Brüstle O, Aguzzi A, Talarico D, Basilico C, Kleihues P, Wiestler O D
Department of Pathology, University of Zürich, Switzerland.
Oncogene. 1992 Jun;7(6):1177-83.
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.
利用逆转录病毒介导的基因转移技术将基因导入神经移植体，我们已在中枢神经系统中表达了人类K-fgf/hst癌基因。在胚胎第13天和第14天取出胎鼠脑的单细胞悬液，将其暴露于编码K-fgf癌基因的逆转录病毒载体中，然后通过立体定位植入同基因成年Fisher大鼠的尾状核壳核。每隔6 - 16个月处死受体动物，未发现神经功能损害的迹象。模拟感染的移植体呈现出典型的器官型分化神经移植体的组织病理学外观。相比之下，暴露于K-fgf基因的移植体表现出丰富的毛细血管增生和毛细血管血管瘤。通过原位杂交分析和免疫组织化学方法，在血管增生附近的神经细胞中检测到了K-fgf的表达。具有丰富K-fgf转录本的神经元和神经胶质细胞在形态上未受影响。为了检测K-fgf基因在神经系统中的转化潜能，我们将逆转录病毒介导的K-fgf癌基因转移与供体动物经胎盘单次暴露于嗜神经致癌物N-乙基-N-亚硝基脲（NEU）相结合。然而，这种转化剂的组合并未导致移植体中形成肿瘤。这些结果为K-fgf在体内对发育中的脑具有强大的血管生成作用提供了证据。
