Hou Rui, Wang Yu-Wei, Liang Hui-Fang, Zhang Zhan-Guo, Liu Zhi-Min, Zhang Bin-Hao, Zhang Bi-Xiang, Chen Xiao-Ping
Department of Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China.
Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
J Cancer Res Clin Oncol. 2015 Nov;141(11):1931-43. doi: 10.1007/s00432-015-1958-6. Epub 2015 Mar 28.
An increasingly high occurrence of bone metastases in hepatocellular carcinoma (HCC) patients highlights the importance of fundamental research on HCC bone metastasis, which has been limited in its success due to the lack of a model system.
Establishment of animal and cellular models of HCC bone metastasis and discovery of HCC bone metastasis-related genes.
Luciferase-transfected HCC cell lines HCCLM3, MHCC97H, and SMMC-7721 were used to inoculate nude mice intracardially. Formation of bone metastases was examined by bioluminescence imaging, SPECT, and pathology study. Metastatic cells in bone were isolated and subcultured. Differences between bone metastatic cells and their parental cells were studied by in vitro/in vivo assays.
Mouse model of HCC bone metastasis was successfully established. Injected tumour cells formed metastases in the skull, the spine, the hind limbs, and the sternum, causing osteolytic lesions via act of MMP-1 and recruitment of osteoclasts. Four bone metastatic cell lines were extracted from HCCLM3-inoculated mice and were demonstrated to exhibit a much stronger ability to form bone metastases as well as other phenotypes, including enhanced in vitro migration/invasion and colony formation. Moreover, the expression of PTHrP, MMP-1, and CTGF was significantly elevated in bone metastatic cells compared to parental HCC cells.
The nude mouse model and bone metastatic cell lines together provide an effective simulation of HCC bone metastasis. This model system will become powerful tool with which to explore the mechanisms and therapies of HCC bone metastasis. Additionally, PTHrP, MMP-1, and CTGF are candidate genes related to HCC bone metastasis.
肝细胞癌（HCC）患者骨转移的发生率日益增高，这凸显了对HCC骨转移进行基础研究的重要性。由于缺乏模型系统，该领域的研究成果有限。
建立HCC骨转移的动物和细胞模型，并发现与HCC骨转移相关的基因。
将荧光素酶转染的HCC细胞系HCCLM3、MHCC97H和SMMC - 7721经心内注射接种到裸鼠体内。通过生物发光成像、单光子发射计算机断层扫描（SPECT）和病理学研究检测骨转移的形成。分离并传代培养骨中的转移细胞。通过体外/体内实验研究骨转移细胞与其亲本细胞之间的差异。
成功建立了HCC骨转移小鼠模型。注射的肿瘤细胞在颅骨、脊柱、后肢和胸骨形成转移灶，通过基质金属蛋白酶 - 1（MMP - 1）的作用和破骨细胞的募集导致溶骨性病变。从接种HCCLM3的小鼠中提取了4种骨转移细胞系，这些细胞系显示出更强的形成骨转移的能力以及其他表型，包括增强的体外迁移/侵袭和集落形成能力。此外，与亲本HCC细胞相比，骨转移细胞中甲状旁腺激素相关蛋白（PTHrP）、MMP - 1和结缔组织生长因子（CTGF）的表达显著升高。
裸鼠模型和骨转移细胞系共同为HCC骨转移提供了有效的模拟。该模型系统将成为探索HCC骨转移机制和治疗方法的有力工具。此外，PTHrP、MMP - 1和CTGF是与HCC骨转移相关的候选基因。
