Astrocyte-specific Expression of Activated p21-ras Results in Malignant Astrocytoma Formation in a Transgenic Mouse Model of Human Gliomas

摘要: Activation of the p21-ras signaling pathway from aberrantly expressed receptors promotes growth malignant human astrocytomas. We developed a transgenic mouse astrocytoma model using glial fibrillary acidic protein (GFAP) promoter to express oncogenic V 12 Ha- ras , specifically in astrocytes. The development GFAP-immunoreactive astrocytomas was directly proportional level transgene expression. Chimeras expressing high levels astrocytes died multifocal within 2 weeks, whereas those with moderate went germ-line transmission. Ninety-five percent these mice solitary or low- and high-grade 2–6 months. These are pathologically similar astrocytomas, mitotic index, nuclear pleomorphism, infiltration, necrosis, increased vascularity. Derivative cells tumorigenic upon inoculation another host. exhibit additional molecular alterations associated including decreased absent expression p16, p19, PTEN as well overexpression EGFR, MDM2, CDK4. Cytogenetic analysis revealed consistent clonal aneuploidies chromosomal regions syntenic comparable loci altered Therefore, this recapitulates many histopathological characteristics reproducible, germ-line-transmitted, high-penetrance manner.