title: Antiangiogenic and Antitumor Activities of Aflibercept, a Soluble VEGF Receptor-1 and -2, in a Mouse Model of Hepatocellular Carcinoma.
abstract: Aflibercept known as ziv-aflibercept in the United States is a soluble decoy receptor of both vascular endothelial growth factor (VEGF) receptor-1 and -2 known to inhibit the binding of VEGF and placental growth factor (PlGF) to VEGF receptor-1 and -2. Here, we analyzed the mechanisms of the antitumor effects of aflibercept in mouse hepatoma models.
  
  
  
  In in vitro studies, we determined the effects of aflibercept on human umbilical vein cell (HUVEC) proliferation and bone marrow (BM) cell differentiation to endothelial progenitor cells (EPCs). In in vivo experiments, aflibercept was injected intraperitoneally in hepatoma cell tumor-bearing mice, and its inhibitory effects on tumor growth and BM cell migration to tumor tissues were evaluated.
  
  
  
  Aflibercept suppressed phosphorylation of VEGF receptor-1 and -2 in HUVEC and dose-dependently inhibited VEGF-induced HUVEC proliferation. It suppressed the differentiation of BM cells to EPCs and migration of BM cells to tumor tissues. It also suppressed tumor growth and prolonged survival time of tumor-bearing mice without side effects. In tumor tissues, aflibercept upregulated the expression of hypoxia inducible factor1-α, VEGF, PlGF, fibroblast growth factor-2, platelet derived growth factor-BB, and transforming growth factor-α and reduced microvascular density. It also reduced sinusoidal density in noncancerous liver tissues.
  
  
  
  Our results demonstrated potent antitumor activity for aflibercept in a mouse model of hepatocellular carcinoma. These effects were mediated through inhibition of neovascularization, caused by inhibition of endothelial cell proliferation, EPC differentiation, and BM cell migration to tumor tissues.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume, Japan. Electronic address: tori@med.kurume-u.ac.jp.
authors.forename: Takuji
authors.initials: T
authors.lastname: Torimura
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan. Electronic address: iwamoto_hideki@med.kurume-u.ac.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Iwamoto
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Abe
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ikezono
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Wada
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Sakaue
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Masuda
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Hashimoto
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Koga
authors.affiliation: Asakura Medical Association Hospital, Asakura, Japan.
authors.forename: Takato
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Yano
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D066026:Endothelial Progenitor Cells / Q000166:cytology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2