Sheila Mansouri

One of the most prominent features of glioblastoma (GBM) is hyper-vascularization. Bone marrow-derived macrophages are actively recruited to the tumor and referred to as glioma-associated macrophages (GAMs) which are thought to provide a critical role in tumor neo-vascularization. However, the mechanisms by which GAMs regulate endothelial cells (ECs) in the process of tumor vascularization and response to anti-angiogenic therapy (AATx) is not well-understood. Here we show that GBM cells secrete IL-8 and CCL2 which stimulate GAMs to produce TNFα. Subsequently, TNFα induces a distinct gene expression signature of activated ECs including VCAM-1, ICAM-1, CXCL5, and CXCL10. Inhibition of TNFα blocks GAM-induced EC activation both in vitro and in vivo and improve survival in mouse glioma models. Importantly we show that high TNFα expression predicts worse response to Bevacizumab in GBM patients. We further demonstrated in mouse model that treatment with B20.4.1.1, the mouse analog of Bevacizumab, increased macrophage recruitment to the tumor area and correlated with upregulated TNFα expression in GAMs and increased EC activation, which may be responsible for the failure of AATx in GBMs. These results suggest TNFα is a novel therapeutic that may reverse resistance to AATx. Future clinical studies should be aimed at inhibiting TNFα as a concurrent therapy in GBMs.

The invasive capacity of GBM is one of the key tumoral features associated with treatment resistance, recurrence, and poor overall survival. The molecular machinery underlying GBM invasiveness comprises an intricate network of signaling pathways and interactions with the extracellular matrix and host cells. Among them, PI3k/Akt, Wnt, Hedgehog, and NFkB play a crucial role in the cellular processes related to invasion. A better understanding of these pathways could potentially help in developing new therapeutic approaches with better outcomes. Nevertheless, despite significant advances made over the last decade on these molecular and cellular mechanisms, they have not been translated into the clinical practice. Moreover, targeting the infiltrative tumor and its significance regarding outcome is still a major clinical challenge. For instance, the pre- and intraoperative methods used to identify the infiltrative tumor are limited when trying to accurately define the tumor boundaries and the burden of tumor cells in the infiltrated parenchyma. Besides, the impact of treating the infiltrative tumor remains unclear. Here we aim to highlight the molecular and clinical hallmarks of invasion in GBM.

Glioblastomas are the most frequent and aggressive primary brain tumor in adults and despite recent therapeutic advances, they are resistant to treatment. Increasing malignancy of gliomas correlates with an increase in cellularity and a poorly organized tumor vasculature, leading to insufficient blood supply, hypoxic areas, and ultimately to the formation of necrosis. Hypoxia induces direct or indirect changes in the biology of solid tumor and their microenvironment through the activation of HIF transcription factors, leading to increased aggressiveness and tumor resistance to therapy. Not much is known about the epigenetic alterations induced by hypoxia and how they could alter tumor biology. In the present study, we have utilized PIMO as a specific marker of hypoxia in glioblastoma patients, treated with PIMO preoperatively. We have estimated PIMO positivity in each tumor (5-45%) and determined that it positively correlates with the hypoxia marker CA IX (r=0.57). In addition, 10 surgical PIMO cases were dissociated, immune labeled using PIMO antibody, followed by DNA isolation and methylation profiling. Our analysis of differentially top 4000 differentially methylated probes suggests that PIMO-positive (hypoxic) cells are differentially methylated compared to the PIMO-negative cells and these changes are associated with genes involved in hypoxic cellular response. We will validate these findings in additional glioblastoma cases and assess the mechanism of these epigenetic alterations in vitro in glioma stem cell culture conditions and upon exposure of the cells hypoxic conditions.

The RNAse III endonuclease DICER is a key regulator of microRNA (miRNA) biogenesis and is frequently down-regulated in a variety of malignancies. We characterized the role of Dicer in glioblastoma (GB), specifically demonstrating its effects on the ability of glioma stem-like cells to form tumors in a mouse model of GB. DICER silencing in glioma stem-like cells (GSCs) reduced their stem cell characteristics, while tumors arising from these cells were more aggressive, larger in volume, and displayed a higher proliferation index and lineage differentiation. The resulting tumors, however, were more sensitive to radiation treatment. Our results demonstrate that DICER affects the tumorigenic potential of GSCs, providing a platform for analysis of specific relevant miRNAs and development of potentially novel therapies against GB.

Tumors with high glycolytic or hypoxic properties must produce sufficient levels of acetyl-CoA to maintain cellular survival and proliferation under adverse nutrient conditions. Acetyl-CoA can be generated by oxidation of glucose, glutamine, or fatty acids. There are principal differences between the metabolism of normal, well-fed cells and tumor cells, especially under nutrient-deprived conditions. Whereas the former consume glucose/pyruvate/acetyl-CoA-derived citrate to synthesize acetyl-CoA, which is then used for fatty acid and cholesterol synthesis, generation of nucleotides and amino acids, and histone acetylation, the latter divert the main metabolite of glucose into aerobic glycolysis from pyruvate-derived mitochondrial acetyl-CoA to lactate. The “bioenergetic substrate gap” develops when under oxygen-limiting conditions the ability of a cell to make acetyl-CoA is impaired, and the question arises how sufficient amounts of citrate via ATP citrate lyase are produced. In the brain, glial cells are capable of oxidizing acetate.

Meningiomas are among the most common primary adult brain tumors, which arise either spontaneously or secondary to environmental factors such as ionizing radiation. The latter are referred to as radiation-induced meningiomas (RIMs) which, while much less common than their spontaneous counterparts, are challenging from a management point of view. Similar to spontaneous meningiomas, the optimal management of RIMs is complete surgical resection. However, given their high grade, multiplicity, tendency to invade bone and venous sinuses, and high recurrence rate, this cannot always be accomplished safely. Therefore, other therapeutic modalities, such as stereotactic radiosurgery, have emerged. In the current review, we provide an overview of the historical outcomes achieved for RIMs through radiosurgery and microsurgical resection. Furthermore, we provide a discussion of clinical and radiological parameters that affect the decision-making process with regard to the management of RIMs. We also provide an outline of recent changes in our understanding of RIMs, based on molecular and genetic markers, and how these will change our management perspective. We conclude the review by summarizing some of the current obstacles in the management of RIMs with SRS and how current and future research can address these challenges.