title: In vivo direct molecular imaging of early tumorigenesis and malignant progression induced by transgenic expression of GFP-Met.
abstract: 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.
authors.affiliation: Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Moshitch-Moshkovitz
authors.forename: Galia
authors.initials: G
authors.lastname: Tsarfaty
authors.forename: Dafna W
authors.initials: DW
authors.lastname: Kaufman
authors.forename: Gideon Y
authors.initials: GY
authors.lastname: Stein
authors.forename: Keren
authors.initials: K
authors.lastname: Shichrur
authors.forename: Eddy
authors.initials: E
authors.lastname: Solomon
authors.forename: Robert H
authors.initials: RH
authors.lastname: Sigler
authors.forename: James H
authors.initials: JH
authors.lastname: Resau
authors.forename: George F
authors.initials: GF
authors.lastname: Vande Woude
authors.forename: Ilan
authors.initials: I
authors.lastname: Tsarfaty
mesh_terms: D000818:Animals; D003952:Diagnostic Imaging / Q000295:instrumentation / Q000379:methods*; D018450:Disease Progression; D005260:Female; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence / Q000379:methods*; D009362:Neoplasm Metastasis; D010641:Phenotype; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D019076:Transgenes
chemical_list: D049452:Green Fluorescent Proteins; D019859:Proto-Oncogene Proteins c-met