Clinical Research Center, National Hospital Organization Nagasaki Medical Center and Division of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
World J Gastroenterol. 2012 Aug 7;18(29):3875-82. doi: 10.3748/wjg.v18.i29.3875.
To establish an animal model with human hepatocyte-repopulated liver for the study of liver cancer metastasis.
Cell transplantation into mouse livers was conducted using alpha-fetoprotein (AFP)-producing human gastric cancer cells (h-GCCs) and h-hepatocytes as donor cells in a transgenic mouse line expressing urokinase-type plasminogen activator (uPA) driven by the albumin enhancer/promoter crossed with a severe combined immunodeficient (SCID) mouse line (uPA/SCID mice). Host mice were divided into two groups (A and B). Group A mice were transplanted with h-GCCs alone, and group B mice were transplanted with h-GCCs and h-hepatocytes together. The replacement index (RI), which is the ratio of transplanted h-GCCs and h-hepatocytes that occupy the examined area of a histological section, was estimated by measuring h-AFP and h-albumin concentrations in sera, respectively, as well as by immunohistochemical analyses of h-AFP and human cytokeratin 18 in histological sections.
The h-GCCs successfully engrafted, repopulated, and colonized the livers of mice in group A (RI = 22.0% ± 2.6%). These mice had moderately differentiated adenocarcinomatous lesions with disrupted glandular structures, which is a characteristics feature of gastric cancers. The serum h-AFP level reached 211.0 ± 142.2 g/mL (range, 7.1-324.2 g/mL). In group B mice, the h-GCCs and h-hepatocytes independently engrafted, repopulated the host liver, and developed colonies (RI = 12.0% ± 6.8% and 66.0% ± 12.3%, respectively). h-GCC colonies also showed typical adenocarcinomatous glandular structures around the h-hepatocyte-colonies. These mice survived for the full 56 day-study and did not exhibit any metastasis of h-GCCs in the extrahepatic regions during the observational period. The mice with an h-hepatocyte-repopulated liver possessed metastasized h-GCCs and therefore could be a useful humanized liver animal model for studying liver cancer metastasis in vivo.
A novel animal model of human liver cancer metastasis was established using the uPA/SCID mouse line. This model could be useful for in vivo testing of anti-cancer drugs and for studying the mechanisms of human liver cancer metastasis.
建立一种具有人肝细胞再殖的肝癌转移动物模型。
使用α-胎蛋白（AFP）产生的人胃癌细胞（h-GCCs）和 h 肝细胞作为供体细胞，在转尿激酶型纤溶酶原激活剂（uPA）驱动的白蛋白增强子/启动子与严重联合免疫缺陷（SCID）小鼠系（uPA/SCID 小鼠）杂交的转基因小鼠系中进行细胞移植到小鼠肝脏中。宿主小鼠分为两组（A 和 B）。A 组小鼠单独移植 h-GCCs，B 组小鼠共同移植 h-GCCs 和 h 肝细胞。通过分别测量血清 h-AFP 和 h 白蛋白浓度，以及组织学切片中 h-AFP 和人细胞角蛋白 18 的免疫组织化学分析，估计移植 h-GCCs 和 h 肝细胞在组织学切片检查区域中所占的替代指数（RI）。
h-GCCs 在 A 组小鼠中成功植入、再殖和定植（RI=22.0%±2.6%）。这些小鼠具有中等分化的腺癌性病变，腺体结构破坏，这是胃癌的特征性特征。血清 h-AFP 水平达到 211.0±142.2 g/mL（范围，7.1-324.2 g/mL）。在 B 组小鼠中，h-GCCs 和 h 肝细胞分别植入、再殖宿主肝脏并形成菌落（RI=12.0%±6.8%和 66.0%±12.3%）。h-GCC 菌落周围也显示出典型的腺癌性腺体结构。这些小鼠在整个 56 天的研究中存活下来，并且在观察期间未在肝外区域出现 h-GCCs 的转移。具有 h 肝细胞再殖的肝脏的小鼠具有转移性 h-GCCs，因此可以成为研究体内肝癌转移的有用的人源化肝脏动物模型。
使用 uPA/SCID 小鼠系建立了一种新型人肝癌转移动物模型。该模型可用于体内抗癌药物的测试，并用于研究人肝癌转移的机制。
