Abstract
Enhanced platelet-derived growth factor (PDGF) signaling in glioma drives its development and progression. In this study, we define a unique role for stroma-derived PDGF signaling in maintaining tumor homeostasis within the glioma microenvironment. Large numbers of PDGF receptor-α (PDGFRα)-expressing stromal cells derived from oligodendrocytes progenitor cells (OPC) were discovered at the invasive front of high-grade gliomas, in which they exhibited a unique perivascular distribution. In PDGFRα-deficient host mice, in which orthotopic Gl261 tumors displayed reduced outgrowth, we found that tumor-associated blood vessels displayed smaller lumens and normalized vascular morphology, with tumors in host animals injected with the vascular imaging agent gadolinium also being enhanced less avidly by MRI. Notably, glioma-associated OPC promoted endothelial sprouting and tubule formation, in part by abrogating the inhibitory effect that perivascular astrocytes exert on vascular endothelial conjunctions. Stromal-derived PDGF-CC was crucial for the recruitment and activation of OPC, insofar as mice genetically deficient in PDGF-CC phenocopied the glioma/vascular defects observed in PDGFRα-deficient mice. Clinically, we showed that higher levels of PDGF-CC in glioma specimens were associated with more rapid disease recurrence and poorer overall survival. Our findings define a PDGFRα/PDGF-CC signaling axis within the glioma stromal microenvironment that contributes to vascular remodeling and aberrant tumor angiogenesis in the brain.
Highlights
The tumor microenvironment is a complex amalgam of tumor cells, intermingling parenchymal cells, infiltrating immune system cells, and a vascular network of endothelial cells, which in concert determine the pathologic and biological features of distinct tumors
To better understand the temporal and spatial variation within the glioma microenvironment of PDGF receptor-a (PDGFRa)-expressing cells and inflammatory bone marrow–derived cells (BMDC), PDGFRa staining was performed on orthotopic Gl261 tumors in mice, which had previously been adoptively transplanted with GFP bone marrow
We demonstrated that most PDGFRaþ cells, located in the invasive front, were nontumor cells
Summary
The tumor microenvironment is a complex amalgam of tumor cells, intermingling parenchymal cells, infiltrating immune system cells, and a vascular network of endothelial cells, which in concert determine the pathologic and biological features of distinct tumors. Cancer diagnoses and grades significantly vary the composition of the tumor microenvironment [1,2,3]. Malignances arising from glial cells within the central nervous system (CNS), harbor multiple cell types in addition to cells with tumorigenicity. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Comparatively little is known about the composition, features, and functions of nontransformed glial cells and neural progenitor cells within the natural progression of glioma
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