title: Molecular imaging of c-Met tyrosine kinase activity.
abstract: The receptor tyrosine kinase c-Met and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), modulate signaling cascades implicated in cellular proliferation, survival, migration, invasion, and angiogenesis. Therefore, dysregulation of HGF/c-Met signaling can compromise the cellular capacity to moderate these activities and can lead to tumorigenesis, metastasis, and therapeutic resistance in various human malignancies. To facilitate studies investigating HGF/c-Met receptor coupling or c-Met signaling events in real time and in living cells and animals, here we describe a genetically engineered reporter where bioluminescence can be used as a surrogate for c-Met tyrosine kinase activity. c-Met kinase activity in cultured cells and tumor xenografts was monitored quantitatively and dynamically in response to the activation or inhibition of the HGF/c-Met signaling pathway. Treatment of tumor-bearing animals with a c-Met inhibitor and the HGF neutralizing antibody stimulated the reporter's bioluminescence activity in a dose-dependent manner and led to a regression of U-87 MG tumor xenografts. Results obtained from these studies provide unique insights into the pharmacokinetics and pharmacodynamics of agents that modulate c-Met activity and validate c-Met as a target for human glioblastoma therapy.
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Limin
authors.initials: L
authors.lastname: Zhang
authors.forename: Shama
authors.initials: S
authors.lastname: Virani
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mahaveer S
authors.initials: MS
authors.lastname: Bhojani
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Burgess
authors.forename: Angela
authors.initials: A
authors.lastname: Coxon
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Galban
authors.forename: Brian D
authors.initials: BD
authors.lastname: Ross
authors.forename: Alnawaz
authors.initials: A
authors.lastname: Rehemtulla
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D045744:Cell Line, Tumor; D005808:Genes, Recessive; D005909:Glioblastoma / Q000628:therapy; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D057054:Molecular Imaging / Q000379:methods*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism* / Q000627:therapeutic use; D015398:Signal Transduction; D014183:Transplantation, Heterologous
chemical_list: D057134:Antibodies, Neutralizing; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met