Journal List > Korean J Gastroenterol > v.66(6) > 1007452

TOOLS
Korean J Gastroenterol. 2015 Dec;66(6):325-339. Korean.
Published online December 22, 2015.  https://doi.org/10.4166/kjg.2015.66.6.325
Copyright © 2015 The Korean Society of Gastroenterology
Inflammation and Cancer Development in Pancreatic and Biliary Tract Cancer
Sang Hoon Lee,1,2 and Seung Woo Park1,2
1Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
2Pancreatobiliary Cancer Center, Yonsei Cancer Hospital, Seoul, Korea.

Correspondence to: Seung Woo Park. Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. Tel: +82-2-2228-1964, Fax: +82-2-393-6884, Email: swoopark@yuhs.ac

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Abstract

Chronic inflammation has been known to be a risk for many kinds of cancers, including pancreatic and biliary tract cancer. Recently, inflammatory process has emerged as a key mediator of cancer development and progression. Many efforts with experimental results have been given to identify the underlying mechanisms that contribute to inflammation-induced tumorigenesis. Diverse inflammatory pathways have been investigated and inhibitors for inflammation-related signaling pathways have been developed for cancer treatment. This review will summarize recent outcomes about this distinctive process in pancreatic and biliary tract cancer. Taking this evidence into consideration, modulation of inflammatory process will provide useful options for pancreatic and biliary tract cancer treatment.

Keywords: Inflammation; Pancreatic adenocarcinoma; Cholangiocarcinoma; Anti-inflammatory agents

Figures


 Fig. 1
Inflammatory signaling pathways contributing to carcinogenesis. The binding of TNF-α to its receptor (TNFR) induce the aggregation of TRADD, which serves as a platform for subsequent binding of adaptor proteins, such as FADD, cIAP-1, TRAF2 and RIP. Finally, TNF-α leads the activation of JNK-mediated AP-1 signaling pathway, NF-κB signaling pathways through IKK activation, and pro-apoptotic pathways induced by caspase-8 activation.
IL-6 binds to its receptor (IL-6Rα) and activates receptor-associated tyrosine kinases such as JAK family and SRC, which in return phosphorylates STAT proteins on their tyrosine residue. The activated STAT3 protein forms dimeric STAT3 complexes, which translocate to the nucleus and induce specific gene transcription. STAT3 and NF-κB co-regulates numerous genes involving cell proliferation and survival.

When IL-10 binds to its receptor (IL-10R), Jak1 and Tyk2 tyrosine kinases phosphorylate an IL-10R intracellular domain, subsequently allowing it to interact with STAT proteins. IL-10 can inhibit NF-κB signaling pathways and induces a sustained STAT3 phosphorylation, which differs from IL-6 mediated STAT3 activation.

The canonical NFAT signaling pathways is activated by intracellular Ca2+ influx leading to activation of the phosphatase calcineurin and dephophorylation of NFAT protein, which translocate to the nucleus and bind to their target promotors.

Upon ligand binding, TGF-β type I and TGF-β type II receptors heterodimerize and the type II receptor phosphorylates the receptor I domain. The TGF-β signaling pathway is further forwarded by phosphorylation of SMAD proteins, which is performed only by the type I receptor. The activated SMAD proteins translocate into the nucleus and leads to activation of transcription of target genes.

TNF-α, tumor necrosis factor-α; TNFR, TNF-α receptor; TRADD, TNFR1-associated signal transducer; FADD, Fas-associated death domain; cIADP-1, cellular inhibitor of apoptosis protein-1; TRAF2, TNF-αR-associated factor 2; RIP, receptor interacting protein; JNK, c-JUN NH2-terminal kinase; AP-1, activator protein-1; NF-κB, nuclear factor kappa-B; IKK, IκB kinase; IL, interleukin; IL-6Rα, IL-6 receptor α; JAK, janus kinase; STAT3, signal transducer and activator of transcription 3; IL-10R, IL-10 receptor; NFAT, nuclear factor of activated T cells; CaM, calmodulin; TGF-β, transforming growth factor-β; TβR1/2, TGF-β receptor type1 and type 2.
Click for larger image


Fig. 2
Overview of tumorigenesis of pancreatic cancer in chronic pancreatitis. Recurrent and continued pancreatic injury leads chronic pancreatitis, which can progress to pancreatic ductal adenocarcinoma. Inflammatory mediators and signaling pathways from injured acinar cells, inflammatory cells, tumor cells and activated pancreatic stellate cells (PSCs) affect not only activation of PSCs but also development and progression of pancreatic cancer.
ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α; IL, interleukin; TGF-β, transforming growth factor-β; PDGF, platelet-derived growth factor. Adapted from the article of Jaster et al.190 (Mol Cancer 2004;3:26).
Click for larger image


Fig. 3
Overview of tumorigenesis of biliary tract cancer. Chronic inflammation from primary sclerosing cholangitis (PSC), liver flukes, hepatholithiasis and pancreaticobiliary maljunction (PBM) induce several inflammatory mediators and signaling pathways, which contribute to development and progression of biliary tract cancer.
NO, nitric oxide; ROS, reactive oxygen species; IL-6, interleukin-6; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; PDGF, platelet-derived growth factor.
Click for larger image

Notes

Financial support:None.

