Abstract
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.
Highlights
Gliomas are primary brain tumors that are among the most lethal forms of cancer [1, 2]
We show that Plexin-B2 is consistently upregulated in human gliomas and that its expression levels correlate with glioma grade and poor survival
In the TCGA glioblastoma samples, PLXNB2 expression was on average upregulated by more than 2.5-fold in classical and mesenchymal subtypes, and more than 1.5-fold in proneural and neural subtypes, while the expression levels of PLXNB1 and -B3 were largely similar between subtypes (Fig. 1B; Fig. S1B)
Summary
Gliomas are primary brain tumors that are among the most lethal forms of cancer [1, 2]. Genomic analyses have unraveled molecular pathways that drive gliomagenesis [4], the mechanisms by which glioma cells infiltrate healthy brain tissue remain largely unknown, and the signaling molecules that regulate the cell-cell or cell-matrix interactions between glioma and the tumor microenvironment remain poorly defined. Recent studies suggest that glioma cells actively migrate through the tortuous extracellular spaces of the brain, in much the same way as embryonic neurons and glia cells migrate along preferred extracellular routes in the developing brain [5]. In this regard, glioma cells retain much of their neural origin, and may utilize similar signaling pathways as in development. Several members of the semaphorin and plexin families are highly expressed in gliomas [8, 9], www.impactjournals.com/oncotarget but direct evidence for their engagement in the invasive growth of glioma is lacking
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