Glioblastoma multiforme: The terminator

Abstract

Glioblastoma multiforme is the most aggressive of the gliomas, a collection of tumors arising from glia or their precursors within the central nervous system. Clinically, gliomas are divided into four grades; unfortunately, the most aggressive of these, grade 4 or glioblastoma multiforme (GBM), is also the most common in humans. Because most patients with GBMs die of their disease in less than a year and essentially none has long-term survival, these tumors have drawn significant attention; however, they have evaded increasingly cleaver and intricate attempts at therapy over the last half-century. The paper by Gromeier et al. (1) in this issue of PNAS is the newest chapter in this saga, describing a hybrid virus that infects and kills clonal human glioma cell lines, in culture and implanted in athymic mice, without affecting nonneoplastic cells within the brain. For those viewing this battle from a distance, the continued unsuccessful attempts at novel therapies for this disease may be difficult to understand. However, for those treating these patients, and certainly for the patients themselves, the importance and urgency of each attempt is clear. One of the reasons for the resistance of GBM to therapeutic intervention is the complex character of the tumor itself. As the name implies, glioblastoma is multiforme. It is multiforme grossly, showing regions of necrosis and hemorrhage. It is multiforme microscopically, with regions of pseudopalisading necrosis, pleomorphic nuclei and cells, and microvascular proliferation. And it is multiforme genetically, with various deletions, amplifications, and point mutations leading to activation of signal transduction pathways downstream of tyrosine kinase receptors such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR), as well as to disruption of cell-cycle arrest pathways by INK4a-ARF loss or by p53 mutations associated with CDK4 amplification or Rb loss (2). These tumors also show …