In vivo molecular imaging of Met tyrosine kinase growth factor receptor activity in normal organs and breast tumors

Molecular imaging techniques allow visualization of specific gene products and their physiological processes in living tissues. In this study, we pres ent a new approach for molecular imaging of endogenous tyrosine kinase rece ptor activity. Met and its ligand hepatocyte growth factor scatter factor ( HGF/SF), which mediate mitogenicity, tumorigenicity, and angiogenesis, were used as a model, HGF/SF and Met play a significant role in the pathogenesi s and biology of a wide variety of human epithelial cancers and, therefore, may serve as potential targets for cancer prognosis and therapy. We have s hown previously that in vitro activation of Met by HGF/SF increases oxygen consumption. In this study, we demonstrate that Met activation in vivo by H CF/SF alters the hemodynamics of normal and malignant Met-expressing tissue s. Tumor-bearing BALB/C mice were i.v. injected with HCF/SF and imaged usin g magnetic resonance imaging (MRI) and Doppler ultrasound. Organs and tumor s expressing high levels of Met showed the most substantial alteration in b lood oxygenation levels as measured by blood oxygenation level depended (BO LD)-MRI. No significant alteration was observed in tumors or organs that do es not express Met. In the liver, which expresses high levels of Met, MRI s ignal alteration of about 60% was observed. In the kidneys, signal alterati on was approximately 30%, and no change was observed in muscles, The extent of MRI signal alteration was also in correlation with HGF/SF doses. Inject ion of 7 and 170 ng/g body weight resulted in signal alteration of 5% and 3 0%, respectively, in tumors. Doppler ultrasound measurements demonstrated t hat these MRI changes are at least partially attributable to altered blood now. These hemodynamic alterations, measured by MRI and Doppler ultrasound, were used in this study for the molecular imaging of Met activity in vivo. This novel molecular imaging technique may be used for in vivo diagnosis, prognosis, and therapy of Met-expressing tumors.