Conflict of interest:None.

References
1. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860–867.
2. Whitcomb DC. Inflammation and Cancer V. Chronic pancreatitis and pancreatic cancer. Am J Physiol Gastrointest Liver Physiol 2004;287:G315–G319.
3. Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma. Hepatology 2011;54:173–184.
4. Bergquist A, Ekbom A, Olsson R, et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol 2002;36:321–327.
5. Kaewpitoon N, Kaewpitoon SJ, Pengsaa P, Sripa B. Opisthorchis viverrini: the carcinogenic human liver fluke. World J Gastroenterol 2008;14:666–674.
6. Funabiki T, Matsubara T, Miyakawa S, Ishihara S. Pancreaticobiliary maljunction and carcinogenesis to biliary and pancreatic malignancy. Langenbecks Arch Surg 2009;394:159–169.
7. Huang MH, Chen CH, Yen CM, et al. Relation of hepatolithiasis to helminthic infestation. J Gastroenterol Hepatol 2005;20:141–146.
8. Kinzler KW, Vogelstein B. Landscaping the cancer terrain. Science 1998;280:1036–1037.
9. Erkan M, Reiser-Erkan C, Michalski CW, Kleeff J. Tumor microenvironment and progression of pancreatic cancer. Exp Oncol 2010;32:128–131.
10. Baumgart S, Ellenrieder V, Fernandez-Zapico ME. Oncogenic transcription factors: cornerstones of inflammation-linked pancreatic carcinogenesis. Gut 2013;62:310–316.
11. Chen G, Goeddel DV. TNF-R1 signaling: a beautiful pathway. Science 2002;296:1634–1635.
12. Balkwill F. Tumour necrosis factor and cancer. Nat Rev Cancer 2009;9:361–371.
13. Zhong Z, Wen Z, Darnell JE Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 1994;264:95–98.
14. Shuai K, Ziemiecki A, Wilks AF, et al. Polypeptide signalling to the nucleus through tyrosine phosphorylation of Jak and Stat proteins. Nature 1993;366:580–583.
15. Frank DA. STAT3 as a central mediator of neoplastic cellular transformation. Cancer Lett 2007;251:199–210.
16. Cao X, Tay A, Guy GR, Tan YH. Activation and association of Stat3 with Src in v-Src-transformed cell lines. Mol Cell Biol 1996;16:1595–1603.
17. Gasche JA, Hoffmann J, Boland CR, Goel A. Interleukin-6 promotes tumorigenesis by altering DNA methylation in oral cancer cells. Int J Cancer 2011;129:1053–1063.
18. Kim SY, Kang JW, Song X, et al. Role of the IL-6-JAK1-STAT3-Oct-4 pathway in the conversion of non-stem cancer cells into cancer stem-like cells. Cell Signal 2013;25:961–969.
19. Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 2005;41:2502–2512.
20. Kleeff J, Korc M. Up-regulation of transforming growth factor (TGF)-beta receptors by TGF-beta1 in COLO-357 cells. J Biol Chem 1998;273:7495–7500.
21. Massagué J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 2000;103:295–309.
22. Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 1997;390:465–471.
23. Kleeff J, Maruyama H, Friess H, Büchler MW, Falb D, Korc M. Smad6 suppresses TGF-beta-induced growth inhibition in COLO-357 pancreatic cancer cells and is overexpressed in pancreatic cancer. Biochem Biophys Res Commun 1999;255:268–273.
24. Kleeff J, Ishiwata T, Maruyama H, et al. The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer. Oncogene 1999;18:5363–5372.
25. Xu J, Lamouille S, Derynck R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res 2009;19:156–172.
26. Bierie B, Moses HL. Transforming growth factor beta (TGF-beta) and inflammation in cancer. Cytokine Growth Factor Rev 2010;21:49–59.
27. Sabat R, Grütz G, Warszawska K, et al. Biology of interleukin-10. Cytokine Growth Factor Rev 2010;21:331–344.
28. Braun DA, Fribourg M, Sealfon SC. Cytokine response is determined by duration of receptor and signal transducers and activators of transcription 3 (STAT3) activation. J Biol Chem 2013;288:2986–2993.
29. Schottelius AJ, Mayo MW, Sartor RB, Baldwin AS Jr. Interleukin-10 signaling blocks inhibitor of kappaB kinase activity and nuclear factor kappaB DNA binding. J Biol Chem 1999;274:31868–31874.
30. Hamidullah, Changkija B, Konwar R. Role of interleukin-10 in breast cancer. Breast Cancer Res Treat 2012;133:11–21.
31. Kundu N, Fulton AM. Interleukin-10 inhibits tumor metastasis, downregulates MHC class I, and enhances NK lysis. Cell Immunol 1997;180:55–61.
32. Alas S, Emmanouilides C, Bonavida B. Inhibition of interleukin 10 by rituximab results in down-regulation of bcl-2 and sensitization of B-cell non-Hodgkin\'s lymphoma to apoptosis. Clin Cancer Res 2001;7:709–723.
33. Zeng L, O'Connor C, Zhang J, Kaplan AM, Cohen DA. IL-10 promotes resistance to apoptosis and metastatic potential in lung tumor cell lines. Cytokine 2010;49:294–302.
