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

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.

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