Interestingly, in GBM tumors, the majority of vascular pericytes are derived from glioma stem cells (GSCs) through trans-differentiation ( Cheng et al., 2013). Consistent with the essential functions of pericytes in maintaining the BBB, loss of pericytes has been observed in brain disorders including Alzheimer’s disease and ischemia, which is believed to exacerbate the diseases ( Hall et al., 2014 Sagare et al., 2013). Pericyte depletion disrupted the BBB and elevated vascular permeability in Pdgfb knock-out mice ( Armulik et al., 2010 Daneman et al., 2010). Vascular pericytes that attach on endothelial cells play a pivotal role in maintaining the BBB. These facts suggest a possibility to selectively disrupt the BTB in the tumor without affecting the BBB in normal brain tissue, which will enhance delivery of the poor BTB-penetrating but potent anti-cancer drugs into brain tumors to improve chemotherapy efficacy but limit the unwanted toxicity to the normal brain. In addition, the perivascular components such as astrocytic end-feet on tumor vessels are altered ( Watkins et al., 2014). These tumor vessels may have aberrant expression of transcytotic proteins ( Strickland et al., 2005).
The BTB is formed by highly proliferative, morphologically abnormal tumor capillaries ( Pries et al., 2010 Verbeek et al., 1994). Despite their similarities, the BBB and BTB differ from many aspects. Besides, molecular effusion through endothelial cells is actively regulated by transcytosis, the vesicular transport of macromolecules across cells ( Shue et al., 2008 Zhao et al., 2015). The BBB and BTB are composed of several components including tight junctions, vessel basement membrane, and astrocyte end-feet that cover endothelial cells to form a physical barrier ( Watkins et al., 2014 Yao et al., 2014). Thus, it is crucial to selectively disrupt the BTB in GBM tumors while sparing the BBB in normal brain tissues during chemotherapy. However, as the BBB serves as an indispensable vascular barrier to protect normal brain by blocking entry of harmful materials ( Bergers and Song, 2005), abnormal breakdown of the BBB could result in neuronal degenerative changes or diseases ( Bell et al., 2010). Thus, breaking the BTB or BBB will significantly impact GBM treatment. The BTB and BBB exclude most compounds except highly lipidized small molecules of less than 400 daltons, rendering potentially powerful anti-cancer drugs impotent for GBM treatment ( Pardridge, 2002). As a filtering barrier of capillaries, the BTB and the blood-brain barrier (BBB) prevent most anti-cancer agents from penetrating GBM tumors and limit therapeutic efficacy ( Fellner et al., 2002 Neuwelt et al., 1986). This striking failure could be ascribed to multiple factors, but the blood-tumor barrier (BTB) represents a formidable obstacle. Despite a significant advance in cancer treatment, there has been little improvement in the prognosis of GBM patients over decades ( Chinot et al., 2014 McNamara et al., 2014). Glioblastoma (GBM) is a highly lethal brain tumor resistant to current therapies. These findings highlight the clinical potential of targeting neoplastic pericytes to significantly enhance treatment of brain tumors.
Inhibiting BMX with ibrutinib selectively targeted neoplastic pericytes and disrupts the BTB, but not the BBB, thereby increasing drug effusion into established tumors and enhancing chemotherapeutic efficacy of drugs with poor BTB penetration. We identified BMX as an essential factor for maintaining GSC-derived pericytes. Eliminating GSC-derived pericytes in xenograft models disrupted BTB tight junctions and increased vascular permeability.
We found that pericyte coverage of tumor vasculature is inversely correlated with GBM patient survival after chemotherapy. Here, we show that targeting glioma stem cell (GSC)-derived pericytes specifically disrupts the BTB and enhances drug effusion into brain tumors. Disrupting the BTB is therefore highly desirable, but complicated by the need to maintain the normal blood-brain barrier (BBB). The blood-tumor barrier (BTB) is a major obstacle for drug delivery to malignant brain tumors such as glioblastoma.