Comparison of three recombinant murine leukemia viruses carrying the v‐src oncogene of avian sarcoma virus: Differences in in vitro transformation and in vivo pathogenicity

Abstract

We previously described a recombinant Moloney murine leukemia virus (Mo-MuLV) carrying the v-src oncogene, Mo-MuLV(src). Mo-MuLV(src) encodes a gag-src fusion protein, transforms cells in culture, and induces fibrosarcomas in vivo. To compare transforming properties of the gag-src fusion protein to pp60src encoded by Rous sarcoma virus, we constructed a new recombinant virus, Mo-MuLV(+ src). Mo-MuLV(+ src) encodes pp60src in the context of Mo-MuLV. Cells transformed by Mo-MuLV(+ src) were round and formed colonies in soft agar, whereas Mo-MuLV(src)-infected cells were fusiform and did not grow in suspension. Thus, the extent of transformation induced by Mo-MuLV(+ src) was greater than that induced by Mo-MuLV(src). Subcutaneous inoculation of either virus into neonatal NIH Swiss mice resulted in fibrosarcomas at the site of injection. Further studies indicated that tumors induced by Mo-MuLV(+ src) grew rapidly but rarely metastasized. In contrast, tumors induced by Mo-MuLV(src) grew somewhat more slowly but metastasized with a high frequency (60%). These viruses may provide a useful model system for tumor metastasis. Another src-containing virus was also studied, MRSV (constructed by Anderson and Scolnick). MRSV also encodes pp60src but in the context of amphotropic MuLV. When injected intravenously into six-week-old mice, MRSV induced splenomegaly and spleen foci but no solid tumors, as reported previously. In contrast, Mo-MuLV(src)-induced fibrosarcomas mostly in the spleen under the same inoculation protocol. These results suggest that the v-src oncogene was the major pathogenic determinant in neonatal mice for all three src-containing viruses; however, variations in the nature of the transforming protein modulated the behavior of the induced tumors. In adult mice, greater differences in pathogenicity were observed.

Generation of recombinant murine retroviral genomes containing the v-src oncogene: isolation of a virus inducing hemangiosarcomas in the brain

“…We have made use of these processes to generate a panel of new viruses and have found one such virus inducing tumors restricted to the brain. The tropism of this virus is distinct from that of any other retrovirus carrying the v-src gene (1,10,11,20,37).…”

Low-frequency loss of heterozygosity in Moloney murine leukemia virus-induced tumors in BRAKF1/J mice

“…It seemed possible that LOH might be observed more frequently in tumors induced by acute retroviruses that carry oncogenes. Therefore, we induced fibrosarcomas in BRAKF1 mice by infection with two M-MuLV-based viruses expressing the v-src oncogene of avian sarcoma virus [M-MuLV(src) and M-MuLV(ϩsrc)] (24,25). However, when 28 tumors induced by these viruses were screened, only one tumor with an LOH (on chromosome 19) was found.…”

Host range restrictions of oncogenes: myc genes transform avian but not mammalian cells and mht/raf genes transform mammalian but not avian cells.

“…For example, the murine retroviral ras gene with a native or artificial retroviral promoter fails to transform human cells (40)(41)(42). However, human cells infected or transfected with ras genes linked to retroviral promoters have a higher than normal risk of transformation, although the role of ras in this transformation is uncertain (40)(41)(42) (44,45). Rous sarcoma virus has even been reported to cause tumors in monkeys but only after latencies of 3-9 months (46).…”