Brain neurovascular unit in response to intra- and extra-central nervous system cancers: implications, mechanisms, and challenges

The neurovascular unit (NVU) plays an important role in maintaining central nervous system (CNS) homeostasis by the dynamic control of the blood-brain barrier (BBB). An increasing amount of evidence indicates that endogenous and exogenous brain tumors can disrupt NVU integrity and function, promoting tumor progression from the brain to the blood side and vice versa. Endogenous CNS tumors promote substantial BBB remodeling through enhanced angiogenesis, tight-junction rearrangements, matrix metalloproteinase activation, and inflammatory mechanisms. In contrast, exogenous brain tumors can hijack the endothelial adhesion molecules and chemokines crossing barriers to the BBB and create a functionally variable blood-tumor barrier (BTB). The resulting microenvironment that presents significant obstacles to delivery is characterized by increased permeability, abnormal vasculature, and retained efflux transporter functionalities. This review summarizes the current understanding of NVU responses to endogenous and exogenous brain tumors, highlighting molecular mechanisms, regional heterogeneity, and translational challenges. We emphasize emerging therapeutic techniques, from transcytotic targeting to nanocarrier systems, that are currently being developed, which circumvent or modify dysfunctional barriers. Insights into induced NVU remodeling over space and time also present new ways for advancing diagnosis, improving drug delivery, and ultimately, patient outcomes in neuro-oncology.