title: Suppression of tumor growth and metastasis by a VEGFR-1 antagonizing peptide identified from a phage display library.
abstract: Although the VEGF-Flk-1-pathway has been known as the major driving force of angiogenesis, new evidence has shown that VEGFR-1/Flt-1 plays important roles during the neovascularization under pathological conditions including tumor, atherosclerosis and arthritis. In search of Flt-1 receptor antagonizing peptides, we screened a phage display 12-mer-peptide library with recombinant Flt-1 protein. Seven candidate peptides were identified that specifically bound to VEGF receptor Flt-1, of which peptide F56 (WHSDMEWWYLLG) almost abolished VEGF binding to receptor Flt-1 in vitro. In vivo, F56 fused with DHFR (DHFR-F56) inhibited angiogenesis in a CAM assay. Moreover, DHFR-F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC-803 in BALB/c nude mice. Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with DHFR-F56. In the severe combined immunodeficiency disease (SCID) mouse model for studying metastasis of the human breast cancer cell line BICR-H1, synthetic peptide F56 significantly inhibited tumor growth and lung metastases. Taken together, our results have demonstrated that peptide F56, as a Flt-1 receptor antagonist, fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between VEGF and receptor Flt-1. Thus, short peptide F56 may have clinical potential in tumor therapy.
authors.affiliation: Beijing Institute for Cancer Research, Peking University School of Oncology, Western District, Beijing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: An
authors.forename: Hetian
authors.initials: H
authors.lastname: Lei
authors.forename: Jianzhi
authors.initials: J
authors.lastname: Zhang
authors.forename: Shumei
authors.initials: S
authors.lastname: Song
authors.forename: Luowen
authors.initials: L
authors.lastname: He
authors.forename: Genglin
authors.initials: G
authors.lastname: Jin
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Liu
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.forename: Lin
authors.initials: L
authors.lastname: Meng
authors.forename: Meisheng
authors.initials: M
authors.lastname: Liu
authors.forename: Chengchao
authors.initials: C
authors.lastname: Shou
mesh_terms: D000818:Animals; D002455:Cell Division; D018450:Disease Progression; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D009842:Oligopeptides / Q000494:pharmacology*; D019151:Peptide Library; D010455:Peptides / Q000494:pharmacology; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000473:pathology; D014407:Tumor Cells, Cultured; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000502:physiology*
chemical_list: D009842:Oligopeptides; D019151:Peptide Library; D010455:Peptides; C488235:peptide F56; D040281:Vascular Endothelial Growth Factor Receptor-1