PDF - 9162K, Supplementary Methods: Including additional materials and methods Supplementary References: Including reference cited in the supplementary methods Supplementary Figures and Legends: S1. expression of stromal PDGFRalpha in various animal models. S2. Lineage and distribution of stromal PDGFRalpha+ cells. S3. Blood vessel density and pericytes in Gl261 glioma model. S4. Knocking out PDGFRalpha suppresses infiltration of BMDCs without affecting hematopoiesis. S5. Isolation and verification of OPCs from glioma S6. Endothelial tubule formation, endothelial sprouting, and permeability with GA-OPCs and astrocytes. S7. Proliferation of glioma cells with or without activated endothelial cells S8. Microarray analysis on GFP+/F4/80+ BMDCs S9. Hematopoiesis in PDGF-C -/- mice. S10. Astrocytes and endothelial cells express PDGF-C & pro-angiogenic profile of OPCs. S11. Blood vessel staining of grade III Patients S12. Expression of PDGF-C was analyzed in REMBRANDT database. S13. the correlation of PDGF-C with paitents' survial in Mesenchymal, Neural, Pro-neural subsets of GBM. S14. The correlation of PDGF-A and PDGF-B with paitent's survial in classical subset of GBM.
ARTICLE 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. Cancer Res; 74(4); 1011–21. ©2013 AACR.
