Addressing blood-brain-tumor-barrier heterogeneity in pediatric brain tumors with innovative preclinical models

Abstract

Brain tumors represent the leading cause of disease-related mortality and morbidity in children, with effective treatments urgently required. One factor limiting the effectiveness of systemic therapy is the blood-brain-barrier (BBB), which limits the brain penetration of many anticancer drugs. BBB integrity is often compromised in tumors, referred to as the blood-brain-tumor-barrier (BBTB), and the impact of a compromised BBTB on the therapeutic sensitivity of brain tumors has been clearly shown for a few selected agents. However, the heterogeneity of barrier alteration observed within a single tumor and across distinct pediatric tumor types represents an additional challenge. Herein, we discuss what is known regarding the heterogeneity of tumor-associated vasculature in pediatric brain tumors. We discuss innovative and complementary preclinical model systems that will facilitate real-time functional analyses of BBTB for all pediatric brain tumor types. We believe a broader use of these preclinical models will enable us to develop a greater understanding of the processes underlying tumor-associated vasculature formation and ultimately more efficacious treatment options.

Automated Capture and Analysis of Circulating Tumor Cells in Pediatric, Adolescent and Young Adult Patients with Central Nervous System Tumors

“…Historically, these tumors have a very low rate of neural metastases of only 10% and very rarely disseminate extraneurally. Additionally, the relatively lower incidence of CTCs in this population compared to other CNS tumors may be due to the origin of the primary tumor itself, which is situated in the glial cells of the brainstem, as well as the heterogenous nature of the blood-brain barrier and its increased permeability in other tumors versus patients with diffuse midline gliomas [41]. Furthermore, 34.5% of all patients in this study were receiving corticosteroids at the time of collection which is known to have anti-inflammatory effects and decrease the permeability of the blood-brain barrier, potentially decreasing the migration of CTCs into the peripheral blood [42].…”

HSP60 chaperone deficiency disrupts the mitochondrial matrix proteome and dysregulates cholesterol synthesis

“…However, once the blood-brain barrier is established, cholesterol for myelination must be synthesized locally in the CNS by astrocytes 19 . In humans, this occurs around birth, and in zebrafish, the blood-brain barrier begins to form at around 3 dpf and is fully functional at 10 dpf 50 . Cholesterol availability from the yolk is the likely reason why we did not observe severe myelination phenotypes in zebrafish embryos by 8 dpf.…”

Non-cellular immunotherapies in pediatric central nervous system tumors

“…pHGG models showed slightly decreased expression of Glut1 and increased and more disorganized expression of Cldn5, while the DMG vasculature was far similar to the expression patterns of these proteins in normal brain vasculature. In a review by Morris, et al (50), similar differences in expression patterns were noted across different subtypes of medulloblastoma including wingless (WNT), sonic hedgehog (SHH), and group 3. The heterogeneity of the TME, BBB, and BBTB when compared to pediatric versus adult tumors, and the variability across different pediatric tumor types, could help to explain why some CNS tumors respond better than others to various types of immune therapies, both in the pediatric arena and when compared to adult tumors (40-46).…”