{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T08:58:59Z","timestamp":1790758739498,"version":"4.1.0"},"reference-count":41,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,10,4]],"date-time":"2021-10-04T00:00:00Z","timestamp":1633305600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fonds Agir pour les Maladies Chroniques","award":["2017-2019"],"award-info":[{"award-number":["2017-2019"]}]},{"name":"La Ligue contre le cancer AURA","award":["38"],"award-info":[{"award-number":["38"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Hepatocellular carcinoma (HCC) is the most common type of liver cancer. The majority of HCC cases are associated with liver fibrosis or cirrhosis developing from chronic liver injuries. The immune system of the liver contributes to the severity of tissue damage, the establishment of fibrosis and the disease\u2019s progression towards HCC. Herein, we provide a detailed characterization of the DEN-induced HCC rat model during fibrosis progression and HCC development with a special focus on the liver\u2019s inflammatory microenvironment. Fischer 344 male rats were treated weekly for 14 weeks with intra-peritoneal injections of 50 mg\/kg DEN. The rats were sacrificed before starting DEN-injections at 0 weeks, after 8 weeks, 14 weeks and 20 weeks after the start of DEN-injections. We performed histopathological, immunohistochemical, RT-qPCR, RNA-seq and flow cytometry analysis. Data were compared between tumor and non-tumor samples from the DEN-treated versus untreated rats, as well as versus human HCCs. Chronic DEN injections lead to liver damage, hepatocytes proliferation, liver fibrosis and cirrhosis, disorganized vasculature, and a modulated immune microenvironment that mimics the usual events observed during human HCC development. The RNA-seq results showed that DEN-induced liver tumors in the rat model shared remarkable molecular characteristics with human HCC, especially with HCC associated with high proliferation. In conclusion, our study provides detailed insight into hepatocarcinogenesis in a commonly used model of HCC, facilitating the future use of this model for preclinical testing.<\/jats:p>","DOI":"10.3390\/cancers13194981","type":"journal-article","created":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T09:24:04Z","timestamp":1633598644000},"page":"4981","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["DEN-Induced Rat Model Reproduces Key Features of Human Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"13","author":[{"given":"Keerthi","family":"Kurma","sequence":"first","affiliation":[{"name":"Universit\u00e9 Grenoble Alpes, 38000 Grenoble, France"},{"name":"Institute for Advanced Biosciences, Research Center Inserm U 1209\/CNRS 5309, 38700 La Tronche, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Manches","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences, Research Center Inserm U 1209\/CNRS 5309, 38700 La Tronche, France"},{"name":"Etablissement Fran\u00e7ais du Sang, Rhone-Alpes Auvergne, 38043 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florent","family":"Chuffart","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Grenoble Alpes, 38000 Grenoble, France"},{"name":"Institute for Advanced Biosciences, Research Center Inserm U 1209\/CNRS 5309, 38700 La Tronche, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Sturm","sequence":"additional","affiliation":[{"name":"Service d\u2019Anatomo-Pathologie, P\u00f4le de Biologie, CHU Grenoble Alpes, 38700 La Tronche, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khaldoun","family":"Gharzeddine","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Grenoble Alpes, 38000 Grenoble, France"},{"name":"Institute for Advanced Biosciences, Research Center Inserm U 1209\/CNRS 5309, 38700 La Tronche, France"},{"name":"Research Department, CHU Grenoble Alpes, 38700 La Tronche, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Grenoble Alpes, 38000 Grenoble, France"},{"name":"Institute for Advanced Biosciences, Research Center Inserm U 1209\/CNRS 5309, 38700 La Tronche, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0667-2513","authenticated-orcid":false,"given":"Marion","family":"Mercey-Ressejac","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Grenoble Alpes, 38000 Grenoble, France"},{"name":"Institute for Advanced Biosciences, Research Center Inserm U 1209\/CNRS 5309, 38700 La Tronche, France"},{"name":"Service d\u2019H\u00e9pato-Gastroent\u00e9rologie, P\u00f4le Digidune, CHU Grenoble Alpes, 38700 La Tronche, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5246-5350","authenticated-orcid":false,"given":"Sophie","family":"Rousseaux","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Grenoble Alpes, 38000 Grenoble, France"},{"name":"Institute for Advanced Biosciences, Research Center Inserm U 1209\/CNRS 5309, 38700 La Tronche, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3547-7533","authenticated-orcid":false,"given":"Arnaud","family":"Millet","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Grenoble Alpes, 38000 Grenoble, France"},{"name":"Institute for Advanced Biosciences, Research Center Inserm U 1209\/CNRS 5309, 38700 La Tronche, France"},{"name":"Service d\u2019H\u00e9pato-Gastroent\u00e9rologie, P\u00f4le Digidune, CHU Grenoble Alpes, 38700 La Tronche, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herve","family":"Lerat","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Grenoble Alpes, 38000 Grenoble, France"},{"name":"Institute for Advanced Biosciences, Research Center Inserm U 1209\/CNRS 5309, 38700 La Tronche, France"},{"name":"Unit\u00e9 Mixte de Service Universit\u00e9 Grenoble Alpes hTAG, Inserm U046, CNRS UAR2019, 38700 La Tronche, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8930-9340","authenticated-orcid":false,"given":"Patrice N.","family":"Marche","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Grenoble Alpes, 38000 Grenoble, France"},{"name":"Institute for Advanced Biosciences, Research Center Inserm U 1209\/CNRS 5309, 38700 La Tronche, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2553-5971","authenticated-orcid":false,"given":"Zuzana","family":"Macek Jilkova","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Grenoble Alpes, 38000 Grenoble, France"},{"name":"Institute for Advanced Biosciences, Research Center Inserm U 1209\/CNRS 5309, 38700 La Tronche, France"},{"name":"Service d\u2019H\u00e9pato-Gastroent\u00e9rologie, P\u00f4le Digidune, CHU Grenoble Alpes, 38700 La Tronche, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0928-0048","authenticated-orcid":false,"given":"Thomas","family":"Decaens","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Grenoble Alpes, 38000 Grenoble, France"},{"name":"Institute for Advanced Biosciences, Research Center Inserm U 1209\/CNRS 5309, 38700 La Tronche, France"},{"name":"Service d\u2019H\u00e9pato-Gastroent\u00e9rologie, P\u00f4le Digidune, 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