c-Met ectodomain shedding rate correlates with malignant potential.
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.
Athauda
Gagani
G
Urologic Oncology Branch, Laboratory of Molecular Pharmacology, and Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892-1107, USA.
Giubellino
Alessio
A
Coleman
Jonathan A
JA
Horak
Christine
C
Steeg
Patricia S
PS
Lee
Ming-Jung
MJ
Trepel
Jane
J
Wimberly
Jennifer
J
Sun
Jan
J
Coxon
Angela
A
Burgess
Teresa L
TL
Bottaro
Donald P
DP
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
D014408:Biomarkers, Tumor; D011994:Recombinant Proteins; D019859:Proto-Oncogene Proteins c-met