Plexin-B2 promotes invasive growth of malignant glioma
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Audrey P. Le1,*, Yong Huang1,*, Sandeep C. Pingle4, Santosh Kesari4, Huaien Wang2,3, Raymund L. Yong2,3, Hongyan Zou1,2 and Roland H. Friedel1,2
1 Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2 Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3 Comprehensive Brain Tumor Program, Icahn School of Medicine at Mount Sinai, New York, NY, USA
4 Translational Neuro-Oncology Laboratories, Moores UCSD Cancer Center and Department of Neurosciences, La Jolla, CA, USA
* These authors have contributed equally to this work
Roland H. Friedel, email:
Keywords: plexin, semaphorin, glioma invasion, tumor vasculature
Received: January 15, 2015 Accepted: January 18, 2015 Published: January 31, 2015
Invasive growth is a major determinant of the high lethality of malignant gliomas. Plexin-B2, an axon guidance receptor important for mediating neural progenitor cell migration during development, is upregulated in gliomas, but its function therein remains poorly understood. Combining bioinformatic analyses, immunoblotting and immunohistochemistry of patient samples, we demonstrate that Plexin-B2 is consistently upregulated in all types of human gliomas and that its expression levels correlate with glioma grade and poor survival. Activation of Plexin-B2 by Sema4C ligand in glioblastoma cells induced actin-based cytoskeletal dynamics and invasive migration in vitro. This proinvasive effect was associated with activation of the cell motility mediators RhoA and Rac1. Furthermore, costimulation of Plexin-B2 and the receptor tyrosine kinase Met led to synergistic Met phosphorylation. In intracranial glioblastoma transplants, Plexin-B2 knockdown hindered invasive growth and perivascular spreading, and resulted in decreased tumor vascularity. Our results demonstrate that Plexin-B2 promotes glioma invasion and vascularization, and they identify Plexin-B2 as a potential novel prognostic marker for glioma malignancy. Targeting the Plexin-B2 pathway may represent a novel therapeutic approach to curtail invasive growth of glioblastoma.
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