TUMOR-INDUCTION BY RAS AND MYC ONCOGENES IN FETAL AND NEONATAL BRAIN - MODULATING EFFECTS OF DEVELOPMENTAL STAGE AND RETROVIRAL DOSE

Introduction into fetal rat brain cells of a replication-defective ret roviral vector harboring v-Haras and v-gag-myc rapidly causes the indu ction of highly malignant undifferentiated neuroectodermal tumors foll owing transplantation into the brains of syngeneic hosts [Wiestler, et al. (1992) Cancer Res. 52: 3760-37671. In the present study, we have investigated the modulating effect of the developmental stage of neura l target cells and of the dose of the retroviral vector used in the gr afting experiments. Exposure of fetal cells from embryonic day (E)12 o r E14 produced a 100% incidence of malignant neuroectodermal tumors wh ich led to the death of recipient animals after a median latency perio d of 32 days. A 100-fold reduction of the virus dose from 2.062 X 10(6 ) to 2.062 X 10(4) focus-forming units/ml resulted in a lower tumor in cidence of 25%. Of six neural grafts exposed to v-Ha-ras and v-myc at E16, only one showed evidence of tumorigenesis (low-grade astrocytoma and hemangioma). All other transplants were morphologically normal for observation periods of 26 weeks, indicating a marked loss of transfor ming activity of ras and myc in more advanced stages of brain developm ent. In retrovirus-exposed donor cells which caused the development of neural tumors in recipient rats, malignant transformation was also ev ident during culture in vitro, usually after 9-12 days. Oncogene compl ementation was also studied in the newborn rat brain. After microinjec tion of the retroviral vector into the brain at postnatal day (P)0, P1 and P3, 5 out of 20 animals (25%) developed a total of seven brain tu mors. Histopathologically, three of these neoplasms were malignant neu roectodermal tumors which, in contrast to those induced in fetal brain transplants showed evidence of focal glial and/or neuronal differenti ation. In addition, we observed one oligodendroglioma, two hemangiomas and a malignant hemangioendothelioma. These data indicate that neural precursor cells and endothelia of the rat brain represent the major t arget cells for the complementary action of ras and myc and that the u se of target cells from later developmental stages (E16 and postnatal) leads to the induction of both primitive and more differentiated neop lasms.