Development and malignant progression of astrocytomas in GFAP-v-src transgenic mice.
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.
Weissenberger
J
J
Institute of Neuropathology, University Hospital of Zürich, Switzerland.
Steinbach
J P
JP
Malin
G
G
Spada
S
S
Rülicke
T
T
Aguzzi
A
A
D000818:Animals; D001254:Astrocytoma / Q000235:genetics* / Q000473:pathology; D015687:Cell Hypoxia; D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D005814:Genes, Viral; D016391:Genes, src; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics*; D005909:Glioblastoma / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D005911:Gliosis / Q000209:etiology / Q000235:genetics / Q000473:pathology; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation; D015688:Oncogene Protein pp60(v-src) / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D017978:Receptors, Growth Factor / Q000096:biosynthesis / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000633:toxicity*; D019076:Transgenes; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D005904:Glial Fibrillary Acidic Protein; D008222:Lymphokines; D009363:Neoplasm Proteins; D017978:Receptors, Growth Factor; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D015688:Oncogene Protein pp60(v-src)