Glioma-Derived Platelet-Derived Growth Factor-BB Recruits Oligodendrocyte Progenitor Cells via Platelet-Derived Growth Factor Receptor-α and Remodels Cancer Stroma

• Published in: The American journal of pathology Vol. 186; no. 5; pp. 1081 - 1091
• Main Authors: Zheng, Yang, Yamamoto, Seiji, Ishii, Yoko, Sang, Yang, Hamashima, Takeru, Van De, Nguyen, Nishizono, Hirofumi, Inoue, Ran, Mori, Hisashi, Sasahara, Masakiyo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2016
• Subjects: Animals; Antineoplastic Agents, Hormonal - pharmacology; Brain Neoplasms - drug therapy; Brain Neoplasms - pathology; Capillary Permeability - physiology; Cell Line, Tumor; Cerebral Hemorrhage - etiology; Collagen - physiology; Female; Gene Knockout Techniques; Genetic Vectors; Glioblastoma - drug therapy; Glioblastoma - pathology; Male; Mice, Inbred C57BL; Mice, Knockout; Neoplasm Transplantation; Oligodendroglia - physiology; Pathology; Phenotype; Proto-Oncogene Proteins c-sis - physiology; Stem Cells - physiology; Tamoxifen - pharmacology; Transfection; Tumor Burden
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2015.12.020

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.