Abstract
Glioblastoma multiforme (GBM) is the most common brain tumor in adults. It presents an extremely challenging clinical problem, and treatment very frequently fails due to the infiltrative growth, facilitated by extensive angiogenesis and neovascularization. Pericytes constitute an important part of the GBM microvasculature. The contribution of endogenous brain pericytes to the tumor vasculature in GBM is, however, unclear. In this study, we determine the site of activation and the extent of contribution of endogenous brain pericytes to the GBM vasculature. GL261 mouse glioma was orthotopically implanted in mice expressing green fluorescent protein (GFP) under the pericyte marker regulator of G protein signaling 5 (RGS5). Host pericytes were not only activated within the glioma, but also in cortical areas overlying the tumor, the ipsilateral subventricular zone and within the hemisphere contralateral to the tumor. The host-derived activated pericytes that infiltrated the glioma were mainly localized to the tumor vessel wall. Infiltrating GFP positive pericytes co-expressed the pericyte markers platelet-derived growth factor receptor-β (PDGFR-β) and neuron-glial antigen 2. Interestingly, more than half of all PDGFR-β positive pericytes within the tumor were contributed by the host brain. We did not find any evidence that RGS5 positive pericytes adopt another phenotype within glioma in this paradigm. We conclude that endogenous pericytes become activated in widespread areas of the brain in response to an orthotopic mouse glioma. Host pericytes are recruited into the tumor and constitute a major part of the tumor pericyte population.
Highlights
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults, with a median survival of only 14.6 months even when all available treatment is givenPLOS ONE | DOI:10.1371/journal.pone.0123553 April 13, 2015Activated Brain Pericytes Contribute to Mouse Glioma Vasculature funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
green fluorescent protein (GFP) positive pericytes show a flat morphology with a small cell body indicating a quiescent state (Fig 1A and 1B)
The number of activated GFP positive pericytes was significantly increased within the contralateral hemisphere of tumor-bearing rgs5GFP/+ mice, indicating a widespread activation of perivascular cells (Fig 1C, 1F)
Summary
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults, with a median survival of only 14.6 months even when all available treatment is given. Activated Brain Pericytes Contribute to Mouse Glioma Vasculature funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. An important cellular component of the GBM vasculature is the pericytes. Tumor pericytes mediate immunosuppression [3] and promote endothelial cell survival [4,5], facilitating tumor growth. Whether brain-derived pericytes contribute to the tumor vasculature is not known. We investigate the contribution of normal brain pericytes to GBM vasculature using an orthotopic mouse glioma model. We implanted GL261 mouse glioma cells [16,17] into these mice and show that endogenous pericytes are activated in widespread areas of the brain, recruited into established intracerebral GL261 gliomas and integrate with the tumor vessels. Quantification revealed that more than half of all platelet-derived growth factor receptor-β (PDGFR-β) positive pericytes within the glioma are host brain-derived
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