{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T23:30:06Z","timestamp":1786404606944,"version":"build-2736575974"},"reference-count":40,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22K06020"],"award-info":[{"award-number":["22K06020"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25K02164"],"award-info":[{"award-number":["25K02164"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23KJ0056"],"award-info":[{"award-number":["23KJ0056"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Vet Comparative Oncology"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Tumour cells commonly exhibit aerobic glycolysis and produce lactate despite oxygen availability. Lactate dehydrogenase (LDH) catalyses pyruvate\u2010lactate interconversion and regulates intracellular lactate levels. Endothelial cells also depend on glycolysis for ATP production, which prompted us to investigate LDH in canine hemangiosarcoma (HSA), a malignant endothelial tumour. We inhibited LDH with (R)\u2010GNE\u2010140 or sodium oxamate in two canine HSA cell lines (HU\u2010HSA\u20102 and HU\u2010HSA\u20103) and generated HU\u2010HSA\u20103 clones with knockout of\n                    <jats:italic>LDHA<\/jats:italic>\n                    or\n                    <jats:italic>LDHB<\/jats:italic>\n                    to evaluate the effects of LDH perturbation. (R)\u2010GNE\u2010140 and sodium oxamate suppressed proliferation and reduced global histone lactylation levels in both cell lines. mRNA\u2010sequencing (mRNA\u2010seq) of (R)\u2010GNE\u2010140\u2010treated HU\u2010HSA\u20102 cells identified cholesterol\/lipid metabolism\u2010related gene sets among the top negatively enriched pathways. Representative cholesterol\/lipid metabolism genes such as\n                    <jats:italic>SREBF2<\/jats:italic>\n                    ,\n                    <jats:italic>SQLE<\/jats:italic>\n                    and\n                    <jats:italic>LDLR<\/jats:italic>\n                    responded differently depending on cell lines and inhibitors. (R)\u2010GNE\u2010140 decreased these genes in HU\u2010HSA\u20102 but not HU\u2010HSA\u20103, whereas sodium oxamate decreased them in HU\u2010HSA\u20103 with limited effects in HU\u2010HSA\u20102. In HU\u2010HSA\u20103,\n                    <jats:italic>LDHA<\/jats:italic>\n                    and\n                    <jats:italic>LDHB<\/jats:italic>\n                    knockout clones decreased SREBP2 expression and reduced the number of lipid droplets. Fluvastatin, a cholesterol metabolism inhibitor, inhibited HSA cell growth in\u00a0vitro but did not significantly suppress tumour growth in two HSA patient\u2010derived xenograft (PDX) models. In contrast, combined fluvastatin and dipyridamole treatment inhibited proliferation in\u00a0vitro and tumour growth in PDX models. Collectively, these results suggest a context\u2010dependent association between LDH and cholesterol\/lipid metabolism in canine HSA cell lines and provide a rationale for further evaluation of combined cholesterol pathway inhibition.\n                  <\/jats:p>","DOI":"10.1111\/vco.70097","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T23:10:50Z","timestamp":1786403450000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fluvastatin Plus Dipyridamole Suppresses Canine Hemangiosarcoma Growth in Patient\u2010Derived Xenograft Models Through Lactate Dehydrogenase\u2010Associated Cholesterol\/Lipid Metabolism"],"prefix":"10.1111","author":[{"given":"Tamami","family":"Suzuki","sequence":"first","affiliation":[{"name":"Laboratory of Comparative Pathology, Department of Clinical Sciences, Faculty of Veterinary Medicine Hokkaido University  Sapporo Hokkaido Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzune","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Pathology, Department of Clinical Sciences, Faculty of Veterinary Medicine Hokkaido University  Sapporo Hokkaido Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keika","family":"Kishimoto","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Pathology, Department of Clinical Sciences, Faculty of Veterinary Medicine Hokkaido University  Sapporo Hokkaido Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuma","family":"Goto","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Pathology, Department of Clinical Sciences, Faculty of Veterinary Medicine Hokkaido University  Sapporo Hokkaido Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jumpei","family":"Yamazaki","sequence":"additional","affiliation":[{"name":"Translational Research Unit, Veterinary Teaching Hospital, Faculty of Veterinary Medicine Hokkaido University  Sapporo Hokkaido Japan"},{"name":"Cancer Research Unit, One Health Research Center Hokkaido University  Sapporo Hokkaido Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7286-8365","authenticated-orcid":false,"given":"Takashi","family":"Kimura","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Pathology, Department of Clinical Sciences, Faculty of Veterinary Medicine Hokkaido University  Sapporo Hokkaido Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2987-0793","authenticated-orcid":false,"given":"Keisuke","family":"Aoshima","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Pathology, Department of Clinical Sciences, Faculty of Veterinary Medicine Hokkaido University  Sapporo Hokkaido Japan"},{"name":"Cancer Research Unit, One Health Research Center Hokkaido University  Sapporo Hokkaido Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"issue":"3","key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.semradonc.2004.04.004","article-title":"Lactate: Mirror and Motor of Tumor Malignancy","volume":"14","author":"Walenta S.","year":"2004","journal-title":"Seminars in Radiation Oncology"},{"issue":"9","key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"3685","DOI":"10.1172\/JCI69741","article-title":"Targeting Lactate Metabolism for Cancer Therapeutics","volume":"123","author":"Doherty J. 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