MR CHARACTERIZATION OF VASCULARIZATION IN XENOGRAPH AND SYNGENEIC MOUSE MODELS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。导读：肿瘤血管生成的研究往往依赖于荷瘤动物模型；因此，了解血管生成行为和微环境对肿瘤进展的贡献是至关重要的。在本研究中，利用MRI对异种和同基因小鼠模型中的肿瘤生长进行了表征，以验证宿主环境可以显著改变小鼠模型中生长的人类癌细胞血管化的假设。方法与讨论：人源性胶质母细胞瘤U87细胞采用Xenograph模型，鼠源性胶质瘤GL261细胞或鼠鳞状细胞癌VII细胞在小鼠后侧腹皮下植入采用同系模型。动物在肿瘤直径达到5mm左右时开始1.5T MRI成像。分别在注射造影剂Gd（DTPA）前后获得T1（自旋回波）和T2（快速自旋回波）加权图像。使用T1和T2-wt MR增强和非增强成像特征来表征肿瘤的不同时间分期。用组织学染色来描述这些肿瘤的病理特征。xenograph模型在肿瘤植入后约4周肿瘤直径达到5mm。对比后的T1和T2-wt MR图像在整个肿瘤中都是均匀的（1期）。肿瘤进展到第2期，持续3-5天，对比后T1-wt呈边缘增强，T2-wt呈均匀MR模式。这些特征对应于活肿瘤周围血管化活动的增加。肿瘤在第5周进展到第3期，该区域的T2-wt信号升高，对比后的T1-wt图像没有增强。这些特征与坏死的发展有关。结果经组织学染色证实。同系模型肿瘤在肿瘤植入后约2-3周达到上述MR成像模式的第1期；第二阶段：约3-5周；5周左右进入第三阶段。在异种模型和同基因模型中发现了三个不同的观察结果：(1)异种模型中肿瘤的初始生长速度大大延迟；(2)与阶段1相关的均匀对比后T1图像的绝对MR强度在xenograph模型中更亮；(3) xenograph模型2期肿瘤进展极短。组织学染色也证实了这一结果。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Introduction: Research in tumor angiogenesis often relies on tumor bearing animal models; thus understanding the angiogenic behavior, and the contribution of the microenvironment to tumor progression is critical. In this study, tumor growth in both xenograph and syngeneic mouse models was characterized using MRI to validate the hypothesis that the host environment can significantly alter the vascularization of human cancer cells grown in mouse model. Methods and Discussion: Xenograph model was used with human glioblastoma U87 cells, and sygeneic model was used with murine glioma GL261 or murine squamous cell carcinoma VII cells implanted subcutaneously in the rear flank of mice. Animals were imaged at 1.5T MRI starting when the tumors reached a diameter of about 5 mm. T1 (spin-echo) and T2 (fast spin-echo) weighted images were acquired pre- and post- contrast agent Gd(DTPA) administration. T1- and T2-wt MR contrast-enhancing and non-enhancing imaging features were used to characterize tumors to differential temporal stages. Histological staining was used to characterize the pathological features of these tumors. Tumors in the xenograph model reached 5 mm in diameter about 4 weeks after tumor implantation. Post-contrast T1- and T2-wt MR images were homogeneous throughout the tumors (Stage 1). Tumors progressed to Stage 2 and last for 3-5 days, with a rim-enhanced post-contrast T1-wt and a homogeneous T2-wt MR patterns. These features correspond to an increasing activity of vascularization on the periphery of viable tumors. Tumors progress to Stage 3 by week 5, with an elevated T2-wt signal at the area with no enhancement in the post-contrast T1-wt images. These features correlate with the development of the necrosis. The results were confirmed by histological staining. Tumors in the sygeneic model reached Stage 1 with MR imaging patterns as described above about 2-3 weeks after tumor implantation; Stage 2 at about 3-5 weeks; and Stage 3 at about 5 weeks. Three differential observations were identified between the xenograph and syngeneic models: (1) Initial rate of tumor growth is much delayed in xenograph model; (2) The absolute MR intensity in the homogeneous post-contrast T1 image associated with Stage 1 is brighter in the xenograph model; (3) Stage 2 tumor progression in xenograph model was extremely short. The results were also confirmed by histological staining.