Multimodal Imaging of Growth and Rapamycin-Induced Regression of Colonic Adenomas in Apc Mutation-Dependent Mouse
Multimodal Imaging of Growth and Rapamycin-Induced Regression of Colonic Adenomas in Apc Mutation-Dependent Mouse
复制标题
DOI：
10.1593/tlo.12226
复制
发表时间：
2012-10-01
影响因子：
5
通讯作者：
Wang, Thomas D.
中科院分区：
文献类型：
--
作者：
Miller, Sharon J.;Heist, Kevin A.;Wang, Thomas D.
我们证明，雷帕霉素可以诱导基因工程小鼠（CPC; APC）的腺瘤性结肠息肉病（APC）突变依赖性结肠腺瘤的消退。使用内窥镜每周观察CPC; Apc小鼠中的腺瘤，持续10周。使用测距仪和数字生成的网格测量病变表面积。在磁共振成像（MRI）上进行冠状扫描以定位腺瘤，并从连续轴向扫描上绘制的感兴趣区域测量肿瘤体积。每天腹膜内施用雷帕霉素（5 mg/kg），持续5周。每周进行内窥镜检查和MRI以监测腺瘤消退。在死后对腺瘤进行卡尺测量和免疫组织化学（IHC）。测量了n = 7只动物中n = 30个腺瘤的尺寸。内窥镜检查的腺瘤表面积与MRI和死后卡尺测量的体积相关，R-2 = 0.84和R-2 = 0.81。内窥镜检查和MRI检查的平均腺瘤倍增时间分别为0.95 +/- 0.14和1.21 +/- 0.16周。内窥镜检查和MRI检查的最小腺瘤表面积和体积分别为0.69 mm（2）和1.76 mm（3）。在组织学上，雷帕霉素治疗的腺瘤显示出有限的发育不良区域。雷帕霉素治疗导致哺乳动物雷帕霉素信号传导和细胞增殖的靶点低得多。与溶剂处理的病变相比，在IHC上观察到磷酸化-S6的表达降低和Ki 67阳性细胞的数量减少。内镜检查可以通过MRI验证为定量监测治疗的可靠方法，代表了未来临床前评估新型结直肠癌预防策略效用的有前途的方法。
We demonstrate that rapamycin can induce regression of adenomatous polyposis coli (Apc) mutation-dependent colonic adenomas in genetically engineered mice (CPC;Apc). An endoscope was used to visualize adenomas in CPC; Apc mice weekly for 10 weeks. The lesion surface areas were measured using a distance gauge and digitally generated grid. Coronal scans were performed on magnetic resonance imaging (MRI) to localize adenomas, and tumor volumes were measured from regions of interest drawn on consecutive axial scans. Rapamycin (5 mg/kg) was administered intraperitoneally daily for 5 weeks. Endoscopy and MRI were performed weekly to monitor adenoma regression. Caliper measurements and immunohistochemistry (IHC) were performed on adenomas postmortem. Dimensions from n = 30 adenomas in n = 7 animals were measured. Adenoma surface areas on endoscopy correlated with volumes on MRI and with postmortem caliper measurements, R-2 = 0.84 and R-2 = 0.81, respectively. The mean adenoma doubling times on endoscopy and MRI were 0.95 +/- 0.14 and 1.21 +/- 0.16 weeks, respectively. The minimum detectable adenoma surface area and volume on endoscopy and MRI was 0.69 mm(2) and 1.76 mm(3), respectively. On histology, the rapamycin-treated adenomas showed limited regions of dysplasia. Rapamycin therapy resulted in much lowermammalian target of rapamycin signaling and cell proliferation. Lower expression of phospho-S6 and reduced numbers of Ki67-positive cells were seen on IHC compared to vehicle-treated lesions. Endoscopy can be validated by MRI as a robust methodology for quantitative monitoring of therapy, representing a promising approach for future preclinical efforts to assess utility of novel colorectal cancer prevention strategies.