathol. 2005;12:81–91.
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.
Malka D, et al. Risk of pancreatic adenocarcinoma in chronic pancreatitis. Gut. 2002;51:849–52.
Mazur PK, Herner A, Neff F, Siveke JT. Current methods in mouse models of pancreatic cancer. Methods Mol Biol. 2015;1267:185–215.
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.
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.
McKay CJ, Glen P, McMillan DC. Chronic inflammation and pancreatic cancer. Best Pract Res Clin Gastroenterol. 2008;22:65–73.
Mitchem JB, et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 2013;73:1128–41.
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.
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.
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.
Neesse A, et al. Stromal biology and therapy in pancreatic cancer. Gut. 2011;60:861–8.
Olive KP, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324:1457–61.
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.
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.
Raimondi S, Maisonneuve P, Lowenfels AB. Epidemiology of pancreatic cancer: an overview. Nat Rev Gastroenterol Hepatol. 2009;6:699–708.
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.
Rozenblum E, et al. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res. 1997;57:1731–4.
Sakorafas GH, Tsiotou AG. Pancreatic cancer in patients with chronic pancreatitis: a challenge from a surgical perspective. Cancer Treat Rev. 1999;25:207–17.
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.
Schneider A, Whitcomb DC. Hereditary pancreatitis: a model for inflammatory diseases of the pancreas. Best Pract Res Clin Gastroenterol. 2002;16:347–63.
Schultz NA, et al. MicroRNA biomarkers in whole blood for detection of pancreatic cancer. JAMA. 2014;311:392–404.
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.
Shimizu K, et al. Thiazolidinedione derivatives as novel therapeutic agents to prevent the development of chronic pancreatitis. Pancreas. 2002;24:184–90.
Suzuki J, et al. Novel IkB kinase inhibitors for treatment of nuclear factor-kB-related diseases. Expert Opin Investig Drugs. 2011;20:395–405.
Uomo I, Miraglia S, Pastorello M. Inflammation and pancreatic ductal adenocarcinoma: a potential scenario for novel drug targets. JOP. 2010;11:199–202.
Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378:607–20.
Vogelstein B, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319:525–32.
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.
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.
Xie D, Xie K. Pancreatic cancer stromal biology and therapy. Genes Dis. 2015;2:133–43.
Yu JH, Kim H. Oxidative stress and cytokines in the pathogenesis of pancreatic cancer. J Cancer Prev. 2014;19:97–102.
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.
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.
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Kong, XY., Xie, KP. (2017). Chronic Pancreatitis and Pancreatic Cancer. In: Li, ZS., Liao, Z., Chen, JM., Férec, C. (eds) Chronic Pancreatitis. Springer, Singapore. https://doi.org/10.1007/978-981-10-4515-8_12
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