Cell delivery of Met docking site peptides inhibit angiogenesis and vascular tumor growth.
Cell delivery of Met docking site peptides inhibit angiogenesis and vascular tumor growth.
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DOI：
10.1038/onc.2010.267
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发表时间：
2010-09-23
期刊：
影响因子：
8
通讯作者：
Albini, A.
中科院分区：
文献类型：
--
作者：
Cantelmo, A. R.;Cammarota, R.;Noonan, D. M.;Focaccetti, C.;Comoglio, P. M.;Prat, M.;Albini, A.
肝细胞生长因子 (HGF) 及其受体 Met 负责多种细胞反应，包括胚胎发育和组织稳态期间的生理反应，以及病理学反应，特别是在肿瘤生长和传播期间。在癌症中，Met 可以作为肿瘤细胞的癌基因，以及激活内皮细胞并诱导新血管形成的促血管生成因子。干扰 Met 活性的分子可能是有价值的治疗剂。在这里，我们研究了模拟 Met 羧基末端尾部对接位点的合成肽的抗血管生成特性，该合成肽通过与触角足或 HIV-Tat 的内化序列融合而被递送到细胞中。我们发现，与 Met 抑制剂 PHA-665752 相比，这些肽在体外更大程度地抑制配体依赖性内皮细胞增殖、运动、侵袭和形态发生，且毒性要低得多，而 PHA-665752 与 HGF 依赖性下游信号传导的干扰相关。在体内，这些肽在基质胶海绵测定中抑制了 HGF 诱导的血管生成，并损害了卡波西肉瘤中的异种移植肿瘤生长和血管化。这些数据表明，干扰 Met 受体胞内序列会损害 HGF 诱导的血管生成，这表明使用反对接位点化合物作为治疗策略来对抗癌症以及其他疾病中的血管生成。
Hepatocyte growth factor (HGF) and its receptor Met are responsible for a wide variety of cellular responses, both physiologically during embryo development and tissue homeostasis, and pathologically, particularly during tumor growth and dissemination. In cancer, Met can act as an oncogene on tumor cells, as well as a pro-angiogenic factor activating endothelial cells and inducing new vessel formation. Molecules interfering with Met activity could be valuable therapeutic agents. Here we have investigated the antiangiogenic properties of a synthetic peptide mimicking the docking site of the Met carboxyl-terminal tail, which was delivered into the cells by fusion with the internalization sequences from Antennapedia or HIV-Tat. We showed that these peptides inhibit ligand-dependent endothelial cell proliferation, motility, invasiveness and morphogenesis in vitro to an even greater extent and with much less toxicity than the Met inhibitor PHA-665752, which correlated with interference of HGF-dependent downstream signaling. In vivo, the peptides inhibited HGF-induced angiogenesis in the matrigel sponge assay and impaired xenograft tumor growth and vascularization in Kaposi's sarcoma. These data show that interference with the Met receptor intracellular sequence impairs HGF-induced angiogenesis, suggesting the use of antidocking site compounds as a therapeutic strategy to counteract angiogenesis in cancer as well as in other diseases.
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影响因子：
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