高胆固醇血症诱导血管生成并加速活体内乳腺肿瘤的生长
肥胖和代谢综合征能够增加绝经后妇女乳腺癌的患病率。肥胖、代谢综合征和西方富于饱和脂肪酸的饮食习惯，这三者共同的特征就是高水平的胆固醇循环。流行病学报告关于高水平的胆固醇循环、降胆固醇药物与乳腺癌之间的关系仍然是有争议的，因此我们通过控制饮食和等热量饮食来建立临床前动物模型来模拟这一复杂状况。通过低脂肪/无胆固醇饮食来喂养雌性SCID裸鼠，然后随机分成四组等热量饮食组：低脂肪/无胆固醇组（使用和不使用依替米贝两组）（依替米贝是一种降胆固醇药物），高脂肪/高胆固醇组（使用和不使用依替米贝两组）。然后裸鼠被原位植入MDA-MB-231细胞。高脂肪/高胆固醇组的乳腺肿瘤显示了最快的进展，且组间血清胆固醇水平明显不同，而肿瘤内的胆固醇水平却没有明显差别。为了判定胆固醇诱导肿瘤进展的作用机制，我们分析了肿瘤的增殖、凋亡和血管生成，并发现高脂肪/高胆固醇组的裸鼠肿瘤内有较高比例的增殖细胞；和血清胆固醇低的裸鼠肿瘤相比，血清胆固醇高的裸鼠肿瘤内显示了显著减少的凋亡现象；和其它组肿瘤相比，高脂肪/高胆固醇组裸鼠的肿瘤显示了较高的微血管密度。以上结果表明：高胆固醇血症能够诱导血管生成并加速活体内乳腺肿瘤的生长。 Am J Pathol. 2014, 184(7): 2099 -110.
Obesity and metabolic syndrome are linked to an increased prevalence of breast cancer among post-menopausal women. A common feature of obesity, metabolic syndrome, and a Western diet rich in saturated fat is a high level of circulating cholesterol. Epidemiological reports investigating the rela-tionship between high circulating cholesterol levels, cholesterol-lowering drugs, and breast cancer are con flicting. Here, we modeled this complex condition in a well-controlled, preclinical animal model using innovative isocaloric diets. Female severe combined immunodeficient mice were fed a low-fat/no-cholesterol diet and then randomized to four isocaloric diet groups: low-fat/no-cholesterol diet, with or without ezetimibe (cholesterol-lowering drug), and high-fat/high-cholesterol diet, with or without ezetimibe. Mice were implanted orthotopically with MDA-MB-231 cells. Breast tumors from animals fed the high-fat/high-cholesterol diet exhibited the fastest progression. Significant differences in serum cholesterol level between groups were achieved and maintained throughout the study; however, no differences were observed in intratumoral cholesterol levels. To determine the mechanism of cholesterol-induced tumor progression, we analyzed tumor proliferation, apoptosis, and angiogen-esis and found a signi ficantly greater percentage of proliferating cells from mice fed the high-fat/high-cholesterol diet. Tumors from hypercholesterolemic animals displayed signi ficantly less apoptosis compared with the other groups. Tumors from high-fat/high-cholesterol mice had signi ficantly higher microvessel density compared with tumors from the other groups. These results demonstrate that hy-percholesterolemia induces angiogenesis and accelerates breast tumor growth in vivo . (Am J Pathol 2014, 184: 2099 e2110;