Disruption of astrocyte–vascular coupling and the blood–brain barrier by invading glioma cells

Abstract

Astrocytic endfeet cover the entire cerebral vasculature and serve as exchange sites for ions, metabolites, and energy substrates from the blood to the brain. They maintain endothelial tight junctions that form the blood-brain barrier (BBB) and release vasoactive molecules that regulate vascular tone. Malignant gliomas are highly invasive tumors that use the perivascular space for invasion and co-opt existing vessels as satellite tumors form. Here we use a clinically relevant mouse model of glioma and find that glioma cells, as they populate the perivascular space of pre-existing vessels, displace astrocytic endfeet from endothelial or vascular smooth muscle cells. This causes a focal breach in the BBB. Furthermore, astrocyte-mediated gliovascular coupling is lost, and glioma cells seize control over regulation of vascular tone through Ca2+-dependent release of K+. These findings have important clinical implications regarding blood flow in the tumor-associated brain and the ability to locally deliver chemotherapeutic drugs in disease.

A frightening thought: Neuronal activity enhances tumor growth

“…However, the paper expands on a recent argument that gliomas must be examined from a more "neurocentric" perspective -in the context of the many interactions of the tumor with the surrounding brain tissue rather than merely a cancerous growth within the skull [7]. This realization is also supported by studies suggesting that glioma is a neurodegenerative disease [8,9]. Progressively exerting its detrimental function by disrupting the barrier function of endothelial cells, digesting the extracellular matrix, and releasing the neuronal excitatory neurotransmitter glutamate, causes seizures and neuronal cell death [8,9].…”

“…This realization is also supported by studies suggesting that glioma is a neurodegenerative disease [8,9]. Progressively exerting its detrimental function by disrupting the barrier function of endothelial cells, digesting the extracellular matrix, and releasing the neuronal excitatory neurotransmitter glutamate, causes seizures and neuronal cell death [8,9]. Understanding the molecular signals between all the involved cell types in the brain may allow us to gain a more holistic perspective of this devastating disease.…”

A review of potential applications of MR-guided focused ultrasound for targeting brain tumor therapy

“…32 As the tumors grow, astrocyte foot processes are displaced from blood vessels by malignant cells, leading to perpetual fenestration of the BBB. 58 Although the level of disruption often remains subtherapeutic, BTB-targeted drug delivery holds promise for effective treatment of brain tumors through increased permeability. therapeutic threshold concentration but must remain at a low concentration peripherally and within normal brain to limit side effects.…”

Local Glioma Cells Are Associated with Vascular Dysregulation

“…1 Most prominent among these is a breakdown of the blood-brain barrier, associated with the main tumor mass [1][2][3] and clinically evident through the extravasation of gadolinium-conjugated contrast media. 4 However, other vascular deficits are identifiable in the infiltrative margin of the tumor.…”