Format

Send to

Choose Destination
Cell Stem Cell. 2017 Nov 2;21(5):591-603.e4. doi: 10.1016/j.stem.2017.10.002.

Targeting Glioma Stem Cell-Derived Pericytes Disrupts the Blood-Tumor Barrier and Improves Chemotherapeutic Efficacy.

Author information

1
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
2
Institute of Pathology and Southwest Cancer Center, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China.
3
Department of Neurosurgery, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China.
4
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
5
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH 44195, USA.
6
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Electronic address: baos@ccf.org.
7
Institute of Pathology and Southwest Cancer Center, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China. Electronic address: bianxiuwu@263.net.

Abstract

The blood-tumor barrier (BTB) is a major obstacle for drug delivery to malignant brain tumors such as glioblastoma (GBM). Disrupting the BTB is therefore highly desirable but complicated by the need to maintain the normal blood-brain barrier (BBB). Here we show that targeting glioma stem cell (GSC)-derived pericytes specifically disrupts the BTB and enhances drug effusion into brain tumors. We found that pericyte coverage of tumor vasculature is inversely correlated with GBM patient survival after chemotherapy. Eliminating GSC-derived pericytes in xenograft models disrupted BTB tight junctions and increased vascular permeability. We identified BMX as an essential factor for maintaining GSC-derived pericytes. Inhibiting BMX with ibrutinib selectively targeted neoplastic pericytes and disrupted the BTB, but not the BBB, thereby increasing drug effusion into established tumors and enhancing the chemotherapeutic efficacy of drugs with poor BTB penetration. These findings highlight the clinical potential of targeting neoplastic pericytes to significantly improve treatment of brain tumors.

KEYWORDS:

BMX; blood-brain barrier (BBB); blood-tumor barrier (BTB); glioma stem cells; ibrutinib; pericytes

PMID:
29100012
PMCID:
PMC5687837
DOI:
10.1016/j.stem.2017.10.002
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center