Patterns of Invasive Growth in Malignant Gliomas—The Hippocampus Emerges as an Invasion-Spared Brain Region

Abstract

BACKGROUND: Widespread infiltration of tumor cells into surrounding brain parenchyma is a hallmark of malignant gliomas, but little data exist on the overall invasion pattern of tumor cells throughout the brain. METHODS: We have studied the invasive phenotype of malignant gliomas in two invasive mouse models and patients. Tumor invasion patterns were characterized in a patient-derived xenograft mouse model using brain-wide histological analysis and magnetic resonance (MR) imaging. Findings were histologically validated in a cdkn2a−/− PDGF-β lentivirus-induced mouse glioblastoma model. Clinical verification of the results was obtained by analysis of MR images of malignant gliomas. RESULTS: Histological analysis using human-specific cellular markers revealed invasive tumors with a non-radial invasion pattern. Tumors cells accumulated in structures located far from the transplant site, such as the optic white matter and pons, whereas certain adjacent regions were spared. As such, the hippocampus was remarkably free of infiltrating tumor cells despite the extensive invasion of surrounding regions. Similarly, MR images of xenografted mouse brains displayed tumors with bihemispheric pathology, while the hippocampi appeared relatively normal. In patients, most malignant temporal lobe gliomas were located lateral to the collateral sulcus. Despite widespread pathological fluid-attenuated inversion recovery signal in the temporal lobe, 74% of the “lateral tumors” did not show signs of involvement of the amygdalo-hippocampal complex. CONCLUSIONS: Our data provide clear evidence for a compartmental pattern of invasive growth in malignant gliomas. The observed invasion patterns suggest the presence of preferred migratory paths, as well as intra-parenchymal boundaries that may be difficult for glioma cells to traverse supporting the notion of compartmental growth. In both mice and human patients, the hippocampus appears to be a brain region that is less prone to tumor invasion.

Glioma Migration Through the Corpus Callosum and the Brainstem Detected by Diffusion and Magnetic Resonance Imaging: Initial Findings

“…This result may be a reflection of the tumor cell migration, which is in line with a histopathological investigation on mouse models that reported the accumulation of tumor cells in regions far from the transplant side (Mughal et al, 2018).…”

The efficacy of a coordinated pharmacological blockade in glioblastoma stem cells with nine repurposed drugs using the CUSP9 strategy

“…We have extensive experience in culturing and characterization of the GSC population from patient-derived GBM biopsies (Varghese et al 2008 ; Vik-Mo et al 2010 ; Mughal et al 2018 ).…”

“…We have previously characterized selected GSC cultures (T10965, T1008) in this sample cohort (Vik-Mo et al 2010 ; Joel et al 2015 ; Mughal et al 2018 ). Of the remaining GSC cultures, we confirmed stem cell properties by functional assays of self-renewal potential, expression of stem cell markers, ability to generate different brain cell lineages upon differentiation with differential expression profiles, along with the ability to form tumors upon xenografting to immunocompromised mice in both cultures derived from treatment-naïve and heavily pretreated recurrent disease (Fig.…”

Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma

“…This trait could be reminiscent of neuroblasts that use radial glial fibers as migratory tracks to guide them during embryonic brain development (85,86). GBM tumors have been shown to travel along white matter tracts (87) or to follow blood vessels (88). Although information on DIPG invasion routes is limited, perivascular spread has been observed in patient autopsy material (89).…”