title: Crosstalk between glioma-initiating cells and endothelial cells drives tumor progression.
abstract: Glioma-initiating cells (GIC), which reside within the perivascular microenvironment to maintain self-renewal capacity, are responsible for glioblastoma initiation, progression, and recurrence. However, the molecular mechanisms controlling crosstalk between GICs and endothelial cells are poorly understood. Here, we report that, in both GICs and endothelial cells, platelet-derived growth factor (PDGF)-driven activation of nitric oxide (NO) synthase increases NO-dependent inhibitor of differentiation 4 (ID4) expression, which in turn promotes JAGGED1-NOTCH activity through suppression of miR129 that specifically represses JAGGED1 suppression. This signaling axis promotes tumor progression along with increased GIC self-renewal and growth of tumor vasculature in the xenograft tumors, which is dramatically suppressed by NOTCH inhibitor. ID4 levels correlate positively with NOS2 (NO synthase-2), HES1, and HEY1 and negatively with miR129 in primary GICs. Thus, targeting the PDGF-NOS-ID4-miR129 axis and NOTCH activity in the perivascular microenvironment might serve as an efficacious therapeutic modality for glioblastoma.
authors: School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea. Institute of Life Science and Natural Resources, Korea University, Seoul, Republic of Korea.
authors: Hye-Min
authors: HM
authors: Jeon
authors: Institute of Life Science and Natural Resources, Korea University, Seoul, Republic of Korea. Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors: Sung-Hak
authors: SH
authors: Kim
authors: School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
authors: Xun
authors: X
authors: Jin
authors: Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea.
authors: Jong Bae
authors: JB
authors: Park
authors: Department of Pathology, Yonsei University of School of Medicine, Seoul, Republic of Korea.
authors: Se Hoon
authors: SH
authors: Kim
authors: Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors: Kaushal
authors: K
authors: Joshi
authors: Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors: Ichiro
authors: I
authors: Nakano
authors: School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea. Institute of Life Science and Natural Resources, Korea University, Seoul, Republic of Korea. hg-kim@korea.ac.kr.
authors: Hyunggee
authors: H
authors: Kim
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction