Malignant astrocytic glioma: genetics, biology, and paths to treatment

Abstract

Malignant astrocytic gliomas such as glioblastoma are the most common and lethal intracranial tumors. These cancers exhibit a relentless malignant progression characterized by widespread invasion throughout the brain, resistance to traditional and newer targeted therapeutic approaches, destruction of normal brain tissue, and certain death. The recent confluence of advances in stem cell biology, cell signaling, genome and computational science and genetic model systems have revolutionized our understanding of the mechanisms underlying the genetics, biology and clinical behavior of glioblastoma. This progress is fueling new opportunities for understanding the fundamental basis for development of this devastating disease and also novel therapies that, for the first time, portend meaningful clinical responses.Malignant gliomas are classified and subtyped on the basis of histopathological features and clinical presentation (Fig. 1). The most common and biologically aggressive of these is glioblastoma (GBM), World Health Organization (WHO) grade IV, and is defined by the hallmark features of uncontrolled cellular proliferation, diffuse infiltration, propensity for necrosis, robust angiogenesis, intense resistance to apoptosis, and rampant genomic instability. As reflected in the old moniker "multiforme," GBM presents with significant intratumoral heterogeneity on the cytopathological, transcriptional, and genomic levels. This complexity, combined with a putative cancer stem cell (CSC) subpopulation and an incomplete atlas of (epi)genetic lesions driving GBM pathogenesis, has conspired to make this cancer one of the most difficult to understand and to treat. Despite implementation of intensive therapeutic strategies and supportive care, the median survival of GBM has remained at 12 mo over the past decade.In this review, we summarize current basic and translational challenges and highlight the striking scientific advances that promise to improve the clinical course of this lethal disease. These advances include a more comprehensive view of the altered genes and pathways in glioma and how such alterations drive the hallmark pathobiological features of the disease, the identification of new molecular subtypes in GBM, an improved understanding of the cellular origins of the disease and how CSCs may influence therapeutic responses, refined model systems for use in research and preclinical experimental therapeutics, and novel therapeutic strategies for targeting keystone genetic lesions and their pathways. For reasons of length, we have not discussed the advances in such important areas as tumor immunology, the blood-brain barrier, and tumor imaging. For the first time, there is a strong sentiment that meaningful therapeutic advances will soon flow from this explosion of new molecular and biological knowledge; the remarkable technological advances in

Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas

“…Gliomas are the most common primary tumors in the central nervous system derived from glial cells or glial progenitors, with glioblastomas as the most malignant entity (DeAngelis, 2001;Furnari et al, 2007). Despite multimodal therapy regimens including neurosurgical resection, radiotherapy and cytotoxic chemotherapy, the prognosis of glioma patients remains poor, that is, o3% of patients survive more than 5 years (Ohgaki and Kleihues, 2005).…”

Notch1 signaling promotes survival of glioblastoma cells via EGFR-mediated induction of anti-apoptotic Mcl-1

“…39 In this study, we characterized the anti-apoptotic actions of Notch1 signaling in glioblastomas and identified the Notch1-dependent, EGFRmediated regulation of the Mcl-1 protein as a crucial pathway that renders brain tumor cells resistant to apoptosis. Traditionally, Notch1 is regarded as a multi-functional receptor mainly controlling cell fate specifications and self-renewal processes in stem cell biology.…”

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

“…Glioblastoma (GBMs) remains one of the most fatal and least successfully treated solid tumors (Furnari et al, 2007;Wen and Kesari, 2008). The median survival of GBM patients treated with multimodal therapies including surgical resection, radiation and chemotherapy is less than 16 months (Stupp et al, 2005;Furnari et al, 2007).…”