34. Chen Z, Hagler J, Palombella VJ, et al. Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway. Genes Dev 1995;9:1586–1597.
35. Hayden MS, Ghosh S. NF-κB in immunobiology. Cell Res 2011;21:223–244.
36. Takahashi M, Mutoh M, Ishigamori R, Fujii G, Imai T. Involvement of inflammatory factors in pancreatic carcinogenesis and preventive effects of anti-inflammatory agents. Semin Immunopathol 2013;35:203–227.
37. Farrow B, Evers BM. Inflammation and the development of pancreatic cancer. Surg Oncol 2002;10:153–169.
38. Bollrath J, Greten FR. IKK/NF-kappaB and STAT3 pathways: central signalling hubs in inflammation-mediated tumour promotion and metastasis. EMBO Rep 2009;10:1314–1319.
39. Serfling E, Berberich-Siebelt F, Avots A, et al. NFAT and NF-kappaB factors-the distant relatives. Int J Biochem Cell Biol 2004;36:1166–1170.
40. König A, Fernandez-Zapico ME, Ellenrieder V. Primers on molecular pathways--the NFAT transcription pathway in pancreatic cancer. Pancreatology 2010;10:416–422.
41. Shou J, Jing J, Xie J, et al. Nuclear factor of activated T cells in cancer development and treatment. Cancer Lett 2015;361:174–184.
42. Schmidt HH, Walter U. NO at work. Cell 1994;78:919–925.
43. 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–G634.
44. Yang GY, Taboada S, Liao J. Induced nitric oxide synthase as a major player in the oncogenic transformation of inflamed tissue. Methods Mol Biol 2009;512:119–156.
45. Agarwal S, Reddy GV, Reddanna P. Eicosanoids in inflammation and cancer: the role of COX-2. Expert Rev Clin Immunol 2009;5:145–165.
46. Bourboulia D, Stetler-Stevenson WG. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion. Semin Cancer Biol 2010;20:161–168.
47. Lowenfels AB, Maisonneuve P, Cavallini G, et al. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med 1993;328:1433–1437.
48. 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;24:349–358.
49. Lowenfels AB, Maisonneuve P, DiMagno EP, et al. Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J Natl Cancer Inst 1997;89:442–446.
50. Miron N, Miron MM, Milea VG, Cristea V. Proinflammatory cytokines: an insight into pancreatic oncogenesis. Roum Arch Microbiol Immunol 2010;69:183–189.
51. Schmiegel W, Roeder C, Schmielau J, Rodeck U, Kalthoff H. Tumor necrosis factor alpha induces the expression of transforming growth factor alpha and the epidermal growth factor receptor in human pancreatic cancer cells. Proc Natl Acad Sci U S A 1993;90:863–867.
52. Means AL, Meszoely IM, Suzuki K, et al. Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development 2005;132:3767–3776.
53. Sawai H, Okada Y, Funahashi H, et al. Integrin-linked kinase activity is associated with interleukin-1 alpha-induced progressive behavior of pancreatic cancer and poor patient survival. Oncogene 2006;25:3237–3246.
54. Sawai H, Okada Y, Funahashi H, et al. Interleukin-1alpha enhances the aggressive behavior of pancreatic cancer cells by regulating the alpha6beta1-integrin and urokinase plasminogen activator receptor expression. BMC Cell Biol 2006;7:8.
55. Melisi D, Niu J, Chang Z, et al. Secreted interleukin-1alpha induces a metastatic phenotype in pancreatic cancer by sustaining a constitutive activation of nuclear factor-kappaB. Mol Cancer Res 2009;7:624–633.
56. Xu D, Matsuo Y, Ma J, et al. Cancer cell-derived IL-1α promotes HGF secretion by stromal cells and enhances metastatic potential in pancreatic cancer cells. J Surg Oncol 2010;102:469–477.
57. Apte RN, Krelin Y, Song X, et al. Effects of micro-environmentand malignant cell-derived interleukin-1 in carcinogenesis, tumour invasiveness and tumour-host interactions. Eur J Cancer 2006;42:751–759.
58. Greco E, Basso D, Fogar P, et al. Pancreatic cancer cells invasiveness is mainly affected by interleukin-1beta not by transforming growth factor-beta1. Int J Biol Markers 2005;20:235–241.
59. Verma G, Bhatia H, Datta M. Gene expression profiling and pathway analysis identify the integrin signaling pathway to be altered by IL-1β in human pancreatic cancer cells: role of JNK. Cancer Lett 2012;320:86–95.
60. Yang YM, Ramadani M, Huang YT. Overexpression of Caspase-1 in adenocarcinoma of pancreas and chronic pancreatitis. World J Gastroenterol 2003;9:2828–2831.
61. Huang C, Yang G, Jiang T, Huang K, Cao J, Qiu Z. Effects of IL-6 and AG490 on regulation of Stat3 signaling pathway and invasion of human pancreatic cancer cells in vitro. J Exp Clin Cancer Res 2010;29:51.
62. Feurino LW, Zhang Y, Bharadwaj U, et al. IL-6 stimulates Th2 type cytokine secretion and upregulates VEGF and NRP-1 expression in pancreatic cancer cells. Cancer Biol Ther 2007;6:1096–1100.
