c-Met ectodomain shedding rate correlates with malignant potential.

Gagani Athauda, Alessio Giubellino, Jonathan A. Coleman, Christine Horak, Patricia S. Steeg, Ming Jung Lee, Jane Trepel, Jennifer Wimberly, Jan Sun, Angela Coxon, Teresa L. Burgess, Donald P. Bottaro

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

PURPOSE: 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. EXPERIMENTAL DESIGN: 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.

Original languageEnglish (US)
Pages (from-to)4154-4162
Number of pages9
JournalClinical cancer research : an official journal of the American Association for Cancer Research
Volume12
Issue number14 Pt 1
DOIs
StatePublished - Jul 15 2006

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Proto-Oncogene Proteins c-met
Hepatocyte Growth Factor
Paracrine Communication
Neoplasms
Gene Rearrangement
Gene Amplification
Tumor Biomarkers
Tumor Burden
Morphogenesis
Immunoassay
Protein-Tyrosine Kinases
Cell Movement
Regeneration
Cultured Cells
Linear Models
Proteins
Homeostasis
Cell Culture Techniques
Cell Proliferation
Pathology

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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c-Met ectodomain shedding rate correlates with malignant potential. / Athauda, Gagani; Giubellino, Alessio; Coleman, Jonathan A.; Horak, Christine; Steeg, Patricia S.; Lee, Ming Jung; Trepel, Jane; Wimberly, Jennifer; Sun, Jan; Coxon, Angela; Burgess, Teresa L.; Bottaro, Donald P.

In: Clinical cancer research : an official journal of the American Association for Cancer Research, Vol. 12, No. 14 Pt 1, 15.07.2006, p. 4154-4162.

Research output: Contribution to journalArticle

Athauda, G, Giubellino, A, Coleman, JA, Horak, C, Steeg, PS, Lee, MJ, Trepel, J, Wimberly, J, Sun, J, Coxon, A, Burgess, TL & Bottaro, DP 2006, 'c-Met ectodomain shedding rate correlates with malignant potential.', Clinical cancer research : an official journal of the American Association for Cancer Research, vol. 12, no. 14 Pt 1, pp. 4154-4162. https://doi.org/10.1158/1078-0432.CCR-06-0250
Athauda, Gagani ; Giubellino, Alessio ; Coleman, Jonathan A. ; Horak, Christine ; Steeg, Patricia S. ; Lee, Ming Jung ; Trepel, Jane ; Wimberly, Jennifer ; Sun, Jan ; Coxon, Angela ; Burgess, Teresa L. ; Bottaro, Donald P. / c-Met ectodomain shedding rate correlates with malignant potential. In: Clinical cancer research : an official journal of the American Association for Cancer Research. 2006 ; Vol. 12, No. 14 Pt 1. pp. 4154-4162.
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T1 - c-Met ectodomain shedding rate correlates with malignant potential.

AU - Athauda, Gagani

AU - Giubellino, Alessio

AU - Coleman, Jonathan A.

AU - Horak, Christine

AU - Steeg, Patricia S.

AU - Lee, Ming Jung

AU - Trepel, Jane

AU - Wimberly, Jennifer

AU - Sun, Jan

AU - Coxon, Angela

AU - Burgess, Teresa L.

AU - Bottaro, Donald P.

PY - 2006/7/15

Y1 - 2006/7/15

N2 - PURPOSE: 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. EXPERIMENTAL DESIGN: 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.

AB - PURPOSE: 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. EXPERIMENTAL DESIGN: 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.

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