Background and Aims
Barrett’s esophagus, a metaplasia resulting from a long-standing reflux disease, and its progression to esophageal adenocarcinoma (EAC) are characterized by activation of pro-inflammatory pathways, induced by cytokines.
An in vitro cell culture system representing the sequence of squamous epithelium (EPC1 and EPC2), Barrett’s metaplasia (CP-A), dysplasia (CP-B) to EAC (OE33 and OE19) was used to investigate TNF-α-mediated induction of interleukin-8 (IL-8).
IL-6 and IL-8 expressions are increasing with the progression of Barrett’s esophagus, with the highest expression of both cytokines in the dysplastic cell line CP-B. IL-8 expression in EAC cells was approx. 4.4-fold (OE33) and eightfold (OE19) higher in EAC cells than in squamous epithelium cells (EPC1 and EPC2). The pro-inflammatory cytokine TNF-α increased IL-8 expression in a time-, concentration-, and stage-specific manner. Furthermore, TNF-α changed the EMT marker profile in OE33 cells by decreasing the epithelial marker E-cadherin and increasing the mesenchymal marker vimentin. The anti-inflammatory compound curcumin was able to repress proliferation and to activate apoptosis in both EAC cell lines.
The increased basal expression levels of IL-8 with the progression of Barrett’s esophagus constrain NFκB activation and its contribution in the manifestation of Barrett’s esophagus. An anti-inflammatory compound, such as curcumin, could create an anti-inflammatory microenvironment and thus potentially support an increase chemosensitivity in EAC cells.
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Dixon MF, Neville PM, Mapstone NP, et al. Bile reflux gastritis and Barrett’s oesophagus: further evidence of a role for duodenogastro–oesophageal reflux? Gut. 2001;49:359–363.
Goldblum JR, Vicari JJ, Falk GW, et al. Inflammation and intestinal metaplasia of the gastric cardia: the role of gastroesophageal reflux and H. pylori infection. Gastroenterology. 1998;114:633–639.
Vaughan TL, Fitzgerald RC. Precision prevention of oesophageal adenocarcinoma. Nat Rev Gastroenterol Hepatol. 2015;12:243–248.
Dubecz A, Gall I, Solymosi N, et al. Temporal trends in long-term survival and cure rates in esophageal cancer: a SEER database analysis. J Thorac Oncol. 2012;7:443–447.
Frommel TO, Zarling EJ. Chronic inflammation and cancer: potential role of Bcl-2 gene family members as regulators of cellular antioxidant status. Med Hypotheses. 1999;52:27–30.
El-Omar EM, Carrington M, Chow WH, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000;404:398–402.
Papadakis KA, Targan SR. Tumor necrosis factor: biology and therapeutic inhibitors. Gastroenterology. 2000;119:1148–1157.
Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357:539–545.
Wang H, Wang H, Zhou B, et al. Epithelial-mesenchymal transition (EMT) induced by TNF-alpha requires AKT/GSK-3β-mediated stabilization of snail in colorectal cancer. PLoS One. 2013;8:e56664.
Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005;5:749–759.
de Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13:97–110.
Sheehan KM, Gulmann C, Eichler GS, et al. Signal pathway profiling of epithelial and stromal compartments of colonic carcinoma reveals epithelial-mesenchymal transition. Oncogene. 2008;27:323–331.
Le Bras GF, Taubenslag KJ, Andl CD. The regulation of cell-cell adhesion during epithelial-mesenchymal transition, motility and tumor progression. Cell Adhes Migr. 2012;6:365–373.
Joe B, Vijaykumar M, Lokesh BR. Biological properties of curcumin-cellular and molecular mechanisms of action. Crit Rev Food Sci Nutr. 2004;44:97–111.
Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as “Curecumin”: from kitchen to clinic. Biochem Pharmacol. 2008;75:787–809.
Zhang Z, Chen H, Xu C, et al. Curcumin inhibits tumor epithelialmesenchymal transition by downregulating the Wnt signaling pathway and upregulating NKD2 expression in colon cancer cells. Oncol Rep. 2016;35:2615–2623.
Harada H, Nakagawa H, Oyama K, et al. Telomerase induces immortalization of human esophageal keratinocytes without p16INK4a inactivation. Mol Cancer Res. 2003;1:729–738.