63. Miyamoto Y, Hosotani R, Doi R, et al. Interleukin-6 inhibits radiation induced apoptosis in pancreatic cancer cells. Anticancer Res 2001;21:2449–2456.
64. Wolf JS, Chen Z, Dong G, et al. IL (interleukin)-1alpha promotes nuclear factor-kappaB and AP-1-induced IL-8 expression, cell survival, and proliferation in head and neck squamous cell carcinomas. Clin Cancer Res 2001;7:1812–1820.
65. Takamori H, Oades ZG, Hoch OC, Burger M, Schraufstatter IU. Autocrine growth effect of IL-8 and GROalpha on a human pancreatic cancer cell line, Capan-1. Pancreas 2000;21:52–56.
66. Miyamoto M, Shimizu Y, Okada K, Kashii Y, Higuchi K, Watanabe A. Effect of interleukin-8 on production of tumor-associated substances and autocrine growth of human liver and pancreatic cancer cells. Cancer Immunol Immunother 1998;47:47–57.
67. Farrow B, Sugiyama Y, Chen A, Uffort E, Nealon W, Mark Evers B. Inflammatory mechanisms contributing to pancreatic cancer development. Ann Surg 2004;239:763–769. discussion 769–discussion 771.
68. Li M, Zhang Y, Feurino LW, et al. Interleukin-8 increases vascular endothelial growth factor and neuropilin expression and stimulates ERK activation in human pancreatic cancer. Cancer Sci 2008;99:733–737.
69. Villanueva A, Garcia C, Paules AB, et al. Disruption of the antiproliferative TGF-beta signaling pathways in human pancreatic cancer cells. Oncogene 1998;17:1969–1978.
70. Ellenrieder V, Hendler SF, Ruhland C, Boeck W, Adler G, Gress TM. TGF-beta-induced invasiveness of pancreatic cancer cells is mediated by matrix metalloproteinase-2 and the urokinase plasminogen activator system. Int J Cancer 2001;93:204–211.
71. Simeone DM, Pham T, Logsdon CD. Disruption of TGFbeta signaling pathways in human pancreatic cancer cells. Ann Surg 2000;232:73–80.
72. Friess H, Yamanaka Y, Buchler M, et al. Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 1993;105:1846–1856.
73. Friess H, Yamanaka Y, Buchler M, et al. Enhanced expression of the type II transforming growth factor beta receptor in human pancreatic cancer cells without alteration of type III receptor expression. Cancer Res 1993;53:2704–2707.
74. Hahm KB, Im YH, Lee C, et al. Loss of TGF-beta signaling contributes to autoimmune pancreatitis. J Clin Invest 2000;105:1057–1065.
75. Liu K, Qin CK, Wang ZY, Liu SX, Cui XP, Zhang DY. Expression of tumor necrosis factor-alpha-induced protein 8 in pancreas tissues and its correlation with epithelial growth factor receptor levels. Asian Pac J Cancer Prev 2012;13:847–850.
76. Lakshmikesari A, Radhakrishna R, Bhanumathi A, et al. Expression of epidermal and transforming growth factors in pancreatic cancer. Oncol Rep 1996;3:963–966.
77. Huang B, Zhao J, Unkeless JC, Feng ZH, Xiong H. TLR signaling by tumor and immune cells: a double-edged sword. Oncogene 2008;27:218–224.
78. Ochi A, Graffeo CS, Zambirinis CP, et al. Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans. J Clin Invest 2012;122:4118–4129.
79. Ikebe M, Kitaura Y, Nakamura M, et al. Lipopolysaccharide (LPS) increases the invasive ability of pancreatic cancer cells through the TLR4/MyD88 signaling pathway. J Surg Oncol 2009;100:725–731.
80. DiDonato JA, Mercurio F, Karin M. NF-κB and the link between inflammation and cancer. Immunol Rev 2012;246:379–400.
81. Steinle AU, Weidenbach H, Wagner M, Adler G, Schmid RM. NF-kappaB/Rel activation in cerulein pancreatitis. Gastroenterology 1999;116:420–430.
82. Karin M. The NF-kappa B activation pathway: its regulation and role in inflammation and cell survival. Cancer J Sci Am 1998;4 Suppl 1:S92–S99.
83. Huang H, Liu Y, Daniluk J, et al. Activation of nuclear factor-κB in acinar cells increases the severity of pancreatitis in mice. Gastroenterology 2013;144:202–210.
84. Maniati E, Bossard M, Cook N, et al. Crosstalk between the canonical NF-κB and Notch signaling pathways inhibits Pparγ expression and promotes pancreatic cancer progression in mice. J Clin Invest 2011;121:4685–4699.
85. Daniluk J, Liu Y, Deng D, et al. An NF-κB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice. J Clin Invest 2012;122:1519–1528.
86. Ling J, Kang Y, Zhao R, et al. KrasG12D-induced IKK2/β/NF-κB activation by IL-1α and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell 2012;21:105–120.
87. Yamamoto Y, Gaynor RB. Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J Clin Invest 2001;107:135–142.
88. Kong R, Sun B, Jiang H, et al. Downregulation of nuclear factor-with gemcitabine to inhibit the growth of pancreatic cancer. Cancer Lett 2010;291:90–98.
