内皮抑素对结肠癌增殖和转移抑制效应的实验观察

Experimental study of the effect of endostatin on the proliferation and metastasis of human colon cancer xenograft in nude mice

目的研究内皮抑素对结肠癌增殖和转移的抑制作用,并探讨基质金属蛋白酶13(MMP13)对结肠癌血管生成的作用。方法采用人结肠癌细胞株SW1116完整组织块于裸小鼠原位种植,建立结肠癌转移裸小鼠模型。种植后第1周开始皮下注射内皮抑素,每天1次,剂量为0mg/kg(对照组)、5mg/kg(实验Ⅰ组)、10mg/kg(实验Ⅱ组)、20mg/kg(实验Ⅲ组),共用6周。种植后第7周处死动物,测量原位肿瘤体积、抑瘤率,检测MMP13、微血管密度(MVD),观察腹膜、肝脏及其它脏器转移情况。结果内皮抑素剂量为0、5、10和20mg/kg时,原位肿瘤体积分别为(1.42±0.45)、(0.54±0.38)、(0.31±0.28)、(0.22±0.16)cm3;抑瘤率分别为0、62.0%、78.2%、84.5%;MMP13分别为81.8%、58.3%、42.9%、21.4%;MVD分别为(11.20±3.9)、(6.10±2.6)、(2.40±1.6)、(1.22±0.4);腹膜转移率分别为81.8%、50.0%、28.5%、7.1%;肝脏转移率分别为63.6%、33.3%、14.3%、0。实验Ⅰ～Ⅲ组与对照组相比,组间结肠癌增殖与转移的抑制作用差异有显著性(P<0.05)。结论MMP13可能是结肠癌重要的促血管生成因素之一;内皮抑素通过抑制肿瘤血管生成,对裸小鼠结肠癌增殖和转移均有抑制作用。

Purpose To investigate the effect of angiogenesis inhibitor (endostatin ) on the proliferation and metastasis of colon cancers in vivo. To explore the role of matrix metalloproteinase-13(MMP-13) on angiogenesis in colon cancers. Methods Metastatic model of human colon cancer was established by implanting histological intact human tumor tissue into colon wall of nude mice. Endostatin was administered every day for six weeks at dose of 0 mg/kg,5 mg/kg,10 mg/kg,20 mg/kg. Seven weeks after implantation,the nude mice were sacrificed. The tumor volume,inhibition rates,matrix metalloproteinase-13 (MMP-13),intratumoral microvessel density (MVD) and the presence of metastases are evaluated.Results Compared with the untreated controls ,proliferation of the orthotopically implanted tumor was significantly reduced in size in nude mice treated with endostatin. Administered at the dosage of 0 mg/kg,5 mg/kg,10 mg/kg,20 mg/kg,inhibition rates were 0,62.0%,78.2% and 84.5% respectively. MMP-13 was 81.8%,58.3%,42.9%,21.4%;MVD was 11.20±3.9,6.1±2.6,2.4±1.6,1.22±0.4;The rates of peritoneal metastasis were 81.8 %,50.0%,28.5%,7.1%;The rates of liver metastasis were 63.6%,33.3%,14.3%,0. Conclusions MMP-13 might be one of the important factors in the angiogenesis of colon cancers. Angiogenesis inhibitor,endostatin can reduce the tumor size by inhibiting tumor angiogenesis,and has inhibitory effect both on tumor proliferation and metastasis of human colon cancer xenograft in nude mice.