title: Glioma-Derived Platelet-Derived Growth Factor-BB Recruits Oligodendrocyte Progenitor Cells via Platelet-Derived Growth Factor Receptor-α and Remodels Cancer Stroma.
abstract: Glioma is an aggressive and incurable disease, and is frequently accompanied by augmented platelet-derived growth factor (PDGF) signaling. Overexpression of PDGF-B ligand characterizes a specific subclass of glioblastoma multiforme, but the significance of the ligand remains to be elucidated. For this end, we implanted a glioma-cell line transfected with PDGF-BB-overexpressing vector (GL261-PDGF-BB) or control vector (GL261-vector) into wild-type mouse brain, and examined the effect of glioma-derived PDGF on the tumor microenvironment. The volume of GL261-PDGF-BB rapidly increased compared with GL261-vector. Recruitment of many PDGF receptor (PDGFR)-α and Olig2-positive oligodendrocyte precursor cells and frequent hemorrhages were observed in GL261-PDGF-BB but not in GL261-vector. We then implanted GL261-PDGF-BB into the mouse brain with and without Pdgfra gene inactivation, corresponding to PDGFRα-knockout (KO) and Flox mice, respectively. The recruitment of oligodendrocyte precursor cells was largely suppressed in PDGFRα-KO than in Flox, whereas the volume of GL261-PDGF-BB was comparable between the two genotypes. Frequent hemorrhage and increased IgG-leakage were associated with aberrant vascular structures within the area where many recruited oligodendrocyte precursor cells accumulated in Flox. In contrast, these vascular phenotypes were largely normalized in PDGFRα-KO. Increased matrix metalloproteinase-9 in recruited oligodendrocyte precursor cells and decreased claudin-5 in vasculature may underlie the vascular abnormality. Glioma-derived PDGF-B signal induces cancer stroma characteristically seen in high-grade glioma, and should be therapeutically targeted to improve cancer microenvironment.
authors.affiliation: Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. Electronic address: yishii@med.u-toyama.ac.jp.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sang
authors.affiliation: Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Hamashima
authors.affiliation: Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Nguyen
authors.initials: N
authors.lastname: Van De
authors.affiliation: Division of Animal Experimental Laboratory, Life Science Research Center, University of Toyama, Toyama, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Nishizono
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Ran
authors.initials: R
authors.lastname: Inoue
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Mori
authors.affiliation: Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sasahara
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002199:Capillary Permeability / Q000502:physiology; D045744:Cell Line, Tumor; D002543:Cerebral Hemorrhage / Q000209:etiology; D003094:Collagen / Q000502:physiology; D005260:Female; D055786:Gene Knockout Techniques; D005822:Genetic Vectors; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009836:Oligodendroglia / Q000502:physiology*; D010641:Phenotype; D020574:Proto-Oncogene Proteins c-sis / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology; D014162:Transfection; D047368:Tumor Burden
chemical_list: D018931:Antineoplastic Agents, Hormonal; D020574:Proto-Oncogene Proteins c-sis; D013629:Tamoxifen; D003094:Collagen