89. Sclabas GM, Fujioka S, Schmidt C, Fan Z, Evans DB, Chiao PJ. Restoring apoptosis in pancreatic cancer cells by targeting the nuclear factor-kappaB signaling pathway with the anti-epidermal growth factor antibody IMC-C225. J Gastrointest Surg 2003;7:37–43. discussion 43.
90. Miyatsuka T, Kaneto H, Shiraiwa T, et al. Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation. Genes Dev 2006;20:1435–1440.
91. Corcoran RB, Contino G, Deshpande V, et al. STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res 2011;71:5020–5029.
92. Lesina M, Kurkowski MU, Ludes K, et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 2011;19:456–469.
93. Fukuda A, Wang SC, Morris JP 4th, et al. Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell 2011;19:441–455.
94. Mancini M, Toker A. NFAT proteins: emerging roles in cancer progression. Nat Rev Cancer 2009;9:810–820.
95. Muller MR, Rao A. NFAT, immunity and cancer: a transcription factor comes of age. Nat Rev Immunol 2010;10:645–656.
96. Buchholz M, Schatz A, Wagner M, et al. Overexpression of c-myc in pancreatic cancer caused by ectopic activation of NFATc1 and the Ca2+/calcineurin signaling pathway. EMBO J 2006;25:3714–3724.
97. Koenig A, Linhart T, Schlengemann K, et al. NFAT-induced histone acetylation relay switch promotes c-Myc-dependent growth in pancreatic cancer cells. Gastroenterology 2010;138:1189–1199. 1199.e1–1199.e2.
98. Saqui-Salces M, Merchant JL. Hedgehog signaling and gastrointestinal cancer. Biochim Biophys Acta 2010;1803:786–795.
99. Kelleher FC. Hedgehog signaling and therapeutics in pancreatic cancer. Carcinogenesis 2011;32:445–451.
100. Elsawa SF, Almada LL, Ziesmer SC, et al. GLI2 transcription factor mediates cytokine cross-talk in the tumor microenvironment. J Biol Chem 2011;286:21524–21534.
101. Tian H, Callahan CA, DuPree KJ, et al. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci U S A 2009;106:4254–4259.
102. Nolan-Stevaux O, Lau J, Truitt ML, et al. GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev 2009;23:24–36.
103. Kasper HU, Wolf H, Drebber U, Wolf HK, Kern MA. Expression of inducible nitric oxide synthase and cyclooxygenase-2 in pancreatic adenocarcinoma: correlation with microvessel density. World J Gastroenterol 2004;10:1918–1922.
104. Takahashi M, Mutoh M, Shoji Y, et al. Transfection of K-rasAsp12 cDNA markedly elevates IL-1beta- and lipopolysaccharide-mediated inducible nitric oxide synthase expression in rat intestinal epithelial cells. Oncogene 2003;22:7667–7676.
105. Araki Y, Okamura S, Hussain SP, et al. Regulation of cyclooxygenase-2 expression by the Wnt and ras pathways. Cancer Res 2003;63:728–734.
106. Sheng H, Shao J, Dubois RN. K-Ras-mediated increase in cyclooxygenase 2 mRNA stability involves activation of the protein kinase B1. Cancer Res 2001;61:2670–2675.
107. Hennig R, Ding XZ, Tong WG, et al. 5-Lipoxygenase and leukotriene B(4) receptor are expressed in human pancreatic cancers but not in pancreatic ducts in normal tissue. Am J Pathol 2002;161:421–428.
108. Hennig R, Grippo P, Ding XZ, et al. 5-Lipoxygenase, a marker for early pancreatic intraepithelial neoplastic lesions. Cancer Res 2005;65:6011–6016.
109. Yip-Schneider MT, Barnard DS, Billings SD, et al. Cyclooxygenase-2 expression in human pancreatic adenocarcinomas. Carcinogenesis 2000;21:139–146.
110. Yamamoto H, Itoh F, Iku S, et al. Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human pancreatic adenocarcinomas: clinicopathologic and prognostic significance of matrilysin expression. J Clin Oncol 2001;19:1118–1127.
111. Crawford HC, Scoggins CR, Washington MK, Matrisian LM, Leach SD. Matrix metalloproteinase-7 is expressed by pancreatic cancer precursors and regulates acinar-to-ductal metaplasia in exocrine pancreas. J Clin Invest 2002;109:1437–1444.
112. Jones LE, Humphreys MJ, Campbell F, Neoptolemos JP, Boyd MT. Comprehensive analysis of matrix metalloproteinase and tissue inhibitor expression in pancreatic cancer: increased expression of matrix metalloproteinase-7 predicts poor survival. Clin Cancer Res 2004;10:2832–2845.
113. Broome U, Olsson R, Loof L, et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut 1996;38:610–615.
114. Chapman MH, Webster GJ, Bannoo S, Johnson GJ, Wittmann J, Pereira SP. Cholangiocarcinoma and dominant strictures in patients with primary sclerosing cholangitis: a 25-year single-centre experience. Eur J Gastroenterol Hepatol 2012;24:1051–1058.
115. Boberg KM, Bergquist A, Mitchell S, et al. Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and clinical presentation. Scand J Gastroenterol 2002;37:1205–1211.
