title: TIMP-2 fusion protein with human serum albumin potentiates anti-angiogenesis-mediated inhibition of tumor growth by suppressing MMP-2 expression.
abstract: TIMP-2 protein has been intensively studied as a promising anticancer candidate agent, but the in vivo mechanism underlying its anticancer effect has not been clearly elucidated by previous works. In this study, we investigated the mechanism underlying the anti-tumor effects of a TIMP-2 fusion protein conjugated with human serum albumin (HSA/TIMP-2). Systemic administration of HSA/TIMP-2 effectively inhibited tumor growth at a minimum effective dose of 60 mg/kg. The suppressive effect of HSA/TIMP-2 was accompanied by a marked reduction of in vivo vascularization. The anti-angiogenic activity of HSA/TIMP-2 was directly confirmed by CAM assays. In HSA/TIMP-2-treated tumor tissues, MMP-2 expression was profoundly decreased without a change in MT1-MMP expression of PECAM-1-positive cells. MMP-2 mRNA was also decreased by HSA/TIMP-2 treatment of human umbilical vein endothelial cells. Zymographic analysis showed that HSA/TIMP-2 substantially decreased extracellular pro-MMP-2 activity (94-99% reduction) and moderately decreased active MMP-2 activity (10-24% reduction), suggesting MT1-MMP-independent MMP-2 modulation. Furthermore, HSA/TIMP-2 had no effect on in vitro active MMP-2 activity and in vivo MMP-2 activity. These studies show that HSA/TIMP-2 potentiates anti-angiogenic activity by modulating MMP-2 expression, but not MMP-2 activity, to subsequently suppress tumor growth, suggesting an important role for MMP-2 expression rather than MMP-2 activity in anti-angiogenesis.
authors.affiliation: Division of Bio-Imaging, Chuncheon Center, Korea Basic Science Institute, Chuncheon, Republic of Korea.
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Lee
authors.forename: Jae-In
authors.initials: JI
authors.lastname: Jung
authors.forename: Seung-Hae
authors.initials: SH
authors.lastname: Kwon
authors.forename: Sang-Mok
authors.initials: SM
authors.lastname: Lee
authors.forename: Kyoji
authors.initials: K
authors.lastname: Morita
authors.forename: Song
authors.initials: S
authors.lastname: Her
mesh_terms: D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011467:Prostate / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000627:therapeutic use; D012709:Serum Albumin / Q000235:genetics / Q000627:therapeutic use*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000627:therapeutic use*
chemical_list: D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2