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

Publication date: 2 November 2017
Source:Cell Stem Cell, Volume 21, Issue 5
Author(s): Wenchao Zhou, Cong Chen, Yu Shi, Qiulian Wu, Ryan C. Gimple, Xiaoguang Fang, Zhi Huang, Kui Zhai, Susan Q. Ke, Yi-Fang Ping, Hua Feng, Jeremy N. Rich, Jennifer S. Yu, Shideng Bao, Xiu-Wu Bian
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.

Graphical abstract

Teaser

The blood-brain barrier (BBB) blocks entry of harmful materials into normal brains, but the blood-tumor barrier (BTB) prevents anti-cancer drugs from penetrating GBM tumors. Targeting GSC-derived neoplastic pericytes selectively disrupted the BTB, but not BBB, and potently enhanced drug delivery to effectively improve GBM treatment.


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