Abstract
We have generated a transgenic mouse model for astrocytoma by expressing the v-src kinase under control of the glial fibrillary acidic protein (GFAP) gene regulatory elements in astrocytes. Abnormal astrogliosis was observed in all transgenic animals already at 2 weeks postnatally, frequently followed by the development of dysplastic changes. Later, small proliferative foci arose, and overt astrocytoma developed in the brain and spinal cord in 14.4% of mice after a follow up time of 65 weeks. While early lesions were histologically consistent with low-grade astrocytoma, at later stages most tumors were highly mitotic and frankly malignant. Vascular endothelial growth factor (VEGF) was expressed by tumor cells already at early stages, suggesting induction by v-src, and it was most pronounced in pseudopalisading cells surrounding necrotic areas, implying additional upregulation by hypoxia. In larger lesions, mitotic activity and expression of flk-1, the cognate receptor of VEGF were induced in endothelial cells. Therefore, end-stage tumors mimicked the morphological and molecular characteristics of human glioblastoma multiforme. Time course and stochastic nature of the process indicate that v-src did not suffice for malignant transformation, and that astrocytomas were the result of a multistep process necessitating co-operation of additional genetic events.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Astrocytoma / genetics*
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Astrocytoma / pathology
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Cell Hypoxia
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Central Nervous System Neoplasms / genetics*
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Central Nervous System Neoplasms / pathology
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Disease Progression
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Endothelial Growth Factors / biosynthesis
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Endothelial Growth Factors / genetics
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Female
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Gene Expression Regulation, Neoplastic
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Gene Expression Regulation, Viral
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Genes, Viral*
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Genes, src*
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Glial Fibrillary Acidic Protein / genetics*
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Glioblastoma / etiology
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Glioblastoma / genetics*
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Glioblastoma / pathology
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Gliosis / etiology
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Gliosis / genetics
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Gliosis / pathology
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Lymphokines / biosynthesis
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Lymphokines / genetics
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Male
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Mice
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Mice, Inbred ICR
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Mice, Nude
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Mice, Transgenic
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Transplantation
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Oncogene Protein pp60(v-src) / physiology*
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Receptor Protein-Tyrosine Kinases / biosynthesis
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Receptor Protein-Tyrosine Kinases / genetics
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Receptors, Growth Factor / biosynthesis
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Receptors, Growth Factor / genetics
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Receptors, Vascular Endothelial Growth Factor
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / toxicity*
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Transgenes
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Tumor Cells, Cultured
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Endothelial Growth Factors
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Glial Fibrillary Acidic Protein
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Lymphokines
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Neoplasm Proteins
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Receptors, Growth Factor
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Recombinant Fusion Proteins
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Receptor Protein-Tyrosine Kinases
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Receptors, Vascular Endothelial Growth Factor
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Oncogene Protein pp60(v-src)