title: Oligodendrocyte progenitor cells promote neovascularization in glioma by disrupting the blood-brain barrier.
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.
authors.affiliation: Authors' Affiliations: Department of Neurological Surgery, The Childhood Brain Tumor Project; Department of Pediatrics; Division of Hematology-Medical Oncology; Pediatric Brain Tumor Research, Children's Cancer and Blood Foundation Laboratories, Weill Cornell Medical College; Departments of Pathology and Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; and National Eye Institute, NIH, Bethesda, Maryland.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Huang
authors.forename: Caitlin
authors.initials: C
authors.lastname: Hoffman
authors.forename: Prajwal
authors.initials: P
authors.lastname: Rajappa
authors.forename: Joon-Hyung
authors.initials: JH
authors.lastname: Kim
authors.forename: Wenhuo
authors.initials: W
authors.lastname: Hu
authors.forename: Jason
authors.initials: J
authors.lastname: Huse
authors.forename: Zhongshu
authors.initials: Z
authors.lastname: Tang
authors.forename: Xuri
authors.initials: X
authors.lastname: Li
authors.forename: Babette
authors.initials: B
authors.lastname: Weksler
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Bromberg
authors.forename: David C
authors.initials: DC
authors.lastname: Lyden
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Greenfield
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology*; D001932:Brain Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D002199:Capillary Permeability / Q000502:physiology; D018450:Disease Progression; D005910:Glioma / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D008222:Lymphokines / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000473:pathology*; D009836:Oligodendroglia / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000473:pathology*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; C411423:platelet-derived growth factor C; D020796:Receptor, Platelet-Derived Growth Factor alpha