Hasegawa Sumitaka, Morokoshi Yukie, Tsuji Atsushi B, Kokubo Toshiaki, Aoki Ichio, Furukawa Takako, Zhang Ming-Rong, Saga Tsuneo
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
Mol Oncol. 2015 Mar;9(3):740-8. doi: 10.1016/j.molonc.2014.11.009. Epub 2014 Dec 3.
Radiation-induced thymic lymphoma (RITL) in mice is induced by fractionated whole-body X-irradiation (FX) and has served as a useful model for studying radiation carcinogenesis. In this model, the initial postirradiation cellular events in the thymus and bone marrow (BM) are critically important for tumorigenesis, and BM transplantation (BMT) prevents RITL. However, direct assessment of these events is so far restricted by the lack of noninvasive monitoring techniques. Here, we have developed positron emission tomography (PET) and magnetic resonance imaging (MRI) methods to quantify the events critical for RITL development and the effects of BMT in living animals. Apparent diffusion coefficients (ADCs) were calculated from diffusion-weighted MRI to evaluate the changes in the BM of mice receiving FX. ADC values dramatically changed in the irradiated BM, corresponding to pathological findings of the irradiated BM, returning to normal levels following BMT sooner than with spontaneous recovery. PET with 4'-[methyl-(11)C]thiothymidine, a novel tracer for cell proliferation, revealed that the irradiated thymus showed significantly higher tracer uptake than the unirradiated thymus 1 week after FX. Interestingly, its increased uptake was completely abolished by BMT, even with very few donor-derived cells in the thymus. Thereafter, the thymus receiving BMT had significantly increased tracer uptake. These findings suggest that BMT first suppresses FX-induced aberrant thymocyte proliferation and then accelerates thymic regeneration. This study demonstrates the feasibility of using PET and MRI for noninvasive monitoring of tumorigenic cellular processes in an animal model of radiation-induced cancer.
小鼠辐射诱导性胸腺淋巴瘤（RITL）由分次全身X射线照射（FX）诱发，已成为研究辐射致癌作用的有用模型。在该模型中，胸腺和骨髓（BM）照射后的初始细胞事件对肿瘤发生至关重要，而骨髓移植（BMT）可预防RITL。然而，由于缺乏非侵入性监测技术，目前对这些事件的直接评估受到限制。在此，我们开发了正电子发射断层扫描（PET）和磁共振成像（MRI）方法，以量化对RITL发展至关重要的事件以及BMT在活体动物中的作用。通过扩散加权MRI计算表观扩散系数（ADC），以评估接受FX照射的小鼠骨髓的变化。照射后的骨髓中ADC值发生显著变化，与照射后骨髓的病理结果相符，BMT后其恢复至正常水平的时间早于自发恢复。使用新型细胞增殖示踪剂4'-[甲基-（11）C]硫代胸腺嘧啶核苷进行PET检查发现，FX照射1周后，照射的胸腺比未照射的胸腺显示出明显更高的示踪剂摄取。有趣的是，即使胸腺中供体来源的细胞很少，BMT也能完全消除其摄取增加的情况。此后，接受BMT的胸腺示踪剂摄取显著增加。这些发现表明，BMT首先抑制FX诱导异常胸腺细胞增殖，然后加速胸腺再生。本研究证明了在辐射诱导癌症的动物模型中使用PET和MRI对致瘤细胞过程进行非侵入性监测的可行性。
