Patient-derived orthotopic xenograft models of medulloblastoma lack a functional blood-brain barrier

Abstract

Background Novel targeted therapies for children diagnosed with medulloblastoma (MB), the most common malignant pediatric brain tumor, are urgently required. A major hurdle in the development of effective therapies is the impaired delivery of systemic therapies to tumor cells due to a specialized endothelial blood-brain barrier (BBB). Accordingly, the integrity of the BBB is an essential consideration in any preclinical model used for assessing novel therapeutics. This study sought to assess the functional integrity of the BBB in several preclinical mouse models of MB. Methods Dynamic contrast enhancement (DCE) magnetic resonance imaging (MRI) was used to evaluate blood-brain tumour-barrier (BBTB) permeability in a murine genetically engineered mouse model (GEMM) of SHH MB, patient-derived orthotopic xenograft (PDOX) models of MB (SHH and Gp3) and orthotopic transplantation of GEMM tumor cells, enabling a comparison of the direct effects of transplantation on the integrity of the BBTB. Immunofluorescence analysis was performed to compare the structural and sub-cellular features of tumor-associated vasculature in all models. Results Contrast enhancement was observed in all transplantation models of MB. No contrast enhancement was observed in the GEMM despite significant tumor burden. Cellular analysis of BBTB integrity revealed aberrancies in all transplantation models, correlating to the varying levels of BBTB permeability observed by MRI in these models. Conclusions These results highlight functional differences in the integrity of the BBTB and tumor vessel phenotype between commonly utilised preclinical models of MB, with important implications for the preclinical evaluation of novel therapeutic agents for MB.

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

“…The invasive front of SHH PDOX tumors displayed minimal contrast enhancement, indicating clear differences in vascular integrity where tumor tissue meets the brain parenchyma. A completely intact functional BBTB was observed in SHH MB tumors initiated in an independent GEMMs despite significant tumor burden (39,50), consistent with findings from an additional GEMM model of SHH MB (50). Together, these findings indicate that distinct biological processes govern tumor vascularization in tumors that initiate endogenously (GEMM tumors) compared to ectopic tumor cell engraftment in an adult host mouse.…”

“…Studies over the past decade have highlighted that not all pediatric brain tumors alter BBTB similarly. Instead, BBTB function is heterogenous between tumor types as well as within individual tumors (39)(40)(41)(42). Understanding BBTB heterogeneity will allow the development of more targeted and effective treatments of distinct tumors.…”

Multivalent, Bispecific αB7-H3-αCD3 Chemically Self-Assembled Nanorings Direct Potent T Cell Responses against Medulloblastoma

“…We speculate that the bispecific CSANs are crossing the BTB via immune cell-mediated transport, likely in a similar manner to that of polymer nanoparticles . However, the functional integrity of the BBB in an orthotopic xenograft model of medulloblastoma is questionable and therefore may allow CSANs to freely cross the BTB . Additionally, significant quantities of bispecific CSANs were detected bound to systemic lymphocytes compared to the nontargeted controls (Figure E).…”

A mitochondria-targeting lipid–small molecule hybrid nanoparticle for imaging and therapy in an orthotopic glioma model

“…In addition, the blood‒brain tumor barrier (BBTB) of glioma has a large fenestration size and interendothelial gaps of 48 nm and 1 μm, respectively 42 . The process of engraftment maybe also compromises BBTB integrity 43 . Therefore, nano-sized LPHNPs could selectively accumulate in glioma tissue.…”