Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
Cancer Biol Ther. 2011 May 15;11(10):910-7. doi: 10.4161/cbt.11.10.15473.
Obese postmenopausal women have a 50% higher risk of breast cancer than non-obese women. There is not an animal model that mimics postmenopausal obesity related to breast cancer progression. Using age-relevant C57BL/6 mice, this study determined whether postmenopausal obesity increases VEGF expression, tumor angiogenesis, and breast tumor growth. Ovariectomy (OVX) was performed in 12 sixty week-old female mice, then followed by a low-fat (5%, LF, n=6) or a high-fat (60%, HF, n=6) diet for 12 weeks. In the eighth week of the dietary program, 10(6) E0771 (mouse breast cancer) cells were injected in the left fourth mammary gland. Tumor size was monitored for 4 weeks. Body weights were monitored weekly. At the end of the experiment, blood samples, visceral fat and tumors were collected for measuring VEGF expression using ELISA and intratumoral microvessel density (IMD) using CD31 immunochemistry. Body weight was significantly increased in OVX/HF mice, compared to OVX/LF group (55.3±1.7 vs. 41.5±1.5 g; p < 0.01). There was a two-fold increase in the ratio of visceral fat/BW in OVX/HF mice, compared to those in OVX/LF group (0.062±0.005 vs. 0.032±0.003; p < 0.01). Postmenopausal obesity significantly increased breast tumor weight over the control (4.62±0.63 vs. 1.98±0.27 g; p < 0.01) and IMD (173±3.7 vs. 139±4.3 IM#/mm^2; p < 0.01). Tumor VEGF levels were higher in OVX/HF mice, compared to OVX/LF group (73.3±3.8 vs. 49.5±4.3 pg/mg protein; p < 0.01). Plasma VEGF levels (69±7.1 vs. 48±3.5 pg/ml) and visceral fat VEGF levels (424.4±39.5 vs. 208.5±22.4 pg/mg protein) were significantly increased in OVX/HF mice, compared to OVX/LF group, respectively (n=6; p < 0.01). Interestingly, adipose tissue primary culture showed that subcutaneous fat released more VEGF, compared to visceral fat (6.77±1.14 vs. 0.94±0.16 pg/mg tissue; n=6; p < 0.01). These findings support the hypothesis that postmenopausal obesity promotes tumor angiogenesis and breast cancer progression, possibly through increased adipose tissue mass and adipokines such as VEGF that could systemically and locally affect breast cancer progression.
绝经后肥胖女性患乳腺癌的风险比非肥胖女性高 50%。目前还没有能够模拟与乳腺癌进展相关的绝经后肥胖的动物模型。本研究使用与年龄相关的 C57BL/6 小鼠，确定绝经后肥胖是否会增加 VEGF 表达、肿瘤血管生成和乳腺肿瘤生长。对 12 只 60 周龄的雌性小鼠进行卵巢切除术（OVX），然后分别给予低脂（5%，LF，n=6）或高脂（60%，HF，n=6）饮食 12 周。在饮食方案的第 8 周，将 10(6) E0771（小鼠乳腺癌）细胞注入左第四乳腺。监测肿瘤大小 4 周。每周监测体重。实验结束时，采集血样、内脏脂肪和肿瘤，通过 ELISA 检测 VEGF 表达，通过 CD31 免疫组织化学检测肿瘤内微血管密度（IMD）。与 OVX/LF 组相比，OVX/HF 组小鼠体重显著增加（55.3±1.7 与 41.5±1.5 g；p<0.01）。OVX/HF 组小鼠内脏脂肪与 BW 的比值是 OVX/LF 组的两倍（0.062±0.005 与 0.032±0.003；p<0.01）。与对照组相比，绝经后肥胖显著增加了乳腺肿瘤的重量（4.62±0.63 与 1.98±0.27 g；p<0.01）和 IMD（173±3.7 与 139±4.3 IM#/mm^2；p<0.01）。与 OVX/LF 组相比，OVX/HF 组肿瘤 VEGF 水平更高（73.3±3.8 与 49.5±4.3 pg/mg 蛋白；p<0.01）。与 OVX/LF 组相比，OVX/HF 组血浆 VEGF 水平（69±7.1 与 48±3.5 pg/ml）和内脏脂肪 VEGF 水平（424.4±39.5 与 208.5±22.4 pg/mg 蛋白）分别显著升高（n=6；p<0.01）。有趣的是，脂肪组织原代培养显示，与内脏脂肪相比，皮下脂肪释放更多的 VEGF（6.77±1.14 与 0.94±0.16 pg/mg 组织；n=6；p<0.01）。这些发现支持绝经后肥胖促进肿瘤血管生成和乳腺癌进展的假设，可能是通过增加脂肪组织质量和脂肪因子（如 VEGF）来实现的，这些因子可能会对乳腺癌进展产生全身和局部影响。
