The blood-brain barrier (BBB) excludes the vast majority of cancer therapeutics from normal brain. However, the importance of the BBB in limiting drug delivery and efficacy is controversial in high-grade brain tumors, such as glioblastoma (GBM). The accumulation of normally brain impenetrant radiographic contrast material in essentially all GBM has popularized a belief that the BBB is uniformly disrupted in all GBM patients so that consideration of drug distribution across the BBB is not relevant in designing therapies for GBM. However, contrary to this view, overwhelming clinical evidence demonstrates that there is also a clinically significant tumor burden with an intact BBB in all GBM, and there is little doubt that drugs with poor BBB permeability do not provide therapeutically effective drug exposures to this fraction of tumor cells. This review provides an overview of the clinical literature to support a central hypothesis: that all GBM patients have tumor regions with an intact BBB, and cure for GBM will only be possible if these regions of tumor are adequately treated.

Gliomas are uniformly fatal forms of primary brain neoplasms that vary from low-grade to high-grade (glioblastoma). While low-grade gliomas are weakly angiogenic, glioblastomas are among the most angiogenic of tumors. Thus, interactions between glioma cells and their tissue microenvironment may play an important role in aggressive tumor formation and progression. To quantitatively explore how tumor cells interact with their tissue microenvironment, we incorporated the interactions of normoxic glioma cells, hypoxic glioma cells, vascular endothelial cells, diffusible angiogenic factors, and necrosis formation into a first-generation, biologically-based mathematical model for glioma growth and invasion. Model simulations quantitatively described the spectrum of in vivo dynamics of gliomas visualized with medical imaging. Further, we investigated how proliferation and dispersal of glioma cells combine to induce increasing degrees of cellularity, mitoses, hypoxia-induced neo-angiogenesis and necrosis, features that characterize increasing degrees of “malignancy”, and we found that changes in the net rates of proliferation ({lower case rho}) and invasion (D) are not always necessary for malignant progression. Thus, although other factors, including the accumulation of genetic mutations, can change cellular phenotype (e.g. proliferation and invasion rates), this study suggests that these are not required for malignant progression. Simulated results are placed in the context of the current clinical World Health Organization grading scheme for studying specific patient examples. This study suggests that through the application of the proposed model for tumor-microenvironment interactions, predictable patterns of dynamic changes in glioma histology distinct from changes in cellular phenotype (e.g. proliferation and invasion rates) may be identified, thus providing a powerful clinical tool.