Development and malignant progression of astrocytomas in GFAP-v-src transgenic mice

Oncogene. 1997 May 1;14(17):2005-13. doi: 10.1038/sj.onc.1201168.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytoma / genetics*
  • Astrocytoma / pathology
  • Cell Hypoxia
  • Central Nervous System Neoplasms / genetics*
  • Central Nervous System Neoplasms / pathology
  • Disease Progression
  • Endothelial Growth Factors / biosynthesis
  • Endothelial Growth Factors / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Expression Regulation, Viral
  • Genes, Viral*
  • Genes, src*
  • Glial Fibrillary Acidic Protein / genetics*
  • Glioblastoma / etiology
  • Glioblastoma / genetics*
  • Glioblastoma / pathology
  • Gliosis / etiology
  • Gliosis / genetics
  • Gliosis / pathology
  • Lymphokines / biosynthesis
  • Lymphokines / genetics
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, Nude
  • Mice, Transgenic
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Transplantation
  • Oncogene Protein pp60(v-src) / physiology*
  • Receptor Protein-Tyrosine Kinases / biosynthesis
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptors, Growth Factor / biosynthesis
  • Receptors, Growth Factor / genetics
  • Receptors, Vascular Endothelial Growth Factor
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / toxicity*
  • Transgenes
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Endothelial Growth Factors
  • Glial Fibrillary Acidic Protein
  • Lymphokines
  • Neoplasm Proteins
  • Receptors, Growth Factor
  • Recombinant Fusion Proteins
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor
  • Oncogene Protein pp60(v-src)