Gliomas are the most common primary tumors of the brain, with an incidence of about 25,000 new cases per year in the United States [1]. At least half of all gliomas exhibit aggressive, malignant behavior. Glioblastoma multiforme (GBM), in particular, is clinically and pathologically malignant [1–3]. Patients with GBM have a poor prognosis, with a median survival of one year with aggressive therapy; fewer than 5% will survive fi ve years [1,4,5]. In spite of its seemingly low incidence, mortality from GBM accounts for 3%–4% of all cancer deaths each year in the US [1].
The mainstays of treatment include surgical resection, radiation, and chemotherapy. Once adjuvant therapy is completed, gliomas generally recur at the surgical resection margin(s), and tend to be more aggressive than at initial presentation (Figure 1). At this stage in the course of disease, most therapy is palliative [1–5]. With the exception of a few early-stage clinical trials, current antiglioma therapies have not yet taken advantage of specifi c genetic abnormalities that lead to and sustain cancer. A new study by Alexander Levitzki and colleagues in this issue of PLoS Medicine presents promising preclinical results that appear to do just this, using a novel ligand-directed method to deliver double-stranded RNA molecules to cancer cells [6].
Figure 1. Representative Clinical, Pathological, and Molecular Genetic Features of Glioblastoma Multiforme The top panel shows an illustrative set of neuroimages from a patient with glioblastoma multiforme. On the left and in the center are gadolinium-enhanced T1-weighted axial magnetic resonance images from the day before and the day after resection of a large left frontal GBM. The patient was treated with postoperative radiation and chemotherapy. He presented again, 11 months after the fi rst surgery, with stupor and a contrast-enhanced computed tomographic scan (right), which showed a massive and fatal recurrence. The middle panel shows histopathological examples of this patient’s tumor. In the left image, there is evidence of hypercellularity, pseudopalisading necrosis (small arrow), and vascular proliferation with hemorrhage (large arrow). In the center image, there is hypercellularity with intermittent mitotic fi gures (small arrows), while in the image to the right, there are several areas with fl orid endothelial proliferation (small arrows). See also Table 1. All fi gures are 200× magnifi cation. The bottom panel shows a schematic of current models of astrocytoma development and progression. The de novo pathway is located on top, and the secondary pathway is located on bottom. The principal genetic changes are noted for each pathway. Neuronal tumors and oligodendrogliomas (left top and bottom, respectively) appear to arise independently. Average survivals are noted for each astrocytoma type. While basic genetic features have been elaborated, they have been inconsistently found in GBMs, and as yet appear not to be consistently effective for targeted therapy. There remains a great deal unknown about the process by which these tumors progress to the most malignant state, whether the tumor is a de novo GBM or arises secondarily. Unknown steps from potential progenitor or pluripotent tumor cell(s) are indicated by small arrows.
Pathologic and Molecular Features
Gliomas are primary brain tumors that display pathological and ultrastructural features of glial cell differentiation. Primary brain tumors are classifi ed on the basis of presumed line of neuroepithelial differentiation: astrocytic, oligodendroglial, and ependymal (Figure 1). Astrocytomas predominate, making up 80%–85% of all glial neoplasms, and will be the focus of this Perspective.
Grading is performed on a scale, from low to high, according to a tumor’s histological features (Figure 1; Table 1). World Health Organization grade IV tumors, the GBMs, are aggressive, invasive, destructive malignancies, with increased mitotic activity, pronounced angiogenesis, necrosis, and proliferation rates two to five times higher than grade III tumors [2]. Roughly 50% of all GBMs are primary or de novo in origin, while the other half arises secondarily from lowergrade tumors [2], often after some years of latency [2]. Current models of gliomagenesis coincide with the two clinically recognized forms of GBM, de novo and progressive (Figure 1).
Most de novo GBMs do not have alterations in TP53 ; rather, nearly all carry EGF receptor (EGFR) gene amplifi cations, often combined with gene rearrangements that lead to a constitutively active, truncated receptor. By contrast, progression from a lowgrade to a high-grade glioma often involves the serial accumulation of genetic alterations that inactivate tumor suppressor genes—such as TP53, p16, RB, PTEN —or activate oncogenes such as MDM2, CDK4 and CDK6 [2–4]. Functionally, gliomas seem to arise along two competing paths [3–5,7]. The first path is altered growth factor signaling— for example, activation of the EGFRRas- mitogen activated protein kinase, platelet-derived growth factor, or Akt pathways—which, both independently and through pathway crosstalk, lead to cell proliferation, cell cycle progression, and apoptosis inhibition (Figure 1). The second path is direct dys-regulation of cell cycle arrest, such as p16ink4a control of Rb or p14arf modulation of MDM2 and Tp53, among others.
