Moshitch-Moshkovitz Sharon, Tsarfaty Galia, Kaufman Dafna W, Stein Gideon Y, Shichrur Keren, Solomon Eddy, Sigler Robert H, Resau James H, Vande Woude George F, Tsarfaty Ilan
Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Neoplasia. 2006 May;8(5):353-63. doi: 10.1593/neo.05634.
The tyrosine kinase receptor Met and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), play an important role in normal developmental processes, as well as in tumorigenicity and metastasis. We constructed a green fluorescent protein (GFP) Met chimeric molecule that functions similarly to the wild-type Met receptor and generated GFP-Met transgenic mice. These mice ubiquitously expressed GFP-Met in specific epithelial and endothelial cells and displayed enhanced GFP-Met fluorescence in sebaceous glands. Thirty-two percent of males spontaneously developed adenomas, adenocarcinomas, and angiosarcomas in their lower abdominal sebaceous glands. Approximately 70% of adenocarcinoma tumors metastasized to the kidneys, lungs, or liver. Quantitative subcellular-resolution intravital imaging revealed very high levels of GFP-Met in tumor lesions and in single isolated cells surrounding them, relative to normal sebaceous glands. These single cells preceded the formation of local and distal metastases. Higher GFP-Met levels correlated with earlier tumor onset and aggressiveness, further demonstrating the role of Met-HGF/SF signaling in cellular transformation and acquisition of invasive and metastatic phenotypes. Our novel mouse model and high-resolution intravital molecular imaging create a powerful tool that enables direct real-time molecular imaging of receptor expression and localization during primary events of tumorigenicity and metastasis at single-cell resolution.
酪氨酸激酶受体Met及其配体肝细胞生长因子/分散因子（HGF/SF）在正常发育过程以及肿瘤发生和转移中发挥着重要作用。我们构建了一种绿色荧光蛋白（GFP）Met嵌合分子，其功能与野生型Met受体相似，并生成了GFP-Met转基因小鼠。这些小鼠在特定的上皮细胞和内皮细胞中普遍表达GFP-Met，并且在皮脂腺中显示出增强的GFP-Met荧光。32%的雄性小鼠在下腹部皮脂腺中自发发生腺瘤、腺癌和血管肉瘤。大约70%的腺癌肿瘤转移至肾脏、肺或肝脏。定量亚细胞分辨率活体成像显示，相对于正常皮脂腺，肿瘤病变及其周围单个分离细胞中的GFP-Met水平非常高。这些单个细胞先于局部和远处转移的形成。较高的GFP-Met水平与更早的肿瘤发生和侵袭性相关，进一步证明了Met-HGF/SF信号在细胞转化以及获得侵袭性和转移表型中的作用。我们的新型小鼠模型和高分辨率活体分子成像创建了一个强大的工具，能够在肿瘤发生和转移的主要事件中以单细胞分辨率对受体表达和定位进行直接实时分子成像。
