Short pigment epithelial-derived factor-derived peptide inhibits angiogenesis and tumor growth.
Short pigment epithelial-derived factor-derived peptide inhibits angiogenesis and tumor growth.
复制标题
DOI：
10.1158/1078-0432.ccr-08-2113
复制
发表时间：
2009-03-01
期刊：
影响因子：
--
通讯作者：
Volpert OV
中科院分区：
文献类型：
--
作者：
Mirochnik Y;Aurora A;Schulze-Hoepfner FT;Deabes A;Shifrin V;Beckmann R;Polsky C;Volpert OV
色素上皮衍生因子（PEDF）是一种有效的血管生成抑制剂，具有多种其他功能，其中一些可促进肿瘤生长。我们先前的研究将PEDF抗血管生成和促存活活性映射到不同的表位。本研究旨在确定PEDF的最小片段，其保持抗血管生成和抗肿瘤功效。我们分析了血管抑制表位（34聚体）的抗原性、亲水性和电荷分布，并设计了覆盖其C-末端的三个肽，P14、P18和P23。我们分析了它们在体外阻断内皮细胞（EC）趋化性和诱导凋亡的能力以及它们在体内的抗血管生成活性。测试所选肽对轻度侵袭性异种移植前列腺癌和高度侵袭性肾细胞癌的抗肿瘤活性。为了验证P18与PEDF的作用方式相同，我们使用免疫组织化学来测量P18处理的脉管系统中PEDF靶标、VEGFR 2和CD 95 L的表达。P14和P18阻断内皮细胞的趋化性，P18和P23诱导内皮细胞凋亡。P18显示出最高的IC 50并在体内阻断血管生成：P23无活性，P14促血管生成。P18在体内可增加内皮细胞CD 95 L的表达，降低VEGFR-2的表达。在肿瘤研究中，P18在阻断前列腺癌的血管生成和生长方面比亲本34-mer更有效;在肾细胞癌中，P18强烈降低血管生成并阻止已建立的肿瘤的进展。P18是一种新型的、有效的抗血管生成生物制剂，具有开发用于治疗前列腺癌和肾癌的潜力。
Pigment epithelial-derived factor (PEDF) is a potent angiogenesis inhibitor with multiple other functions, some of which enhance tumor growth. Our previous studies mapped PEDF anti-angiogenic and pro-survival activities to distinct epitopes. This study was aimed to determine the minimal fragment of PEDF, which maintains anti-angiogenic and anti-tumor efficacy. We analyzed antigenicity, hydrophilicity, and charge distribution of the angioinhibitory epitope (the 34-mer) and designed three peptides covering its C-terminus, P14, P18 and P23. We analyzed their ability to block endothelial cell (EC) chemotaxis and induce apoptosis in vitro and their anti-angiogenic activity in vivo. The selected peptide was tested for the anti-tumor activity against mildly aggressive xenografted prostate carcinoma and highly aggressive renal cell carcinoma. To verify that P18 acts in the same manner as PEDF, we used immunohistochemistry to measure PEDF targets, VEGFR2 and CD95L expression in P18-treated vasculature. P14 and P18 blocked endothelial cell chemotaxis; P18 and P23 induced apoptosis. P18 showed the highest IC50 and blocked angiogenesis in vivo: P23 was inactive and P14 was pro-angiogenic. P18 increased the production of CD95L and reduced the expression of VEGFR-2 by the endothelial cells in vivo. In tumor studies, P18 was more effective in blocking the angiogenesis and growth of the prostate cancer then parental 34-mer; in the renal cell carcinoma P18 strongly decreased angiogenesis and halted the progression of established tumors. P18 is a novel and potent anti-angiogenic biotherapeutic agent, which has potential to be developed for the treatment of prostate and renal cancer.