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BEHAB/brevican requires ADAMTS-mediated proteolytic cleavage to promote glioma invasion

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Abstract

Malignant gliomas are the most common and deadly primary brain tumors, due to their infiltrative invasion of the normal neural tissue that makes them virtually impossible to completely eliminate. We have previously identified and characterized the proteoglycan BEHAB/brevican in gliomas and have demonstrated that upregulation and cleavage of this CNS-specific molecule promote glioma invasion. Here, we have further investigated if the proteolytic processing of BEHAB/brevican by metalloproteases of the ADAMTS family is a necessary step in mediating its pro-invasive effect in glioma. By generating a site-specific (396SRG398 → NVY) mutant form resistant to ADAMTS cleavage, we have shown that the predominant proteolytic processing of BEHAB/brevican by glioma cells occurs only at this site. More importantly, “uncleavable” BEHAB/brevican is unable to enhance glioma cell invasion in vitro and tumor progression in vivo. In addition, our results suggest that the full-length protein and its cleavage products may act independently because the mutant form does not exert a dominant negative effect on normal BEHAB/brevican expression or cleavage. These results illustrate how the regulated processing of major components of the neural extracellular matrix has important functional implications in glioma progression. In addition, our findings underscore the relevance of the ADAMTS family of metalloproteases as attractive targets for novel pharmacological approaches in glioma therapy.

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Acknowledgements

This work was supported by research grants from NIH (R01NS035228) and the Accelerate Brain Cancer Cure foundation (to RTM), and by a fellowship from the Butler Family Foundation/American Brain Tumor Association (to MSV).

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Author notes

  1. Mariano Sebastian Viapiano

    Present address: Department of Neurological Surgery and Center for Molecular Neurobiology, Ohio State University, Columbus, OH, USA

  2. Susan Hockfield

    Present address: Massachusetts Institute of Technology, Cambridge, MA, USA

Authors and Affiliations

  1. Department of Neurobiology, Yale University School of Medicine, New Haven, CT, 06510, USA

    Mariano Sebastian Viapiano, Susan Hockfield & Russell Thomas Matthews

  2. Department of Neuroscience and Physiology, State University of New York Upstate Medical University, 3238 Weiskotten Hall, Syracuse, NY, 13210, USA

    Russell Thomas Matthews

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  1. Mariano Sebastian Viapiano
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  2. Susan Hockfield
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  3. Russell Thomas Matthews
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Correspondence to Russell Thomas Matthews.

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Viapiano, M.S., Hockfield, S. & Matthews, R.T. BEHAB/brevican requires ADAMTS-mediated proteolytic cleavage to promote glioma invasion. J Neurooncol 88, 261–272 (2008). https://doi.org/10.1007/s11060-008-9575-8

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  • DOI: https://doi.org/10.1007/s11060-008-9575-8

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