In vivo direct molecular imaging of early tumorigenesis and malignant progression induced by transgenic expression of GFP-Met.
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.
Moshitch-Moshkovitz
Sharon
S
Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Tsarfaty
Galia
G
Kaufman
Dafna W
DW
Stein
Gideon Y
GY
Shichrur
Keren
K
Solomon
Eddy
E
Sigler
Robert H
RH
Resau
James H
JH
Vande Woude
George F
GF
Tsarfaty
Ilan
I
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
D049452:Green Fluorescent Proteins; D019859:Proto-Oncogene Proteins c-met