Related Experiment Videos
A mouse model for glioma: biology, pathology, and therapeutic opportunities
1M.D. Anderson Cancer Center, Department of Neurosurgery, Houston, Texas 77030, USA. eholland@notes.mdacc.tmc.edu
Abstract:
The epidermal growth factor receptor (EGFR) gene is amplified or mutated in 30-50% of human glioblastoma multiforme. These mutations are usually associated with deletions of the INK4a-ARF locus, which encodes 2 gene products (p16INK4a and p19ARF) involved in cell cycle arrest and apoptosis. We have investigated the role of EGFR mutation in gliomagenesis using avian retroviral vectors to transfer a mutant EGFR gene to glial precursors and astrocytes in transgenic mice. These mice express tv-a, a gene encoding the retrovirus receptor TVA, which is under the control of brain cell type-specific promoters. We demonstrate that expression of a constitutively active, mutant form of EGFR in cells in the glial lineage can induce lesions with many similarities to human gliomas, including increased cell density, vascular proliferation, and immunohistochemical staining for glial fibrillary acidic protein (GFAP) and nestin. We also demonstrate that primary astrocytes cultured from transgenic mice expressing tv-a from the GFAP promoter are efficiently infected in culture, and such genetically modified cell cultures can be tumorigenic in nude mice. The combinations of genetic lesions (eg, mutated EGFR, INK4a-/-) leading to tumor formation in these 2 mouse systems are similar to those found in human gliomas. These genetically defined animal models for gliomas will allow for the testing of therapies that are targeted specifically at the gene products involved in the pathogenesis of gliomas.
Insights
Mutant epidermal growth factor receptor (EGFR) in mice can cause gliomas similar to human glioblastoma. These findings establish new animal models for studying glioma development and testing targeted therapies.
Area of Science:
- Oncology
- Neuroscience
- Genetics
Background:
- Glioblastoma multiforme (GBM) frequently involves epidermal growth factor receptor (EGFR) gene alterations.
- EGFR mutations often co-occur with INK4a-ARF locus deletions, impacting cell cycle control and apoptosis.
Purpose of the Study:
- To investigate the role of EGFR mutations in glioma development.
- To create genetically defined animal models for studying human gliomas.
Main Methods:
- Utilized avian retroviral vectors to introduce mutant EGFR into glial precursors and astrocytes in transgenic mice.
- Employed brain cell type-specific promoters to control the expression of the retrovirus receptor TVA.
- Established primary astrocyte cultures from transgenic mice for tumorigenicity studies.
Main Results:
- Expression of constitutively active mutant EGFR in glial cells induced lesions resembling human gliomas, showing increased cell density and vascular proliferation.
- Tumorigenic potential was confirmed in genetically modified primary astrocytes implanted into nude mice.
- The genetic lesions in these mouse models mirror those found in human gliomas.
Conclusions:
- Mutant EGFR is sufficient to initiate gliomagenesis in vivo.
- Genetically defined mouse models accurately recapitulate key features of human gliomas.
- These models provide a platform for evaluating targeted therapies for glioma treatment.