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Developing an animal model that mimics both early and advanced OSCC stages has been challenging. The 4-Nitroquinoline 1-oxide (4NQO) model is considered one of the most suitable, as it represents all stages of OSCC. Nevertheless, thoroughly understanding the properties of the 4NQO model is essential for preclinical testing of novel therapeutics. Methods: We aimed to characterize the 4NQO rat model using two application methods\u2014drinking water and topical application\u2014over eight months. Monthly sacrifices allowed histopathological analysis and ex vivo magnetic resonance imaging (MRI) to track tumor progression. Results: CIS was observed at three months in the drinking water group, evolving into ISCC by six months, while topical application induced CIS at eight months without ISCC formation. The tongue was divided into three regions and histological properties, lesion size, and invasion depth were analyzed. In the drinking water group, particularly in the body of the tongue, we saw earlier CIS development, larger lesions, and deeper invasion. Additionally, assessment of proliferative properties showed an increased cell division in dysplastic lesions that reduced upon invasion. MRI was able to show macroscopic tumoral lesions, in concordance with histology. Conclusions: Overall, the drinking water method closely mimics human OSCC, validating the 4NQO model for translational OSCC research.<\/jats:p>","DOI":"10.3390\/cancers17132108","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T04:37:21Z","timestamp":1750739841000},"page":"2108","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Optimizing Preclinical Models for Oral Cancer: The Influence of 4NQO Administration Routes on Tumor Development"],"prefix":"10.3390","volume":"17","author":[{"given":"Jolien","family":"Van den Bosch","sequence":"first","affiliation":[{"name":"Laboratory for Functional Imaging and Research on Stem Cells (FIERCE Lab), Biomedical Research Institute (BIOMED), Hasselt University, 3950 Diepenbeek, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7454-2230","authenticated-orcid":false,"given":"Nuran","family":"Caz","sequence":"additional","affiliation":[{"name":"Laboratory for Functional Imaging and Research on Stem Cells (FIERCE Lab), Biomedical Research Institute (BIOMED), Hasselt University, 3950 Diepenbeek, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandrina","family":"Martens","sequence":"additional","affiliation":[{"name":"Laboratory for Functional Imaging and Research on Stem Cells (FIERCE Lab), Biomedical Research Institute (BIOMED), Hasselt University, 3950 Diepenbeek, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u00e9line","family":"Erens","sequence":"additional","affiliation":[{"name":"Laboratory for Functional Imaging and Research on Stem Cells (FIERCE Lab), Biomedical Research Institute (BIOMED), Hasselt University, 3950 Diepenbeek, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2421-150X","authenticated-orcid":false,"given":"Leen","family":"Rasking","sequence":"additional","affiliation":[{"name":"Laboratory for Functional Imaging and Research on Stem Cells (FIERCE Lab), Biomedical Research Institute (BIOMED), Hasselt University, 3950 Diepenbeek, Belgium"},{"name":"Centre for Environmental Sciences, 3950 Diepenbeek, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8320-1320","authenticated-orcid":false,"given":"Pascal","family":"Gervois","sequence":"additional","affiliation":[{"name":"Laboratory for Functional Imaging and Research on Stem Cells (FIERCE Lab), Biomedical Research Institute (BIOMED), Hasselt University, 3950 Diepenbeek, Belgium"},{"name":"Limburg Clinical Research Center (LCRC), 3950 Diepenbeek, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8085-8311","authenticated-orcid":false,"given":"Kim","family":"Nijsten","sequence":"additional","affiliation":[{"name":"Laboratory for Functional Imaging and Research on Stem Cells (FIERCE Lab), Biomedical Research Institute (BIOMED), Hasselt University, 3950 Diepenbeek, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2060-8895","authenticated-orcid":false,"given":"Uwe","family":"Himmelreich","sequence":"additional","affiliation":[{"name":"Biomedical MRI Unit, Department of Imaging & Pathology, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9537-3795","authenticated-orcid":false,"given":"Sofie","family":"Van Cauter","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute (BIOMED), Faculty of Medicine and Life Sciences, Hasselt University, 3950 Diepenbeek, Belgium"},{"name":"Department of medical imaging, Ziekenhuis-Oost Limburg (ZOL), 3600 Genk, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa M.","family":"Hillen","sequence":"additional","affiliation":[{"name":"Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, 6211 Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Herbert","family":"Plasschaert","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ziekenhuis-Oost Limburg (ZOL), 3600 Genk, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7520-0021","authenticated-orcid":false,"given":"Ivo","family":"Lambrichts","sequence":"additional","affiliation":[{"name":"Lab for Histology and Regeneration (HISTOREGEN Lab), Biomedical Research Institute (BIOMED), Hasselt University, 3950 Diepenbeek, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9277-6524","authenticated-orcid":false,"given":"Esther","family":"Wolfs","sequence":"additional","affiliation":[{"name":"Laboratory for Functional Imaging and Research on Stem Cells (FIERCE Lab), Biomedical Research Institute (BIOMED), Hasselt University, 3950 Diepenbeek, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41572-020-00224-3","article-title":"Head and neck squamous cell carcinoma","volume":"6","author":"Johnson","year":"2020","journal-title":"Nat. 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