Limits...
Plexin-B2 promotes invasive growth of malignant glioma.

Le AP, Huang Y, Pingle SC, Kesari S, Wang H, Yong RL, Zou H, Friedel RH - Oncotarget (2015)

Bottom Line: This proinvasive effect was associated with activation of the cell motility mediators RhoA and Rac1.In intracranial glioblastoma transplants, Plexin-B2 knockdown hindered invasive growth and perivascular spreading, and resulted in decreased tumor vascularity.Targeting the Plexin-B2 pathway may represent a novel therapeutic approach to curtail invasive growth of glioblastoma.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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.

Show MeSH

Related in: MedlinePlus

Plexin-B2 expression in glioma correlates with survivalA) Representative images of DAB immunolabeling for Plexin-B2 in normal brain and glioma tissues (n=69). Bar graph summarizes scored signal intensities in different glioma samples (“low” refers to Plexin-B2 immunointensity as found in normal brain). Scale bar: 20 μm. B) Kaplan-Meier survival curves of NCI/Rembrandt glioma patient cohorts. Upregulated Plexin-B2 expression (>2-fold of average normal brain) corresponded with shorter survival time of all glioma patients combined (p<10−4, see Table S1 for details). Upregulated Plexin-B2 expression correlated with shorter survival in astrocytoma patients (p<10−2), and to a lesser degree in oligodendroglioma and glioblastoma patients.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4466685&req=5

Figure 2: Plexin-B2 expression in glioma correlates with survivalA) Representative images of DAB immunolabeling for Plexin-B2 in normal brain and glioma tissues (n=69). Bar graph summarizes scored signal intensities in different glioma samples (“low” refers to Plexin-B2 immunointensity as found in normal brain). Scale bar: 20 μm. B) Kaplan-Meier survival curves of NCI/Rembrandt glioma patient cohorts. Upregulated Plexin-B2 expression (>2-fold of average normal brain) corresponded with shorter survival time of all glioma patients combined (p<10−4, see Table S1 for details). Upregulated Plexin-B2 expression correlated with shorter survival in astrocytoma patients (p<10−2), and to a lesser degree in oligodendroglioma and glioblastoma patients.

Mentions: We next examined Plexin-B2 protein expression by immunohistochemistry on human glioma tissue microarray cores. Using normal brain tissue as a baseline reference, we found elevated Plexin-B2 protein expression in the vast majority of the examined glioma specimens (Fig. 2A).


Plexin-B2 promotes invasive growth of malignant glioma.

Le AP, Huang Y, Pingle SC, Kesari S, Wang H, Yong RL, Zou H, Friedel RH - Oncotarget (2015)

Plexin-B2 expression in glioma correlates with survivalA) Representative images of DAB immunolabeling for Plexin-B2 in normal brain and glioma tissues (n=69). Bar graph summarizes scored signal intensities in different glioma samples (“low” refers to Plexin-B2 immunointensity as found in normal brain). Scale bar: 20 μm. B) Kaplan-Meier survival curves of NCI/Rembrandt glioma patient cohorts. Upregulated Plexin-B2 expression (>2-fold of average normal brain) corresponded with shorter survival time of all glioma patients combined (p<10−4, see Table S1 for details). Upregulated Plexin-B2 expression correlated with shorter survival in astrocytoma patients (p<10−2), and to a lesser degree in oligodendroglioma and glioblastoma patients.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466685&req=5

Figure 2: Plexin-B2 expression in glioma correlates with survivalA) Representative images of DAB immunolabeling for Plexin-B2 in normal brain and glioma tissues (n=69). Bar graph summarizes scored signal intensities in different glioma samples (“low” refers to Plexin-B2 immunointensity as found in normal brain). Scale bar: 20 μm. B) Kaplan-Meier survival curves of NCI/Rembrandt glioma patient cohorts. Upregulated Plexin-B2 expression (>2-fold of average normal brain) corresponded with shorter survival time of all glioma patients combined (p<10−4, see Table S1 for details). Upregulated Plexin-B2 expression correlated with shorter survival in astrocytoma patients (p<10−2), and to a lesser degree in oligodendroglioma and glioblastoma patients.
Mentions: We next examined Plexin-B2 protein expression by immunohistochemistry on human glioma tissue microarray cores. Using normal brain tissue as a baseline reference, we found elevated Plexin-B2 protein expression in the vast majority of the examined glioma specimens (Fig. 2A).

Bottom Line: This proinvasive effect was associated with activation of the cell motility mediators RhoA and Rac1.In intracranial glioblastoma transplants, Plexin-B2 knockdown hindered invasive growth and perivascular spreading, and resulted in decreased tumor vascularity.Targeting the Plexin-B2 pathway may represent a novel therapeutic approach to curtail invasive growth of glioblastoma.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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.

Show MeSH
Related in: MedlinePlus