title: c-Met ectodomain shedding rate correlates with malignant potential.
abstract: OBJECTIVE
  Many proteins are proteolytically released from the cell surface by a process known as ectodomain shedding. Shedding occurs under normal physiologic conditions and can be increased in certain pathologies. Among the many receptors for which ectodomain shedding has been shown is c-Met, the hepatocyte growth factor (HGF) receptor tyrosine kinase. HGF stimulates mitogenesis, motogenesis, and morphogenesis in a variety of cellular targets during development, homeostasis, and tissue regeneration. Inappropriate HGF signaling resulting in unregulated cell proliferation, motility, and invasion occurs in several human malignancies. This can occur through paracrine signaling, autocrine loop formation, receptor mutation, gene amplification, or gene rearrangement, accompanied frequently with overexpression of ligand and/or receptor proteins. We hypothesized that c-Met overexpression in cancer might result in increased ectodomain shedding, and that its measure could be a useful biomarker of tumor progression.
  
  
  METHODS
  We developed a sensitive electrochemiluminescent immunoassay to quantitate c-Met protein in cell lysates, culture supernatants, and biological samples.
  
  
  RESULTS
  A survey of cultured cell models of oncogenic transformation revealed significant direct correlations (P < 0.001, t test or ANOVA) between malignant potential and the rate of c-Met ectodomain shedding that was independent of steady-state receptor expression level. Moreover, weekly plasma and urine samples from mice harboring s.c. human tumor xenografts (n = 4 per group) displayed soluble human c-Met levels that were measurable before tumors became palpable and that correlated directly with tumor volume (R2 > 0.92, linear regression).
  
  
  CONCLUSIONS
  For a variety of human cancers, c-Met ectodomain shedding may provide a reliable and practical indicator of malignant potential and overall tumor burden.
authors.affiliation: Urologic Oncology Branch, Laboratory of Molecular Pharmacology, and Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892-1107, USA.
authors.forename: Gagani
authors.initials: G
authors.lastname: Athauda
authors.forename: Alessio
authors.initials: A
authors.lastname: Giubellino
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Coleman
authors.forename: Christine
authors.initials: C
authors.lastname: Horak
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Steeg
authors.forename: Ming-Jung
authors.initials: MJ
authors.lastname: Lee
authors.forename: Jane
authors.initials: J
authors.lastname: Trepel
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wimberly
authors.forename: Jan
authors.initials: J
authors.lastname: Sun
authors.forename: Angela
authors.initials: A
authors.lastname: Coxon
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Burgess
authors.forename: Donald P
authors.initials: DP
authors.lastname: Bottaro
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000737:chemistry; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry; D006801:Humans; D049449:Luminescence; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D017434:Protein Structure, Tertiary; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D014408:Biomarkers, Tumor; D011994:Recombinant Proteins; D019859:Proto-Oncogene Proteins c-met