Inhibition of tumor growth by systemic treatment with thrombospondin-1 peptide mimetics
Inhibition of tumor growth by systemic treatment with thrombospondin-1 peptide mimetics
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DOI：
10.1002/ijc.10247
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发表时间：
2002-04-10
影响因子：
6.4
通讯作者：
Campbell, SC
中科院分区：
文献类型：
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作者：
Reiher, FK;Volpert, OV;Campbell, SC
许多正常的人类细胞产生血小板反应蛋白-I（TSP-I），一种促进血管静止的有效的抗血管生成蛋白。在各种器官系统中，包括脑、乳腺和膀胱以及成纤维细胞中，在肿瘤发生期间TSP-1分泌减少，从而允许诱导肿瘤生长和转移所需的旺盛的新血管形成。全长和短的TSP-I衍生肽通过诱导内皮细胞凋亡并因此破坏生长肿瘤的脉管系统来抑制血管生成。内皮细胞表面表达的CD 36作为TSP-I的主要抗血管生成受体发挥作用。TSP-1七肽的D-异亮氨酰对映体特异性抑制毛细血管内皮细胞的增殖和迁移。DI-TSP是该肽的约1 kDa封端版本，在体外也具有抗血管生成作用，其比活性接近450 kDa母体分子的比活性。在这里，我们表明，DI-TSP全身剂量依赖性地抑制小鼠黑色素瘤转移瘤在同系动物中的生长，其更可溶的异构体，DI-TSPa，类似地阻断原发性人膀胱肿瘤在原位模型中的免疫缺陷小鼠的进展。与完整的TSP-I一样，这些肽模拟物对体外生长的癌细胞没有影响，但通过诱导受体依赖性凋亡显著抑制内皮细胞的生长。针对CD 36的抗体阻断了肽诱导内皮细胞凋亡的能力，但对肿瘤坏死因子-α诱导的凋亡没有影响。在体内，肽模拟物与内皮细胞和肿瘤细胞区室中显著降低的微血管密度和增加的凋亡指数相关。这种短肽靶向特定的抗血管生成受体，有效的和易于合成，显示出很大的前景作为临床抗血管生成策略的先导化合物。(C)2002 Wiley-Liss，Inc.
Many normal human cells produce thrombospondin-I (TSP-I), a potent antiangiogenic protein that promotes vascular quiescence. In various organ systems, including the brain, breast and bladder and in fibroblasts, TSP-I secretion is reduced during tumorigenesis, thereby allowing induction of the vigorous neovascularization required for tumor growth and metastasis. Full-length and short TSP-I-derived peptides inhibit angiogenesis by inducing endothelial cell apoptosis and thus disrupting the vasculature of the growing tumor. CD36 expressed on the surface of endothelial cells functions as the primary antiangiogenic receptor for TSP-I. A D-isoleucyl enantiomer of a TSP-I heptapeptide specifically inhibits the proliferation and migration of capillary endothelial cells. DI-TSP, an approximately I kDa capped version of this peptide, is also antiangiogenic in vitro, with a specific activity approaching that of the 450 kDa parental molecule. Here, we show that DI-TSP delivered systemically dose-dependently inhibits the growth of murine melanoma metastases in syngeneic animals and that its more soluble isomer, DI-TSPa, similarly blocks the progression of primary human bladder tumors in an orthotopic model in immune-deficient mice. Like intact TSP-I, these peptide mimetics had no effect on cancer cells growing in vitro but markedly suppressed the growth of endothelial cells by inducing receptor-dependent apoptosis. Antibodies raised against CD36 blocked the ability of peptides to induce apoptosis in endothelial cells but had no effect on tumor necrosis factor-alpha-induced apoptosis. In vivo, the peptide mimetics were associated with a significantly reduced microvessel density and increased apoptotic indices in both the endothelial and tumor cell compartments. Such short peptides targeted to a specific antiangiogenic receptor, potent and easy to synthesize, show great promise as lead compounds in clinical antiangiogenic strategies. (C) 2002 Wiley-Liss, Inc.