{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,20]],"date-time":"2025-12-20T22:07:52Z","timestamp":1766268472059,"version":"build-2065373602"},"reference-count":41,"publisher":"Georg Thieme Verlag KG","issue":"CP","license":[{"start":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T00:00:00Z","timestamp":1757894400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["19K08850"],"award-info":[{"award-number":["19K08850"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["22K08489"],"award-info":[{"award-number":["22K08489"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["TH Open"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Direct oral anticoagulants (DOACs) have been widely used in patients with thromboembolism. We previously reported that among DOACs, edoxaban (EDX), a factor Xa (FXa)-specific DOAC, most effectively inhibited the growth of syngeneic non-metastatic murine colon cancer cells implanted in mice via the protease-activated receptor 2 (PAR2) pathway. This study aimed to analyze the effects and mechanism of action of DOACs targeting thrombin or FXa on the metastasis of murine melanoma B16 cells implanted in mice.<\/jats:p><jats:p>B16 cells (106 cells in 100\u2009\u03bcL) were implanted into the tail vein of 8-week-old female C57BL\/6j mice (n\u2009=\u20095 per group), followed by daily oral administration of DOACs targeting thrombin (dabigatran etexilate [DABE], 50\u2009mg\/kg body weight [bw]) or FXa (rivaroxaban [RVX], 5\u2009mg\/kg bw; EDX, 10\u2009mg\/kg bw) for 14 days. The effects on tumor metastasis on day 15 and the inhibitory mechanism of the DOAC with the strongest inhibitory effect were analyzed.<\/jats:p><jats:p>Lung metastasis of B16 cells implanted in mice was significantly suppressed in the following order: EDX\u2009&gt;\u2009RVX\u2009\u2265\u2009DABE, compared with the saline-treated group. DOPA (3,4-dihydroxyphenylalanine)-positive cell density was significantly reduced from approximately 1,250 cells\/mm2 in the saline group to approximately 600 cells\/mm2 (RVX and DABE) and approximately 400 cells\/mm2 (EDX; p\u2009&lt;\u20090.05 or 0.01). Investigating the inhibitory mechanism of EDX revealed that inflammation-associated factors such as PAR2, interleukin 6 (IL-6), and transforming growth factor \u03b21 (TGF\u03b21); angiogenic factors such as vascular endothelial growth factor A and angiopoietin-2; and epithelial\u2013mesenchymal transition (EMT)-associated factors such as vimentin and snail, which were increased in the lungs of the saline-treated group, all significantly decreased in the EDX-treated group (p\u2009&lt;\u20090.05 or 0.01). In contrast, intercellular tight junction factors exhibited an opposite trend. EDX also inhibited FXa-dependent production of melanin, IL-6, and TGF\u03b21 in in vitro cultured B16 cells.<\/jats:p><jats:p>Among the tested DOACs, EDX showed the strongest inhibition of B16 cell metastasis in mice, likely via the suppression of inflammation, angiogenesis, and EMT mediated by the FXa-dependent PAR2 and TGF\u03b2 pathways in tumor and surrounding tissue cells.<\/jats:p>","DOI":"10.1055\/a-2701-4242","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T22:50:17Z","timestamp":1757976617000},"source":"Crossref","is-referenced-by-count":1,"special_numbering":"S","title":["Effects of DOACs on Mouse Melanoma Metastasis and the Inhibitory Mechanism of Edoxaban, a Factor Xa-Specific DOAC"],"prefix":"10.1055","volume":"09","author":[{"given":"Keiichi","family":"Hiramoto","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka City, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taisei","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka City, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masashi","family":"Imai","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka City, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koji","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka City, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"194","published-online":{"date-parts":[[2025,9,30]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.thromres.2017.05.015","article-title":"Venous thromboembolism in the elderly: A narrative review","volume":"155","author":"T Tritschler","year":"2017","journal-title":"Thromb Res"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"437","DOI":"10.2147\/VHRM.S264814","article-title":"The cumulative incidence and risk factors of recurrent venous thromboembolism in the elderly","volume":"16","author":"F AS Aleidan","year":"2020","journal-title":"Vasc Health Risk Manag"},{"issue":"02","key":"ref3","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1056\/NEJMoa025313","article-title":"Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer","volume":"349","author":"A YY Lee","year":"2003","journal-title":"N Engl J Med"},{"issue":"24","key":"ref4","doi-asserted-by":"crossref","first-page":"2342","DOI":"10.1056\/NEJMoa0906598","article-title":"Dabigatran versus warfarin in the treatment of acute venous thromboembolism","volume":"361","author":"S Schulman","year":"2009","journal-title":"N Engl J Med"},{"issue":"01","key":"ref5","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/nrd3185","article-title":"The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor","volume":"10","author":"E Perzborn","year":"2011","journal-title":"Nat Rev Drug Discov"},{"issue":"12","key":"ref6","doi-asserted-by":"crossref","first-page":"2368","DOI":"10.1111\/j.1538-7836.2007.02764.x","article-title":"The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement","volume":"5","author":"M R Lassen","year":"2007","journal-title":"J Thromb Haemost"},{"issue":"15","key":"ref7","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1056\/NEJMoa1306638","article-title":"Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism","volume":"369","author":"H R B\u00fcller","year":"2013","journal-title":"N Engl J Med"},{"issue":"07","key":"ref8","doi-asserted-by":"crossref","first-page":"e334","DOI":"10.1016\/S1470-2045(22)00160-7","article-title":"2022 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer, including patients with COVID-19","volume":"23","author":"D Farge","year":"2022","journal-title":"Lancet Oncol"},{"issue":"22","key":"ref9","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1001\/jama.2023.7843","article-title":"Direct oral anticoagulants vs low-molecular-weight heparin and recurrent VTE in patients with cancer. 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