{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,5]],"date-time":"2026-04-05T05:39:32Z","timestamp":1775367572662,"version":"3.50.1"},"reference-count":40,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T00:00:00Z","timestamp":1677628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["PNRR-MAD-2022-12376188"],"award-info":[{"award-number":["PNRR-MAD-2022-12376188"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Metabolic syndrome (MetS) is a common condition closely associated with non-alcoholic fatty liver disease\/non-alcoholic steatohepatitis (NAFLD\/NASH). Recent meta-analyses show that MetS can be prodromal to intrahepatic cholangiocarcinoma (iCCA) development, a liver tumor with features of biliary differentiation characterized by dense extracellular matrix (ECM) deposition. Since ECM remodeling is a key event in the vascular complications of MetS, we aimed at evaluating whether MetS patients with iCCA present qualitative and quantitative changes in the ECM able to incite biliary tumorigenesis. In 22 iCCAs with MetS undergoing surgical resection, we found a significantly increased deposition of osteopontin (OPN), tenascin C (TnC), and periostin (POSTN) compared to the matched peritumoral areas. Moreover, OPN deposition in MetS iCCAs was also significantly increased when compared to iCCA samples without MetS (non-MetS iCCAs, n = 44). OPN, TnC, and POSTN significantly stimulated cell motility and the cancer-stem-cell-like phenotype in HuCCT-1 (human iCCA cell line). In MetS iCCAs, fibrosis distribution and components differed quantitatively and qualitatively from non-MetS iCCAs. We therefore propose overexpression of OPN as a distinctive trait of MetS iCCA. Since OPN stimulates malignant properties of iCCA cells, it may provide an interesting predictive biomarker and a putative therapeutic target in MetS patients with iCCA.<\/jats:p>","DOI":"10.3390\/ijms24054748","type":"journal-article","created":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T03:29:00Z","timestamp":1677727740000},"page":"4748","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Intrahepatic Cholangiocarcinoma Developing in Patients with Metabolic Syndrome Is Characterized by Osteopontin Overexpression in the Tumor Stroma"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0899-7613","authenticated-orcid":false,"given":"Massimiliano","family":"Cadamuro","sequence":"first","affiliation":[{"name":"General Internal Medicine Unit, Padua University-Hospital, 35128 Padua, Italy"},{"name":"Department of Medicine\u2014DIMED, University of Padua, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha","family":"Sarcognato","sequence":"additional","affiliation":[{"name":"Department of Pathology, Azienda ULSS2 Marca Trevigiana, 31100 Treviso, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riccardo","family":"Camerotto","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine (DMM), University of Padua,  35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noemi","family":"Girardi","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine (DMM), University of Padua,  35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Lasagni","sequence":"additional","affiliation":[{"name":"General Internal Medicine Unit, Padua University-Hospital, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giacomo","family":"Zanus","sequence":"additional","affiliation":[{"name":"4th Surgery Unit, Azienda ULSS2 Marca Trevigiana, 31100 Treviso, Italy"},{"name":"Department of Surgery, Oncology and Gastroenterology\u2014DISCOG, University of Padova, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Umberto","family":"Cillo","sequence":"additional","affiliation":[{"name":"Department of Surgery, Oncology and Gastroenterology\u2014DISCOG, University of Padova, 35128 Padua, Italy"},{"name":"Hepatobiliary Surgery and Liver Transplantation Unit, Padua University-Hospital, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3459-7306","authenticated-orcid":false,"given":"Enrico","family":"Gringeri","sequence":"additional","affiliation":[{"name":"Department of Surgery, Oncology and Gastroenterology\u2014DISCOG, University of Padova, 35128 Padua, Italy"},{"name":"Hepatobiliary Surgery and Liver Transplantation Unit, Padua University-Hospital, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Morana","sequence":"additional","affiliation":[{"name":"Division of Radiology, Treviso Regional Hospital, 31100 Treviso, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"Strazzabosco","sequence":"additional","affiliation":[{"name":"Digestive Disease Section, Liver Center, Yale University, New Haven, CT 06510, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Campello","sequence":"additional","affiliation":[{"name":"General Internal Medicine Unit, Padua University-Hospital, 35128 Padua, Italy"},{"name":"Department of Medicine\u2014DIMED, University of Padua, 35128 Padua, Italy"},{"name":"Thrombotic and Haemorrhagic Disease Unit and Haemophilia Center, Department of Medicine (DIMED), University of Padua, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6744-383X","authenticated-orcid":false,"given":"Paolo","family":"Simioni","sequence":"additional","affiliation":[{"name":"General Internal Medicine Unit, Padua University-Hospital, 35128 Padua, Italy"},{"name":"Department of Medicine\u2014DIMED, University of Padua, 35128 Padua, Italy"},{"name":"Thrombotic and Haemorrhagic Disease Unit and Haemophilia Center, Department of Medicine (DIMED), University of Padua, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Guido","sequence":"additional","affiliation":[{"name":"Department of Medicine\u2014DIMED, University of Padua, 35128 Padua, Italy"},{"name":"Department of Pathology, Azienda ULSS2 Marca Trevigiana, 31100 Treviso, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8538-6317","authenticated-orcid":false,"given":"Luca","family":"Fabris","sequence":"additional","affiliation":[{"name":"General Internal Medicine Unit, Padua University-Hospital, 35128 Padua, Italy"},{"name":"Department of Molecular Medicine (DMM), University of Padua,  35128 Padua, Italy"},{"name":"Digestive Disease Section, Liver Center, Yale University, New Haven, CT 06510, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/s41575-020-0310-z","article-title":"Cholangiocarcinoma 2020: The next horizon in mechanisms and management","volume":"17","author":"Banales","year":"2020","journal-title":"Nat. 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