116. Claessen MM, Vleggaar FP, Tytgat KM, Siersema PD, van Buuren HR. High lifetime risk of cancer in primary sclerosing cholangitis. J Hepatol 2009;50:158–164.
117. Chalasani N, Baluyut A, Ismail A, et al. Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study. Hepatology 2000;31:7–11.
118. Buckles DC, Lindor KD, Larusso NF, Petrovic LM, Gores GJ. In primary sclerosing cholangitis, gallbladder polyps are frequently malignant. Am J Gastroenterol 2002;97:1138–1142.
119. Lewis JT, Talwalkar JA, Rosen CB, Smyrk TC, Abraham SC. Prevalence and risk factors for gallbladder neoplasia in patients with primary sclerosing cholangitis: evidence for a metaplasia-dysplasia-carcinoma sequence. Am J Surg Pathol 2007;31:907–913.
120. Watanapa P, Watanapa WB. Liver fluke-associated cholangio carcinoma. Br J Surg 2002;89:962–970.
121. Haswell-Elkins MR, Satarug S, Tsuda M, et al. Liver fluke infection and cholangiocarcinoma: model of endogenous nitric oxide and extragastric nitrosation in human carcinogenesis. Mutat Res 1994;305:241–252.
122. Parkin DM, Srivatanakul P, Khlat M, et al. Liver cancer in Thailand. I. A case-control study of cholangiocarcinoma. Int J Cancer 1991;48:323–328.
123. Okuda K, Nakanuma Y, Miyazaki M. Cholangiocarcinoma: recent progress. Part 1: epidemiology and etiology. J Gastroenterol Hepatol 2002;17:1049–1055.
124. Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004;24:115–125.
125. Sheen-Chen SM, Chou FF, Eng HL. Intrahepatic cholangiocarcinoma in hepatolithiasis: A frequently overlooked disease. J Surg Oncol 1991;47:131–135.
126. Lee TY, Lee SS, Jung SW, et al. Hepatitis B virus infection and intrahepatic cholangiocarcinoma in Korea: a case-control study. Am J Gastroenterol 2008;103:1716–1720.
127. Zhou YM, Yin ZF, Yang JM, et al. Risk factors for intrahepatic cholangiocarcinoma: a case-control study in China. World J Gastroenterol 2008;14:632–635.
128. Csendes A, Becerra M, Rojas J, Medina E. Number and size of stones in patients with asymptomatic and symptomatic gallstones and gallbladder carcinoma: a prospective study of 592 cases. J Gastrointest Surg 2000;4:481–485.
129. Beltran MA. Pancreaticobiliary reflux in patients with a normal pancreaticobiliary junction: Pathologic implications. World J Gastroenterol 2011;17:953–962.
130. Al-Bahrani R, Abuetabh Y, Zeitouni N, Sergi C. Cholangiocarcinoma: risk factors, environmental influences and oncogenesis. Ann Clin Lab Sci 2013;43:195–210.
131. Techasen A, Namwat N, Loilome W, et al. Tumor necrosis factor-α (TNF-α) stimulates the epithelial-mesenchymal transition regulator Snail in cholangiocarcinoma. Med Oncol 2012;29:3083–3091.
132. Park J, Tadlock L, Gores GJ, Patel T. Inhibition of interleukin 6-mediated mitogen-activated protein kinase activation attenuates growth of a cholangiocarcinoma cell line. Hepatology 1999;30:1128–1133.
133. Kobayashi S, Werneburg NW, Bronk SF, Kaufmann SH, Gores GJ. Interleukin-6 contributes to Mcl-1 up-regulation and TRAIL resistance via an Akt-signaling pathway in cholangiocarcinoma cells. Gastroenterology 2005;128:2054–2065.
134. Sia D, Hoshida Y, Villanueva A, et al. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology 2013;144:829–840.
135. Isomoto H, Kobayashi S, Werneburg NW, et al. Interleukin 6 upregulates myeloid cell leukemia-1 expression through a STAT3 pathway in cholangiocarcinoma cells. Hepatology 2005;42:1329–1338.
136. Meng F, Yamagiwa Y, Ueno Y, Patel T. Over-expression of interleukin-6 enhances cell survival and transformed cell growth in human malignant cholangiocytes. J Hepatol 2006;44:1055–1065.
137. Zheng T, Hong X, Wang J, et al. Gankyrin promotes tumor growth and metastasis through activation of IL-6/STAT3 signaling in human cholangiocarcinoma. Hepatology 2014;59:935–946.
138. Isomoto H, Mott JL, Kobayashi S, et al. Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing. Gastroenterology 2007;132:384–396.
139. Wehbe H, Henson R, Meng F, Mize-Berge J, Patel T. Interleukin-6 contributes to growth in cholangiocarcinoma cells by aberrant promoter methylation and gene expression. Cancer Res 2006;66:10517–10524.
140. Sun Q, Li F, Sun F, Niu J. Interleukin-8 is a prognostic indicator in human hilar cholangiocarcinoma. Int J Clin Exp Pathol 2015;8:8376–8384.
141. Chuang SC, Lee KT, Tsai KB, et al. Immunohistochemical study of DPC4 and p53 proteins in gallbladder and bile duct cancers. World J Surg 2004;28:995–1000.
