Trapping the mouse genome to hunt human alterations
- Anne-Marie Bleau* and
- Eric C. Holland*,†,‡,§
- Departments of *Cancer Biology and Genetics,
- †Surgery (Neurosurgery), and
- ‡Neurology, Memorial Sloan–Kettering Cancer Center, New York, NY 10021
Glioblastoma multiforme (GBM) are the most common and aggressive adult primary brain tumors. Genetic alterations and their consequences in these malignant astrocytomas have been studied extensively and include (i) overexpression of growth factors and their corresponding receptors (fibroblast growth factor, epidermal growth factor, and platelet-derived growth factors), (ii) abnormalities of transduction signaling pathways (activation of PI3 kinase/AKT, RAS/MAP kinase, and protein kinase C), or (iii) disruption of cell cycle arrest (loss of p16INK4A and p14ARF, mutations in p53 protein, and PTEN) (1). Whether these modifications are causative or participate in tumor progression is a pivotal question that can best be answered by modeling glioma formation in mice. In this issue of PNAS, Kamnasaran et al. (2) combine genetically engineered murine (GEM) models of gliomas with a retroviral gene-trapping approach to identify new molecular alterations in human gliomas.
There has been substantial progress made recently in developing GEM models that recapitulate the genesis and progression of human malignancies. In such an effort, several publications from Guha (e.g., ref. 3) have described an astrocytoma mouse model using embryonic stem (ES) cell transgenesis to overexpress oncogenic Ras under the control of a GFAP promoter. These mice express various levels of oncogenic Ras where the highest producers develop astrocytomas with similarities to glioblastomas. Consequently, one strain of the model relies on the development of low-grade astrocytomas (LGA) that progress to anaplastic astrocytomas [high-grade astrocytomas (HGA)]. An alternative approach to inducing tumor formation in mice consists of somatic-cell gene transfer using tissue-specific, replication-competent avian leukosis virus-based retroviral vectors. In such a model, the combined transfer of genes encoding activated Ras and Akt to nestin-expressing CNS progenitors leads to the formation of gliomas (4). However, contrary to the mouse model of Guha, neither Ras nor Akt alone is sufficient to generate glioblastomas. The requirement for combined …
§To whom correspondence should be addressed at:
Departments of Surgery (Neurosurgery), Neurology, and Cancer Biology and Genetics, Memorial Sloan–Kettering Cancer Center, 408 East 69th Street, Z 1304, New York, NY 10021. E-mail: hollande{at}mskcc.org
