Cancer Gene Therapy Group, Molecular Cancer Biology Program, Transplantation Laboratory, Haartman Institute and Finnish Institute of Molecular Medicine, University of Helsinki, Helsinki, Finland.
PLoS One. 2011;6(11):e26810. doi: 10.1371/journal.pone.0026810. Epub 2011 Nov 3.
Development of new cancer treatments focuses increasingly on the relation of cancer tissue with its microenvironment. A major obstacle for the development of new anti-cancer therapies has been the lack of relevant animal models that would reproduce all the events involved in disease progression from the early-stage primary tumor until the development of mature metastatic tissue. To this end, we have developed a readily imageable mouse model of colorectal cancer featuring highly reproducible formation of spontaneous liver metastases derived from intrasplenic primary tumors. We optimized several experimental variables, and found that the correct choice of cell line and the genetic background, as well as the age of the recipient mice, were critical for establishing a useful model system. Among a panel of colorectal cancer cell lines tested, the epithelial carcinoma HT29 line was found to be the most suitable in terms of producing homogeneous tumor growth and metastases. In our hands, SCID mice at the age of 125 days or older were the most suitable in supporting consistent HT29 tumor growth after splenic implantation followed by reproducible metastasis to the liver. A magnetic resonance imaging (MRI) protocol was optimized for use with this mouse model, and demonstrated to be a powerful method for analyzing the antitumor effects of an experimental therapy. Specifically, we used this system to with success to verify by MRI monitoring the efficacy of an intrasplenically administered oncolytic adenovirus therapy in reducing visceral tumor load and development of liver metastases. In summary, we have developed a highly optimized mouse model for liver metastasis of colorectal cancer, which allows detection of the tumor load at the whole body level and enables an accurate timing of therapeutic interventions to target different stages of cancer progression and metastatic development.
新型癌症治疗方法的研发越来越注重癌症组织与其微环境的关系。新抗癌疗法发展的主要障碍一直是缺乏相关的动物模型，这些模型能够重现从早期原发性肿瘤到成熟转移性组织发展过程中涉及的所有事件。为此，我们开发了一种易于成像的结直肠癌小鼠模型，该模型具有源自脾内原发性肿瘤的自发性肝转移的高度重现性形成。我们优化了几个实验变量，发现正确选择细胞系和遗传背景以及受体小鼠的年龄对于建立有用的模型系统至关重要。在测试的一系列结直肠癌细胞系中，上皮癌 HT29 系在产生同质肿瘤生长和转移方面被发现是最合适的。在我们的手中，125 天或以上龄的 SCID 小鼠在脾内植入后最适合支持一致的 HT29 肿瘤生长，随后可重现性地转移到肝脏。优化了一种磁共振成像 (MRI) 方案，用于该小鼠模型，并证明该方案是分析实验治疗抗肿瘤效果的有力方法。具体来说，我们使用该系统通过 MRI 监测脾内给予溶瘤腺病毒治疗在减少内脏肿瘤负荷和肝转移发展方面的疗效，取得了成功。总之，我们开发了一种高度优化的结直肠癌肝转移小鼠模型，该模型可在全身水平检测肿瘤负荷，并能够准确地对不同阶段的癌症进展和转移发展进行治疗干预。
