Magnetic Resonance Elastography reveals effects of anti-angiogenic glioblastoma treatment on tumor stiffness and captures progression in an orthotopic mouse model.

BACKGROUND: Anti-angiogenic treatment of glioblastoma (GBM) complicates radiologic monitoring. We evaluated magnetic resonance elastography (MRE) as an imaging tool for monitoring the efficacy of anti-VEGF treatment of GBM. METHODS: Longitudinal studies were performed in an orthotopic GBM xenograft mouse model. Animals treated with B20 anti-VEGF antibody were compared to untreated controls regarding survival (n = 13), classical MRI-contrasts and biomechanics as quantified via MRE (n = 15). Imaging was performed on a 7 T small animal horizontal bore MRI scanner. MRI and MRE parameters were compared to histopathology. RESULTS: Anti-VEGF-treated animals survived longer than untreated controls (p = 0.0011) with progressively increased tumor volume in controls (p = 0.0001). MRE parameters viscoelasticity |G*| and phase angle Y significantly decreased in controls (p = 0.02 for |G*| and p = 0.0071 for Y). This indicates that untreated tumors became softer and more elastic than viscous with progression. Tumor volume in treated animals increased more slowly than in controls, indicating efficacy of the therapy, reaching significance only at the last time point (p = 0.02). Viscoelasticity and phase angle Y tended to decrease throughout therapy, similar as for control animals. However, in treated animals, the decrease in phase angle Y was significantly attenuated and reached statistical significance at the last time point (p = 0.04). Histopathologically, control tumors were larger and more heterogeneous than treated tumors. Vasculature was normalized in treated tumors compared with controls, which showed abnormal vasculature and necrosis. In treated tumors, a higher amount of myelin was observed within the tumor area (p = 0.03), likely due to increased tumor invasion. Stiffness of the contralateral hemisphere was influenced by tumor mass effect and edema. CONCLUSIONS: Anti-angiogenic GBM treatment prolonged animal survival, slowed tumor growth and softening, but did not prevent progression. MRE detected treatment effects on tumor stiffness; the decrease of viscoelasticity and phase angle in GBM was attenuated in treated animals, which might be explained by normalized vasculature and greater myelin preservation within treated tumors. Thus, further investigation of MRE is warranted to understand the potential for MRE in monitoring treatment in GBM patients by complementing existing MRI techniques.

The functional synergism of microRNA clustering provides therapeutically relevant epigenetic interference in glioblastoma.

MicroRNA deregulation is a consistent feature of glioblastoma, yet the biological effect of each single gene is generally modest, and therapeutically negligible. Here we describe a module of microRNAs, constituted by miR-124, miR-128 and miR-137, which are co-expressed during neuronal differentiation and simultaneously lost in gliomagenesis. Each one of these miRs targets several transcriptional regulators, including the oncogenic chromatin repressors EZH2, BMI1 and LSD1, which are functionally interdependent and involved in glioblastoma recurrence after therapeutic chemoradiation. Synchronizing the expression of these three microRNAs in a gene therapy approach displays significant anticancer synergism, abrogates this epigenetic-mediated, multi-protein tumor survival mechanism and results in a 5-fold increase in survival when combined with chemotherapy in murine glioblastoma models. These transgenic microRNA clusters display intercellular propagation in vivo, via extracellular vesicles, extending their biological effect throughout the whole tumor. Our results support the rationale and feasibility of combinatorial microRNA strategies for anticancer therapies.

Cytomegalovirus promotes murine glioblastoma growth via pericyte recruitment and angiogenesis.

Cytomegalovirus (CMV) has been implicated in glioblastoma (GBM); however, a mechanistic connection in vivo has not been established. The purpose of this study is to characterize the effects of murine CMV (MCMV) on GBM growth in murine models. Syngeneic GBM models were established in mice perinatally infected with MCMV. We found that tumor growth was markedly enhanced in MCMV+ mice, with a significant reduction in overall survival compared with that of controls (P < 0.001). We observed increased angiogenesis and tumor blood flow in MCMV+ mice. MCMV reactivation was observed in intratumoral perivascular pericytes and tumor cells in mouse and human GBM specimens, and pericyte coverage of tumor vasculature was strikingly augmented in MCMV+ mice. We identified PDGF-D as a CMV-induced factor essential for pericyte recruitment, angiogenesis, and tumor growth. The antiviral drug cidofovir improved survival in MCMV+ mice, inhibiting MCMV reactivation, PDGF-D expression, pericyte recruitment, and tumor angiogenesis. These data show that MCMV potentiates GBM growth in vivo by increased pericyte recruitment and angiogenesis due to alterations in the secretome of CMV-infected cells. Our model provides evidence for a role of CMV in GBM growth and supports the application of antiviral approaches for GBM therapy.