Astrocytomas, composed predominantly of astrocyte-like cells, are the most common neoplasm in the central nervous system (CNS) (Kleihues and Cavenee, 2000
). According to the World Health Organization (WHO) grading system, grade II–IV astrocytomas (collectively called malignant astrocytoma) are biologically malignant and diffusely infiltrate the brain. Grade IV astrocytoma, or glioblastoma multiforme (GBM), is one of the most aggressive human cancers, with a median survival of less than 1 year. Unfortunately, this prognosis has not changed significantly over the past two decades, despite advances in neurosurgery, radiation, and chemotherapy (Holland, 2001
; Maher et al., 2001
; Zhu and Parada, 2002
There are two subtypes of GBMs. Primary GBMs arise rapidly or de novo without any evidence of prior clinical disease, whereas secondary GBMs derive from preexisting low-grade lesions after long latency ranging from 5 to 10 years (Kleihues and Cavenee, 2000
; Maher et al., 2001
). Human genetic studies indicate that two frequent molecular characteristics of low-grade astrocytomas are loss of p53 and elevated expression of platelet-derived growth factor (PDGF) and its receptor tyrosine kinase (RTK), PDGFR (Guha et al., 1995
; Hermanson et al., 1992
; Nister et al., 1988
). These observations suggest that these pathways may participate in the initiation of astrocytoma. Individuals afflicted with neurofibromatosis type 1 (NF1) are predisposed to malignant astrocytoma in the brain with a greater than 5-fold increased incidence throughout their lives (Rasmussen et al., 2001
). The NF1 tumor suppressor product neurofibromin is a functional Ras GTPase-activating protein (GAP) (Cichowski and Jacks, 2001
; Zhu and Parada, 2001
). Thus, loss of neurofibromin results in abnormal activation of Ras, a major mediator of RTK signaling.
Heterozygous mice carrying germline null mutations in both p53 and NF1 on the same chromosome (termed cisNF1/p53 mice) develop low- to intermediate-grade astrocytomas, with up to 75% penetrance depending on the genetic background (Reilly et al., 2000
). We reasoned that the increased incidence of astrocytoma in NF1 patients might indicate a convergence on the requirement for Ras signaling with sporadic astrocytomas via PDGFR activation. To refine our understanding of the target cell for p53 inactivation and Ras pathway activation in astrocytoma induction, we combined a germline p53 mutation (Jacks et al., 1994
) with a neural-specific NF1 mutation (Zhu et al., 2001
). The resultant mice develop malignant astrocytomas with 100% penetrance and provide evidence for the cell-of-origin in the subventricular zone (SVZ) of the adult brain and a requirement for p53 loss preceding or concomitant inactivation of NF1. The availability of an accurate mouse model for malignant astrocytoma initiation and progression will permit detailed investigation into the pathogenesis of, and novel therapeutic targets for, this incurable tumor.
Recent studies indicate that brain tumors, including glioblastoma multiforme, contain a subpopulation of cancer cells that display stem cell characteristics, including self-renewal and multipotentiality, and are responsible for in vivo tumor growth. Whether these brain cancer stem cells are derived from neoplastic transformation of normal neural stem cells remains to be determined. Through analysis of mouse models with complete penetrance of malignant astrocytoma, we demonstrate that astrocytoma cells of all grades display stem cell characteristics and that early presymptomatic lesions reside within the subventricular zone (SVZ) of the lateral ventricle, one region of the CNS that contains neurogenic stem cells. These studies provide evidence that the SVZ cells may serve as a cell-of-origin for malignant astrocytoma.