Suppression of tumor growth and metastasis by a vegfr-1 antagonizing peptide identified from a phage display library
Suppression of tumor growth and metastasis by a vegfr-1 antagonizing peptide identified from a phage display library
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DOI：
10.1002/ijc.20214
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发表时间：
2004-08-20
影响因子：
6.4
通讯作者：
Shou, CC
中科院分区：
文献类型：
--
作者：
An, P;Lei, HT;Shou, CC
尽管VEGF-Flk-1通路被认为是血管生成的主要驱动力，但新的证据表明，VEGFR-1/Flt-1在肿瘤、动脉粥样硬化和关节炎等病理条件下的血管生成过程中发挥着重要作用。为了寻找Flt-1受体拮抗肽，我们筛选了含重组Flt-1蛋白的噬菌体展示12肽文库。已鉴定出7个能与受体Flt-1特异性结合的候选多肽，其中F56肽(WHSDMEWWYLLG)在体外几乎完全取消了与受体Flt-1的结合。在体内，在CAM实验中，F56与DHFR融合(DHFR-F56)可抑制血管生成。此外，DHFR-F56对人胃癌细胞系MGC-803在BALB/c裸鼠体内的结节生长有明显的抑制作用。组织学分析显示，经DHFR-F56治疗后，移植瘤的坏死明显增强。在研究人乳腺癌细胞系BICR-H1转移的严重联合免疫缺陷病(SCID)小鼠模型中，合成肽F56显著抑制肿瘤生长和肺转移。综上所述，我们的结果表明，F56作为Flt-1受体拮抗剂，通过特异性干扰血管内皮生长因子和Flt-1受体之间的相互作用，实现了抗血管生成和抗转移的作用。因此，短肽F56可能在肿瘤治疗中具有临床应用潜力。(C)2004年Wiley-Liss公司
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-merpeptide 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. (C) 2004 Wiley-Liss, Inc.