Lyros O, Rafiee P, Nie L, et al. Wnt/beta-catenin signaling activation beyond robust nuclear beta-catenin accumulation in nondysplastic barrett’s esophagus: regulation via dickkopf-1. Neoplasia. 2015;17:598–611.
Jethwa P, Naqvi M, Hardy RG, et al. Overexpression of Slug is associated with malignant progression of esophageal adenocarcinoma. World J Gastroenterol. 2008;14:1044–1052.
Fitzgerald RC, Abdalla S, Onwuegbusi BA, et al. Inflammatory gradient in Barrett’s oesophagus: implications for disease complications. Gut. 2002;51:316–322.
Yoshida N, Uchiyama K, Kuroda M, et al. Interleukin-8 expression in the esophageal mucosa of patients with gastroesophageal reflux disease. Scand J Gastroenterol. 2004;39:816–822.
Monkemuller K, Wex T, Kuester D, et al. Interleukin-1beta and interleukin-8 expression correlate with the histomorphological changes in esophageal mucosa of patients with erosive and non-erosive reflux disease. Digestion. 2009;79:186–195.
Eksteen JA, Scott PA, Perry I, et al. Inflammation promotes Barrett’s metaplasia and cancer: a unique role for TNFalpha. Eur J Cancer Prev. 2001;10:163–166.
Fitzgerald RC, Onwuegbusi BA, Bajaj-Elliott M, et al. Diversity in the oesophageal phenotypic response to gastro-oesophageal reflux: immunological determinants. Gut. 2002;50:451–459.
Katzka DA, Castell DO. Successful elimination of reflux symptoms does not insure adequate control of acid reflux in patients with Barrett’s esophagus. Am J Gastroenterol. 1994;89:989–991.
Ouatu-Lascar R, Triadafilopoulos G. Complete elimination of reflux symptoms does not guarantee normalization of intraesophageal acid reflux in patients with Barrett’s esophagus. Am J Gastroenterol. 1998;93:711–716.
Tselepis C, Perry I, Dawson C, et al. Tumour necrosis factor-alpha in Barrett’s oesophagus: a potential novel mechanism of action. Oncogene. 2002;21:6071–6081.
Rieder F, Biancani P, Harnett K, Yerian L, Falk GW. Inflammatory mediators in gastroesophageal reflux disease: impact on esophageal motility, fibrosis, and carcinogenesis. Am J Physiol Gastrointest Liver Physiol. 2010;298:G571–G581.
Jankowski JA, Harrison RF, Perry I, et al. Barrett’s metaplasia. Lancet. 2000;356:2079–2085.
Moore RJ, Owens DM, Stamp G, et al. Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med. 1999;5:828–831.
Papadakis KA, Targan SR. Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu Rev Med. 2000;51:289–298.
de la Concha EG, Fernandez-Arquero M, Vigil P, et al. Celiac disease and TNF promoter polymorphisms. Hum Immunol. 2000;61:513–517.
Luo M, Yang Y, Luo D, et al. Tumor necrosis factor-alpha promoter polymorphism 308 G/A is not significantly associated with esophageal cancer risk: a meta-analysis. Oncotarget. 2016;7:79901–79913.
Gharahkhani P, Fitzgerald RC, Vaughan TL, et al. Genome-wide association studies in oesophageal adenocarcinoma and Barrett’s oesophagus: a large-scale meta-analysis. Lancet Oncol. 2016;17:1363–1373.
Il’yasova D, Colbert LH, Harris TB, et al. Circulating levels of inflammatory markers and cancer risk in the health aging and body composition cohort. Cancer Epidemiol Biomarkers Prev. 2005;14:2413–2418.
Hardikar S, Onstad L, Song X, et al. Inflammation and oxidative stress markers and esophageal adenocarcinoma incidence in a Barrett’s esophagus cohort. Cancer Epidemiol Biomarkers Prev. 2014;23:2393–2403.
Wang JM, Deng X, Gong W, et al. Chemokines and their role in tumor growth and metastasis. J Immunol Methods. 1998;220:1–17.
