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[目的]研究Notch-1通道阻断剂γ分泌酶抑制剂(gamma-secretase inhibitor,GSI)在抑制骨肉瘤小鼠模型中肿瘤增长以及其抑制肿瘤血管生成作用,进而探讨Notch-1信号通路在小鼠骨肉瘤模型中的作用及其作用机制。[方法]建立人骨肉瘤荷瘤SCID小鼠模型,将荷瘤成功后小鼠随机分为三组,实验组肿瘤内注射Notch通路阻断药物GSI,对照组注射PBS和DMSO。研究各组小鼠生物学指标、肿瘤增长变化及肿瘤组织检测微血管密度(microvessel density,MVD)的表达情况与差异。[结果]处死小鼠测量瘤体,同对照组相比,GSI治疗组小鼠的生物学指标明显较好,其小鼠的体重、饮食、睡眠、运动情况、精神状态、对刺激的反应及小鼠的皮毛光泽度等优于对照组,其皮下肿瘤体积明显较小,实验组平均体积为(196.3 mm3)较DMSO对照组平均体积(650.3 mm3)及PBS对照组平均体积(694.6 mm3)明显缩小,差别具有统计学意义,P<0.01。实验组及对照组内瘤体切片内血管均见不同程度的CD31表达,其表达于血管内皮细胞内,与对照组相比实验组CD31表达均明显降低,实验组及PBS、DMSO对照组CD31平均秩次分别为4.03、28.9和32.5,P<0.05,差异具有统计学意义。[结论](1)证实GSI可抑制SCID小鼠骨肉瘤动物模型肿瘤的生长;(2)GSI对SCID小鼠骨肉瘤动物模型的治疗作用可通过抑制Notch通路进而干预肿瘤血管形成来实现;(3)应用GSI药物阻断Notch信号通路有望成为骨肉瘤抗肿瘤治疗的新方法。
[Objective] To investigate the effect of GSI, a channel blocker of Notch-1, on tumor growth inhibition and tumor angiogenesis in a mouse model of osteosarcoma, and to explore the role of Notch-1 signaling pathway in The role of mouse osteosarcoma model and its mechanism of action. [Method] The SCID mouse model of human osteosarcoma tumor-bearing was established. After successful tumor-bearing, the mice were randomly divided into three groups. The experimental group was injected with Notch pathway to block the GSI in the tumor and PBS and DMSO in the control group. The biological indicators, the growth of tumor and the expression of microvessel density (MVD) in tumor tissue of each group were studied. [Result] Compared with the control group, the mice in the GSI treatment group had significantly better biological indexes than those in the control group. The body weight, diet, sleep, exercise status, mental status and response to the stimulus The fur of mice was superior to that of the control group. The subcutaneous tumor volume was significantly smaller. The average volume of the experimental group (196.3 mm3) was significantly higher than that of the DMSO control group (650.3 mm3) and the PBS control group (694.6 mm3) Narrowing, the difference was statistically significant, P <0.01. In experimental group and control group, the blood vessels in tumor slice showed varying degrees of CD31 expression in vascular endothelial cells, and the expression of CD31 in experimental group was significantly lower than that in control group. In experimental group and PBS and DMSO control group, Rank were 4.03,28.9 and 32.5, P <0.05, the difference was statistically significant. [Conclusion] (1) It was confirmed that GSI can inhibit the growth of tumor in animal model of osteosarcoma in SCID mice. (2) The therapeutic effect of GSI on animal model of osteosarcoma in SCID mice can be achieved by inhibiting Notch pathway and then interfering with tumor angiogenesis. 3) GSI drug blocking Notch signaling pathway is expected to become a new anti-tumor treatment of osteosarcoma.