142. Ling H, Roux E, Hempel D, et al. Transforming growth factor β neutralization ameliorates pre-existing hepatic fibrosis and reduces cholangiocarcinoma in thioacetamide-treated rats. PLoS One 2013;8:e54499.
143. Araki K, Shimura T, Suzuki H, et al. E/N-cadherin switch mediates cancer progression via TGF-β-induced epithelial-to-mesenchymal transition in extrahepatic cholangiocarcinoma. Br J Cancer 2011;105:1885–1893.
144. Cadamuro M, Nardo G, Indraccolo S, et al. Platelet-derived growth factor-D and Rho GTPases regulate recruitment of cancer-associated fibroblasts in cholangiocarcinoma. Hepatology 2013;58:1042–1053.
145. Fingas CD, Bronk SF, Werneburg NW, et al. Myofibroblast-derived PDGF-BB promotes Hedgehog survival signaling in cholangiocarcinoma cells. Hepatology 2011;54:2076–2088.
146. Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 2013;145:1215–1229.
147. Yoon JH, Gwak GY, Lee HS, Bronk SF, Werneburg NW, Gores GJ. Enhanced epidermal growth factor receptor activation in human cholangiocarcinoma cells. J Hepatol 2004;41:808–814.
148. Kiguchi K, Carbajal S, Chan K, et al. Constitutive expression of ErbB-2 in gallbladder epithelium results in development of adenocarcinoma. Cancer Res 2001;61:6971–6976.
149. Lai GH, Radaeva S, Nakamura T, Sirica AE. Unique epithelial cell production of hepatocyte growth factor/scatter factor by putative precancerous intestinal metaplasias and associated "intestinal-type" biliary cancer chemically induced in rat liver. Hepatology 2000;31:1257–1265.
150. Miyamoto M, Ojima H, Iwasaki M, et al. Prognostic significance of overexpression of c-Met oncoprotein in cholangiocarcinoma. Br J Cancer 2011;105:131–138.
151. Matsumoto K, Nakamura T. Hepatocyte growth factor and the Met system as a mediator of tumor-stromal interactions. Int J Cancer 2006;119:477–483.
152. Radaeva S, Ferreira-Gonzalez A, Sirica AE. Overexpression of C-NEU and C-MET during rat liver cholangiocarcinogenesis: A link between biliary intestinal metaplasia and mucin-producing cholangiocarcinoma. Hepatology 1999;29:1453–1462.
153. Prakobwong S, Khoontawad J, Yongvanit P, et al. Curcumin decreases cholangiocarcinogenesis in hamsters by suppressing kappaB p65 subunit by small interfering RNA synergizes inflammation-mediated molecular events related to multistep carcinogenesis. Int J Cancer 2011;129:88–100.
154. Aneknan P, Kukongviriyapan V, Prawan A, Kongpetch S, Sripa B, Senggunprai L. Luteolin arrests cell cycling, induces apoptosis and inhibits the JAK/STAT3 pathway in human cholangiocarcinoma cells. Asian Pac J Cancer Prev 2014;15:5071–5076.
155. Jaiswal M, LaRusso NF, Burgart LJ, Gores GJ. Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Res 2000;60:184–190.
156. Yoon JH, Higuchi H, Werneburg NW, Kaufmann SH, Gores GJ. Bile acids induce cyclooxygenase-2 expression via the epidermal growth factor receptor in a human cholangiocarcinoma cell line. Gastroenterology 2002;122:985–993.
157. Han C, Wu T. Cyclooxygenase-2-derived prostaglandin E2 promotes human cholangiocarcinoma cell growth and invasion through EP1 receptor-mediated activation of the epidermal growth factor receptor and Akt. J Biol Chem 2005;280:24053–24063.
158. Prakobwong S, Yongvanit P, Hiraku Y, et al. Involvement of MMP-9 in peribiliary fibrosis and cholangiocarcinogenesis via Rac1-dependent DNA damage in a hamster model. Int J Cancer 2010;127:2576–2587.
159. Leung PS, Chan YC. Role of oxidative stress in pancreatic inflammation. Antioxid Redox Signal 2009;11:135–165.
160. Banim PJ, Luben R, McTaggart A, et al. Dietary antioxidants and the aetiology of pancreatic cancer: a cohort study using data from food diaries and biomarkers. Gut 2013;62:1489–1496.
161. Han X, Li J, Brasky TM, et al. Antioxidant intake and pancreatic cancer risk: the Vitamins and Lifestyle (VITAL) Study. Cancer 2013;119:1314–1320.
162. Kise Y, Yamamura M, Kogata M, et al. Inhibition by selenium of intrahepatic cholangiocarcinoma induction in Syrian golden hamsters by N'-nitrosobis(2-oxopropyl)amine. Nutr Cancer 1991;16:153–164.
163. Fendrich V, Chen NM, Neef M, et al. The angiotensin-I-converting enzyme inhibitor enalapril and aspirin delay progression of pancreatic intraepithelial neoplasia and cancer formation in a genetically engineered mouse model of pancreatic cancer. Gut 2010;59:630–637.
164. Zhang Z, Rigas B. NF-kappaB, inflammation and pancreatic carcinogenesis: NF-kappaB as a chemoprevention target (review). Int J Oncol 2006;29:185–192.
165. Sclabas GM, Uwagawa T, Schmidt C, et al. Nuclear factor kappa B activation is a potential target for preventing pancreatic carcinoma by aspirin. Cancer 2005;103:2485–2490.
