Kringle 5 of human plasminogen suppresses hepatocellular carcinoma growth both in grafted and xenografted mice by anti-angiogenic activity
Kringle 5 of human plasminogen suppresses hepatocellular carcinoma growth both in grafted and xenografted mice by anti-angiogenic activity
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DOI：
10.4161/cbt.5.4.2511
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发表时间：
2006-02
影响因子：
3.6
通讯作者：
Xia Yang;R. Cheng;Chaoyang Li;Weibin Cai;Jian-xing Ma;Qian-ping Liu;Zhonghan Yang;Zhi-hong Song;Zuguo Liu;G. Gao
中科院分区：
文献类型：
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作者：
Xia Yang;R. Cheng;Chaoyang Li;Weibin Cai;Jian-xing Ma;Qian-ping Liu;Zhonghan Yang;Zhi-hong Song;Zuguo Liu;G. Gao
纤溶酶原kringle 5（K5）是纤溶酶原的蛋白水解片段。是内源性血管生成抑制剂。我们以前已经表明，K5抑制缺血诱导的视网膜新生血管在大鼠模型。然而，其抗血管生成的潜力和在肿瘤性疾病的治疗中的应用尚未得到很好的研究。本研究旨在检测其对肝细胞癌（一种典型的富血供肿瘤）新生血管和生长的影响。重组人K5在E. coli中进行亲和层析纯化。K5呈剂量依赖性地抑制原代内皮细胞的增殖并诱导其凋亡，但对来源于内皮细胞的周细胞无明显影响，提示其具有内皮细胞特异性抑制作用。K5对小鼠HepA和人Bel 7402肝癌细胞的增殖和凋亡无明显影响，提示K5对肿瘤细胞无直接作用。腹腔注射K5可明显抑制小鼠肝癌移植瘤的生长。在裸鼠肝癌移植瘤模型中，K5能显著抑制肿瘤的生长。与对照组相比，在K5处理的小鼠中观察到平均68%的原发性肿瘤生长抑制。K5也抑制肿瘤内的新血管形成的两种癌症模型中确定的微血管密度（MVD）分析。注射K5后，肿瘤组织中caspase-3前体蛋白的裂解明显增加，提示K5还可诱导肿瘤组织的凋亡，K5治疗组肿瘤微血管密度降低可能与K5诱导内皮细胞凋亡有关。这些结果表明，K5的肿瘤生长抑制依赖于其抗血管生成活性，K5可能在肝细胞癌中具有治疗潜力。
Plasminogen kringle 5 (K5), a proteolytic fragment of plasminogen?is an endogenous angiogenic inhibitor. We have previously shown that K5 inhibits ischemia-induced retinal neovascularization in a rat model. However, its anti-angiogenic potential and application in the treatment of neoplastic diseases have not been well investigated. Our present study was designed to test its effect on the neovascularization and growth of hepatocellular carcinoma, a typical hypervascular tumor. Recombinant human K5 was expressed in E. coli and purified by affinity chromatography. K5 inhibited proliferation and induced apoptosis of primary endothelial cells in dose-dependent manner, but no effect on pericytes from the same origin of endothelial cells, which suggested an endothelial cell-specific inhibition. Moreover, K5 had no effect on the proliferation and apoptosis of mouse HepA and human Bel7402 hepatoma cell lines even in the enhanced concentration range, which suggested K5 having no direct effect on tumor cells. Ventral injection of K5 significantly suppressed the tumor growth in grafed hepatocarcinoma mice model, which was established by injection of mouse HepA hepatoma cells. In xenografted hepatocarcinoma athymic mice model, which mimicked human tumors by injection of human Bel7402 hepatoma cells, K5 significantly suppressed the tumor growth. An average of 68% suppression of primary tumor growth was observed in the K5-treated mice compared with control group. K5 also inhibited intratumoral neovascularization in the two cancer models determined by micro vessel density (MVD) analysis. Injection of K5 significantly induced the cleavage of pro-caspase-3 in tumor tissues of grafted mouse model, which suggested K5 also induced apoptosis of tumor tissues and the decreased intratumoral microvascular density in K5 treated group may correlate with K5-induced endothelial cell apoptosis. These results suggest that tumor growth suppression of K5 depends on its anti-angiogenic activity and K5 could have therapeutic potential in hepatocellular carcinoma.