应用IGF-1基因缺失小鼠研究IGF-1与乳腺肿瘤血管生成的关系

背景与目的:胰岛素样生长因子家族(insulin-like growth factors,IGFs)在肿瘤发生发展中所起的作用日益受到重视,但其作用机制尚不清楚.本实验通过在肝特异性胰岛素样生长因子1(insulin-like growth factor 1,IGF-1)基因缺失(LID)小鼠体内建立稳定的原发性乳腺癌模型,探讨血清中IGF-1水平与乳腺肿瘤血管生成可能存在的关系.方法:使用肝特异性IGF-1基因缺失小鼠及对照鼠,用化学致癌剂7,12-二甲基苯蒽[7,12-dimethybenz(a)anthracene,DMBA]诱导原发性乳腺肿瘤,使用人参皂甙Rg3进行干预治疗.比较各组肿瘤发生情况并通过免疫组化方法检测血管内皮生长因子(vascular endothelial growth factor,VEGF)的表达及微血管密度(microvessel density,MVD).结果:未管饲Rg3的对照鼠、未管饲Rg3的LID鼠、管饲Rg3的对照鼠及管饲Rg3的LID鼠的乳腺癌发病率依次为66.67%、33.33%、36.00%及12.00%.肿瘤平均直径四组依次为(0.79±0.20)cm、(0.37±0.08)cm、(0.32±0.08)cm及(0.15±0.05)cm.VEGF表达检测:未管饲Rg3的对照鼠平均光密度为0.34±0.10,阳性百分率(positive rate,PR)为0.04±0.02,均为各组中最高(P＜0.05);管饲Rg3的LID鼠平均光密度0.13±0.03,阳性百分率0.01±0.00,均为各组中最低(P＜0.05).以上四组MVD依次为31.9±5.3、26.8±4.9、20.1±4.9、14.4±4.9(P＜0.05).结论:IGF-1与乳腺肿瘤的发生发展相关,降低血清IGF-1可抑制肿瘤血管生成而对乳腺肿瘤有抑制作用,应用血管生长抑制剂人参皂甙Rg3可增强这一效应.

Correlation of insulin-like growth factor-1 (IGF-1) to angiogenesis of breast cancer in IGF-1-deficient mice

BACKGROUND & OBJECTIVE: Insulin-like growth factors (IGFs) play important roles in the development and progression of tumors. But the mechanism of tumorigenesis in relation to IGF-1 is unclear yet. This study was to explore the correlation of circulating IGF-1 level to the angiogenesis of breast cancer in IGF-1-deficient mice. METHODS: The liver-specific IGF-1-deficient (LID) mice and control mice were injected with 7,12-dimethybenz(a)anthracene (DMBA) to develop breast cancer. Ginsenoside Rg3 was used to intervene tumor growth. The occurrence rates of breast cancer were compared. The expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD) was detected by immunohistochemistry. RESULTS: The occurrence rate of breast cancer was 66.67% in untreated control mice, 33.33% in untreated LID mice, 36.00% in Rg3-treated control mice, and 12.00% in Rg3-treated LID mice. The tumor size was (0.79+/-0.20) cm in untreated control mice, (0.37+/-0.08) cm in untreated LID mice, (0.32+/-0.08) cm in Rg3-treated control mice, and (0.15+/-0.05) cm in Rg3-treated LID mice. The average light density and positive rate of VEGF were the highest in untreated control mice (0.34+/-0.10 and 0.04+/-0.02, P<0.05), and the lowest in Rg3-treated LID mice (0.13+/-0.03 and 0.01+/-0.00, P<0.05). The MVD was 31.9+/-5.3 in untreated control mice, 26.8+/-4.9 in untreated LID mice, 20.1+/-4.9 in Rg3-treated control mice, and 14.4+/-4.9 in Rg3-treated LID mice. CONCLUSIONS: Circulating IGF-1 plays a role in the onset and development of breast cancer. Degrading serum IGF-1 level could inhibit angiogenesis and growth of breast cancer. Rg3 could promote this effect.