Angiogenic activity of the K-fgf/hst oncogene in neural transplants.
Using retrovirus-mediated gene transfer into neural transplants, we have expressed the human K-fgf/hst oncogene in the central nervous system. Single-cell suspensions of fetal rat brains were removed at embryonic days 13 and 14, exposed to a retroviral vector encoding the K-fgf oncogene and stereotaxically implanted into the caudate putamen of syngenic adult Fisher rats. Recipient animals were sacrificed at intervals of 6-16 months without evidence of neurological impairment. Mock-infected grafts showed the characteristic histopathological appearance of organotypically differentiated neural transplants. In contrast, grafts exposed to the K-fgf gene exhibited abundant capillary proliferation and capillary angiomas. By in situ hybridization analysis and immunohistochemistry, expression of K-fgf was detected in neural cells adjacent to vascular proliferations. Neurons and glia with abundant K-fgf transcripts were morphologically unaffected. In order to examine the transforming potential of the K-fgf gene in the nervous system, we combined retrovirus-mediated transfer of the K-fgf oncogene with a single transplacental exposure of the donor animals to the neurotropic carcinogen N-ethyl-N-nitrosourea (NEU). However, this combination of transforming agents did not result in tumor formation in the grafts. These results provide evidence for a powerful angiogenic effect of K-fgf on the developing brain in vivo.
Brüstle
O
O
Department of Pathology, University of Zürich, Switzerland.
Aguzzi
A
A
Talarico
D
D
Basilico
C
C
Kleihues
P
P
Wiestler
O D
OD
D000818:Animals; D016375:Antisense Elements (Genetics); D001932:Brain Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D016380:Brain Tissue Transplantation / Q000473:pathology*; D002421:Caudate Nucleus / Q000473:pathology; D004730:Endothelium, Vascular / Q000502:physiology; D005038:Ethylnitrosourea / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D016332:Fetal Tissue Transplantation / Q000473:pathology; D005333:Fetus / Q000187:drug effects; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors / Q000235:genetics*; D006133:Growth Substances / Q000235:genetics; D006801:Humans; D007267:Injections; D009389:Neovascularization, Pathologic; D009474:Neurons / Q000473:pathology; D009857:Oncogenes; D010920:Placenta; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011699:Putamen / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D011956:Receptors, Cell Surface / Q000502:physiology; D017468:Receptors, Fibroblast Growth Factor; D012190:Retroviridae / Q000235:genetics; D014162:Transfection
D016375:Antisense Elements (Genetics); C496445:FGF4 protein, human; C496447:Fgf4 protein, rat; D051519:Fibroblast Growth Factor 4; D006133:Growth Substances; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; D005038:Ethylnitrosourea