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Identifying Mechanisms for Therapeutic Intervention in Chordoma: c-Met Oncoprotein

Ostroumov, Elena, PhD; Hunter, Christopher J., PhD

doi: 10.1097/BRS.0b013e31817e2d1e
Epidemiology
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Study Design. A human sacral chordoma cell line, CCL3, was established and in vitro characterization of c-Met oncoprotein in chordoma cells was performed.

Objective. Determination of whether c-Met plays an important role in chordoma’s malignancy.

Summary of Background Data. Chordomas are malignant life-threatening tumors that arise from the remnants of the notochord. c-Met is an oncoprotein that is expressed by a variety of solid tumors, including chordomas, and HGF is its high affinity ligand. In the present study, we investigated c-Met and HGF expression, localization, and function in human chordoma cells.

Methods. SDS-PAGE, Western blotting, immunofluorescence techniques, and cell migration functional assays were used to asses c-Met and HGF expression, localization, and functional activity.

Results. Intracellular protein tyrosine phosphorylation was enhanced on HGF binding, and an increase in the amount of 50 kDa α-chain of c-Met was detected in HGF-stimulated cells. Immunostaining of c-Met and HGF revealed membrane/cytoplasmic localization in nonstimulated cells, and perinuclear colocalization in HGF-stimulated cells. Positive chemotactic and migration activity in response to HGF was also demonstrated.

Conclusion. Our data supports our hypothesis that the c-Met oncoprotein plays a leading role in the metastatic process in chordomas, and that a c-Met-HGF pair is involved in chordoma malignancy. Taking into consideration the very limited treatment options and an extremely poor prognosis for the chordoma patients, our results are a valuable and promising addition to the current situation in managing chordomas.

Chordomas are lethal bone tumors of the spine and skull. Abnormal expression of c-Met is a hallmark of malignancy. We performed characterization of the c-Met receptor and its response to the functional ligand, HGF, in a new sacral chordoma line. We report here that chordoma undergoes significant intracellular changes on c-Met-HGF interaction.

From the Centre for Bioengineering Research and Education, University of Calgary, Calgary, Alberta, Canada.

Acknowledgment date: October 17,2007. Revision date: January 14, 2008. Acceptance date: January 21, 2008.

Supported by a grant from the Alberta Heritage Foundation for Medical Research (AHFMR).

Dr. Christopher J. Hunter, PhD, is an AHFMR Scholar and an Alberta Ingenuity Fund New Faculty.

The manuscript submitted does not contain information about medical device(s)/drug(s).

Foundation funds were received in support of this work. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.

Address correspondence and reprint requests to Christopher J. Hunter, PhD, Department of Mechanical and Manufacturing Engineering, 2500 University Dr. NW, Calgary, Alberta T2N 1N4; E-mail: chunter@ucalgary.ca

© 2008 Lippincott Williams & Wilkins, Inc.