166. Anderson KE, Johnson TW, Lazovich D, Folsom AR. Association between nonsteroidal anti-inflammatory drug use and the incidence of pancreatic cancer. J Natl Cancer Inst 2002;94:1168–1171.
167. Schernhammer ES, Kang JH, Chan AT, et al. A prospective study of aspirin use and the risk of pancreatic cancer in women. J Natl Cancer Inst 2004;96:22–28.
168. Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011;377:31–41.
169. Burr NE, Talboys RJ, Savva S, et al. Aspirin may prevent cholangiocarcinoma: a case-control study from the United Kingdom. Dig Dis Sci 2014;59:1567–1572.
170. Liu E, Sakoda LC, Gao YT, et al. Aspirin use and risk of biliary tract cancer: a population-based study in Shanghai, China. Cancer Epidemiol Biomarkers Prev 2005;14:1315–1318.
171. Petrick JL, Sahasrabuddhe VV, Chan AT, et al. NSAID Use and Risk of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: The Liver Cancer Pooling Project. Cancer Prev Res (Phila) 2015;8:1156–1162.
172. El-Rayes BF, Ali S, Sarkar FH, Philip PA. Cyclooxygenase-2-dependent and -independent effects of celecoxib in pancreatic cancer cell lines. Mol Cancer Ther 2004;3:1421–1426.
173. Guerra C, Collado M, Navas C, et al. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell 2011;19:728–739.
174. Eibl G, Reber HA, Wente MN, Hines OJ. The selective cyclooxygenase-2 inhibitor nimesulide induces apoptosis in pancreatic cancer cells independent of COX-2. Pancreas 2003;26:33–41.
175. Yeh CN, Chiang KC, Juang HH, S Pang JH. Reappraisal of the therapeutic role of celecoxib in cholangiocarcinoma. PLoS One 2013;8:e69928.
176. Dragovich T, Burris H 3rd, Loehrer P, et al. Gemcitabine plus celecoxib in patients with advanced or metastatic pancreatic adenocarcinoma: results of a phase II trial. Am J Clin Oncol 2008;31:157–162.
177. Morak MJ, Richel DJ, van Eijck CH, et al. Phase II trial of Uracil/Tegafur plus leucovorin and celecoxib combined with radiotherapy in locally advanced pancreatic cancer. Radiother Oncol 2011;98:261–264.
178. Angevin E, Tabernero J, Elez E, et al. A phase I/II, multiple-dose, dose-escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res 2014;20:2192–2204.
179. Melisi D, Ishiyama S, Sclabas GM, et al. LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther 2008;7:829–840.
180. Ostapoff KT, Cenik BK, Wang M, et al. Neutralizing murine TGFβR2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis. Cancer Res 2014;74:4996–5007.
181. Herbertz S, Sawyer JS, Stauber AJ, et al. Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway. Drug Des Devel Ther 2015;9:4479–4499.
182. Gaspar NJ, Li L, Kapoun AM, et al. Inhibition of transforming growth factor beta signaling reduces pancreatic adenocarcinoma growth and invasiveness. Mol Pharmacol 2007;72:152–161.
183. Lin Y, Zhang B, Liang H, et al. JNK inhibitor SP600125 enhances TGF-β-induced apoptosis of RBE human cholangiocarcinoma cells in a Smad-dependent manner. Mol Med Rep 2013;8:1623–1629.
184. Alberts SR, Foster NR, Morton RF, et al. PS-341 and gemcitabine in patients with metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group (NCCTG) randomized phase II study. Ann Oncol 2005;16:1654–1661.
185. Dhillon N, Aggarwal BB, Newman RA, et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res 2008;14:4491–4499.
186. Renouf DJ, Moore MJ, Hedley D, et al. A phase I/II study of the Src inhibitor saracatinib (AZD0530) in combination with gemcitabine in advanced pancreatic cancer. Invest New Drugs 2012;30:779–786.
187. Hurwitz HI, Uppal N, Wagner SA, et al. Randomized, doubleblind, phase II study of ruxolitinib or placebo in combination with capecitabine in patients with metastatic pancreatic cancer for whom therapy with gemcitabine has failed. J Clin Oncol 2015;33:4039–4047.
188. Mamaghani S, Patel S, Hedley DW. Glycogen synthase kinase-3 inhibition disrupts nuclear factor-kappaB activity in pancreatic cancer, but fails to sensitize to gemcitabine chemotherapy. BMC Cancer 2009;9:132.
189. Beurel E, Michalek SM, Jope RS. Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3). Trends Immunol 2010;31:24–31.
190. Jaster R. Molecular regulation of pancreatic stellate cell function. Mol Cancer 2004;3:26.
TOOLS
Similar articles

Microbiome and Biliary Tract Cancer

Nutritional Support for Patients with Pancreatic Cancer

Relief of Obstruction in the Management of Pancreatic Cancer

Pancreas club international joint symposium on pancreatic cancer 2012, Kyoto: down staging chemo±radiotherapy for borderline resectable pancreatic cancer

Bile Acid Analysis in Biliary Tract Cancer