{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T14:59:24Z","timestamp":1773932364180,"version":"3.50.1"},"reference-count":50,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,4,25]],"date-time":"2021-04-25T00:00:00Z","timestamp":1619308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"H2020 Marie Sk\u0142odowska-Curie Actions","award":["721906"],"award-info":[{"award-number":["721906"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Chronic inflammation plays an important role in the pathogenesis of oesophageal adenocarcinoma (EAC) and its only known precursor, Barrett\u2019s oesophagus (BE). Recent studies have shown that oesophageal TLR2 levels increase from normal epithelium towards EAC. TLR2 signalling is therefore likely to be important during EAC development and progression, which requires an inflammatory microenvironment. Here, we show that, in response to TLR2 stimulation, BE organoids and early-stage EAC cells secrete pro-inflammatory cytokines and chemokines which recruit macrophages to the tumour site. Factors secreted from TLR2-stimulated EAC cells are shown to subsequently activate TLR2 on na\u00efve macrophages, priming them for inflammasome activation and inducing their differentiation to an M2\/TAM-like phenotype. We identify the endogenous TLR2 ligand, HMGB1, as the factor secreted from EAC cells responsible for the observed TLR2-mediated effects on macrophages. Our results indicate that HMGB1 signalling between EAC cells and macrophages creates an inflammatory tumour microenvironment to facilitate EAC progression. In addition to identifying HMGB1 as a potential target for early-stage EAC treatment, our data suggest that blocking TLR2 signalling represents a mechanism to limit HMGB1 release, inflammatory cell infiltration and inflammation during EAC progression.<\/jats:p>","DOI":"10.3390\/cancers13092065","type":"journal-article","created":{"date-parts":[[2021,4,25]],"date-time":"2021-04-25T22:31:39Z","timestamp":1619389899000},"page":"2065","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Identification of TLR2 Signalling Mechanisms Which Contribute to Barrett\u2019s and Oesophageal Adenocarcinoma Disease Progression"],"prefix":"10.3390","volume":"13","author":[{"given":"Ewelina","family":"Flis","sequence":"first","affiliation":[{"name":"School of Biochemistry and Immunology, Trinity Biomedical Science Institute (TBSI), Trinity College Dublin, D02 R590 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6909-6042","authenticated-orcid":false,"given":"Gillian","family":"Barber","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology, Trinity Biomedical Science Institute (TBSI), Trinity College Dublin, D02 R590 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ciara","family":"Nulty","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology, Trinity Biomedical Science Institute (TBSI), Trinity College Dublin, D02 R590 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Keogh","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology, Trinity Biomedical Science Institute (TBSI), Trinity College Dublin, D02 R590 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"McGuirk","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology, Trinity Biomedical Science Institute (TBSI), Trinity College Dublin, D02 R590 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akanksha","family":"Anand","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Technical University of Munich, D-80333 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacintha","family":"O\u2019Sullivan","sequence":"additional","affiliation":[{"name":"Department of Surgery, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St. James\u2019s Hospital, D08 W9RT Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8497-582X","authenticated-orcid":false,"given":"Michael","family":"Quante","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Technical University of Munich, D-80333 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7631-4370","authenticated-orcid":false,"given":"Emma M.","family":"Creagh","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology, Trinity Biomedical Science Institute (TBSI), Trinity College Dublin, D02 R590 Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1002\/ijc.1440","article-title":"Estimating the world cancer burden: Globocan 2000","volume":"94","author":"Bray","year":"2001","journal-title":"Int. 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