Hatzoglou A, Roussel J, Bourgeade MF, et al. TNF receptor family member BCMA (B cell maturation) associates with TNF receptor-associated factor (TRAF) 1, TRAF2, and TRAF3 and activates NF-kappa B, elk-1, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. J Immunol. 2000;165:1322–1330.
Osborne CK, Hobbs K, Trent JM. Biological differences among MCF-7 human breast cancer cell lines from different laboratories. Breast Cancer Res Treat. 1987;9:111–121.
Secrier M, Li X, de Silva N, et al. Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance. Nat Genet. 2016;48:1131–1141.
Contino G, Eldridge MD, Secrier M, et al. Whole-genome sequencing of nine esophageal adenocarcinoma cell lines. F1000Res. 2016;5:1336.
Bailey T, Biddlestone L, Shepherd N, et al. Altered cadherin and catenin complexes in the Barrett’s esophagus-dysplasia-adenocarcinoma sequence: correlation with disease progression and dedifferentiation. Am J Pathol. 1998;152:135–144.
Birchmeier W, Behrens J. Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta. 1994;1198:11–26.
Perry I, Tselepis C, Hoyland J, et al. Reduced cadherin/catenin complex expression in celiac disease can be reproduced in vitro by cytokine stimulation. Lab Invest. 1999;79:1489–1499.
Grimm M, Lazariotou M, Kircher S, et al. Tumor necrosis factor-alpha is associated with positive lymph node status in patients with recurrence of colorectal cancer-indications for anti-TNF-alpha agents in cancer treatment. Cell Oncol. 2011;34:315–326.
Szlosarek P, Charles KA, Balkwill FR. Tumour necrosis factor-alpha as a tumour promoter. Eur J Cancer. 2006;42:745–750.
Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–444.
Yan B, Wang H, Rabbani ZN, et al. Tumor necrosis factor-alpha is a potent endogenous mutagen that promotes cellular transformation. Cancer Res. 2006;66:11565–11570.
Babbar N, Casero RA. Tumor necrosis factor-alpha increases reactive oxygen species by inducing spermine oxidase in human lung epithelial cells: a potential mechanism for inflammation-induced carcinogenesis. Cancer Res. 2006;66:11125–11130.
Lorenz D, Origer J, Pauthner M, et al. Prognostic risk factors of early esophageal adenocarcinomas. Ann Surg. 2014;259:469–476.
Santel T, Pflug G, Hemdan NYA, et al. Curcumin inhibits glyoxalase 1: a possible link to its anti-inflammatory and anti-tumor activity. PLoS One. 2008;3:e3508.
Olyaee M, Sontag S, Salman W, et al. Mucosal reactive oxygen species production in oesophagitis and Barrett’s oesophagus. Gut. 1995;37:168–173.
Kowluru RA, Kanwar M. Effects of curcumin on retinal oxidative stress and inflammation in diabetes. Nutr Metab (Lond). 2007;4:8.
Aggarwal BB, Shishodia S. Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol. 2006;71:1397–1421.
Kanai M, Yoshimura K, Asada M, et al. A phase I/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer. Cancer Chemother Pharmacol. 2011;68:157–164.
The authors would like to thank Franziska Rolfs and Ulrike Schmiedek for excellent technical support. This work was supported by the Junior Research Grant of the Faculty of Medicine, University of Leipzig, to RT and OL.
This work was supported by the Junior Research Grant of the Faculty of Medicine, University of Leipzig to RT.
OC, KG, RT, and IG conceived and designed experiments. OC, KG, LM, OL, and RT developed methodology. OC, KG, LM, IG, and RT analyzed and interpreted the data. AD, UE, OL, BJW, and AH were provided administrative, technical or material support. OC, RT, and IG wrote and/or revised the manuscript. RT and IG supervised and coordinated all aspects of the work.
Conflict of interest
The authors declare no financial competing interests related to this work.
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Chemnitzer, O., Götzel, K., Maurer, L. et al. Response to TNF-α Is Increasing Along with the Progression in Barrett’s Esophagus. Dig Dis Sci 62, 3391–3401 (2017). https://doi.org/10.1007/s10620-017-4821-6
- Barrett’s esophagus
- Esophageal adenocarcinoma