{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:16:17Z","timestamp":1787008577052,"version":"build-2736575974"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2020,5,25]],"date-time":"2020-05-25T00:00:00Z","timestamp":1590364800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["19fk0210022h0103"],"award-info":[{"award-number":["19fk0210022h0103"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["19fk0210018h0003"],"award-info":[{"award-number":["19fk0210018h0003"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["19fk0310101s0503"],"award-info":[{"award-number":["19fk0310101s0503"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["19fk0210048s0501"],"award-info":[{"award-number":["19fk0210048s0501"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["19fk0210058h0001"],"award-info":[{"award-number":["19fk0210058h0001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["19fk0210047s0401"],"award-info":[{"award-number":["19fk0210047s0401"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19K08458"],"award-info":[{"award-number":["19K08458"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,2,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>In hepatocellular carcinoma (HCC), a subset of cells defined by high CD44 and CD133 expression has been reported to possess cancer stem-like cell (CSC) characteristics and to be associated with a poor prognosis. Since the approval of the multikinase inhibitor, lenvatinib, for patients with unresectable HCC, two such inhibitors (sorafenib and lenvatinib) have been employed as first-line systemic chemotherapeutics for these patients. Based on differences in the kinase-affinity profiles between these two drugs, evidence has suggested that both exert different effects on HCC, although these differences are not fully characterized. In this study, using in vitro and a preclinical in vivo xenograft mouse model, we showed that lenvatinib alone (not sorafenib or the cytotoxic agent, 5-fluorouracil) diminished CD44High\/CD133High CSCs in HCC. Furthermore, western blotting and reverse transcriptase-polymerase chain reaction analysis revealed that the expression of fibroblast growth factor receptor (FGFR)-1\u20134 differed between CD44High\/CD133High CSCs and control cells. Analysis of the effects of selective FGFR inhibitors and FGFR small interfering RNAs on CSCs in HCC revealed that lenvatinib diminished CSCs in HCC by inhibiting FGFR1\u20133 signaling, however, FGFR4 signaling was not impacted. Finally, we showed that FGF2 and FGF19 were involved in maintaining CD44High\/CD133High CSCs in HCC, potentially, via FGFR1\u20133. The findings provide novel mechanistic insights into the effects of lenvatinib on CSCs in HCC and provide clues for developing effective targeted therapies against CSCs in HCC.<\/jats:p>","DOI":"10.1093\/carcin\/bgaa049","type":"journal-article","created":{"date-parts":[[2020,5,19]],"date-time":"2020-05-19T07:19:20Z","timestamp":1589872760000},"page":"58-69","source":"Crossref","is-referenced-by-count":33,"title":["Lenvatinib suppresses cancer stem-like cells in HCC by inhibiting FGFR1\u20133 signaling, but not FGFR4 signaling"],"prefix":"10.1093","volume":"42","author":[{"given":"Taku","family":"Shigesawa","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Maehara","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan"},{"name":"Department of Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences Hokkaido University, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goki","family":"Suda","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuteru","family":"Natsuizaka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan"},{"name":"Department of Internal Medicine, Natsuizaka Clinic, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megumi","family":"Kimura","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoe","family":"Shimazaki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kitagataya","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihisa","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuharu","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatsugu","family":"Ohara","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Kawagishi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Machiko","family":"Umemura","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Nakai","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Sho","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Morikawa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1194-4149","authenticated-orcid":false,"given":"Shunsuke","family":"Ohnishi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaya","family":"Sugiyama","sequence":"additional","affiliation":[{"name":"Genome Medical Sciences Project, National Center for Global Health Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Mizokami","sequence":"additional","affiliation":[{"name":"Genome Medical Sciences 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