Gliomas and the vascular fragility of the blood brain barrier

Abstract

Astrocytes, members of the glial family, interact through the exchange of soluble factors or by directly contacting neurons and other brain cells, such as microglia and endothelial cells. Astrocytic projections interact with vessels and act as additional elements of the Blood Brain Barrier (BBB). By mechanisms not fully understood, astrocytes can undergo oncogenic transformation and give rise to gliomas. The tumors take advantage of the BBB to ensure survival and continuous growth. A glioma can develop into a very aggressive tumor, the glioblastoma (GBM), characterized by a highly heterogeneous cell population (including tumor stem cells), extensive proliferation and migration. Nevertheless, gliomas can also give rise to slow growing tumors and in both cases, the afflux of blood, via BBB is crucial. Glioma cells migrate to different regions of the brain guided by the extension of blood vessels, colonizing the healthy adjacent tissue. In the clinical context, GBM can lead to tumor-derived seizures, which represent a challenge to patients and clinicians, since drugs used for its treatment must be able to cross the BBB. Uncontrolled and fast growth also leads to the disruption of the chimeric and fragile vessels in the tumor mass resulting in peritumoral edema. Although hormonal therapy is currently used to control the edema, it is not always efficient. In this review we comment the points cited above, considering the importance of the BBB and the concerns that arise when this barrier is affected.

Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy

“…A previous study from our lab showed that antibodies successfully cross the blood-brain barrier (BBB) and penetrate into the TME; the loss of BBB integrity associated with GBM growth may further support this process. [59][60][61][62][63] A preliminary analysis of Gr-1 antibody-treated mice showed that the efficacy of depletion lasted for approximately 4 days. Therefore, to ensure the maintenance of TK/Flt3L-induced tumor-specific T cell proliferation, we administered the antibody so that MDSCs would be eliminated from the GBM TME around the peak of the T cell response, which occurs 7 days after the administration of gene therapy.…”

NLRC5/MHC class I transactivator is a target for immune evasion in cancer

“…Although the exact mechanism is uncertain, this effect might be caused by the unique anatomy of brain. Because brain mass is limited by the skull, unlike other cancers, one major life-threatening complications of brain tumors is the development of brain edema, which is associated with inflammatory events including impaired blood-brain barrier and destruction of normal brain tissues (31,32). In fact, patients with brain tumors are commonly treated with anti-inflammatory drugs such as corticosteroids (32,33).…”

“…Because brain mass is limited by the skull, unlike other cancers, one major life-threatening complications of brain tumors is the development of brain edema, which is associated with inflammatory events including impaired blood-brain barrier and destruction of normal brain tissues (31,32). In fact, patients with brain tumors are commonly treated with anti-inflammatory drugs such as corticosteroids (32,33). Taken together, these findings show that NLRC5 expression is correlated with higher survival in multiple cancer types, with the exception of brain cancer, in which it appears to be a negative prognostic factor.…”

Aptamer for imaging and therapeutic targeting of brain tumor glioblastoma

“…It consists of endothelial cells united by tight junctions, astrocytic end-feets surrounding blood vessels, pericytes embedded in he vessel basement membranes (BMs), microglia and neurons, all playing essential roles in CNS homeostasis (39). However, the real interactions of the endothelial cells with the extra-endothelial components of the brain microenvironment remain unclear.…”