Enzootic nasal tumor virus (ENTV) induces nasal epithelial cancer in infected sheep, but it is a simple retrovirus lacking a known oncogene. ENTV is closely related to jaagsiekte sheep retrovirus (JSRV), which also causes cancer in sheep but in the epithelial cells of the lower airways and alveoli. Here we show that as with JSRV, the envelope (Env) protein of ENTV can transform cultured cells and thus is likely to be responsible for oncogenesis in animals. In addition, the ENTV Env protein mediates virus entry using the same receptor as does JSRV Env, the candidate tumor suppressor Hyal2. However, ENTV Env mediates entry into cells from a more restricted range of species than does JSRV, and based on this finding we have identified amino acid regions in the Env proteins that are important for virus entry. Also, because ENTV does not efficiently use human Hyal2 as a receptor, we cloned the ovine Hyal2 cDNA and show that the encoded protein functions as an efficient receptor for both ENTV and JSRV. In summary, although ENTV and JSRV use the same cell surface receptor for cell entry and apparently transform cells by the same mechanism, they induce cancer in different tissues of infected sheep, indicating that oncogenesis is regulated at some other level. The transcriptional regulatory elements in these viruses are quite different, indicating that tissue-specific oncogenesis is likely regulated at the level of viral gene expression.
Enzootic nasal tumor virus (ENTV) is a simple retrovirusthat is transmitted horizontally and induces nasal adenocarcinoma in sheep (4, 10) and goats (8, 9). ENTV can be found in the nasal fluid of animals with intranasal tumors, which eventually progress and cause severe cranial deformations and respiratory blockage, resulting in death (41). ENTV is closely related to jaagsiekte sheep retrovirus (JSRV) (Ͼ95% overall amino acid similarity) (4), which is the causative agent of ovine pulmonary adenocarcinoma (also called sheep pulmonary adenomatosis or jaagsiekte) (30). Unlike tumors caused by ENTV, which arise from nasal epithelial cells, JSRV-induced tumors arise from epithelial cells in the lower airway, including type II alveolar and bronchiolar epithelial cells (27). The mechanism of oncogenesis by ENTV and its relationship to that caused by JSRV are unknown. Both of these viruses are present in many countries worldwide and have a significant economic and animal health impact. In addition, the disease induced by JSRV exhibits histological features similar to those of many human pulmonary adenocarcinomas, including bronchioloalveolar carcinoma (28, 33). Thus, study of adenocarcinoma induced by JSRV and ENTV may provide insights into the etiology of human lung cancer. While ENTV and JSRV do not appear to cause lung cancer in humans having occupational exposure to these viruses, a recent study shows that antiserum directed against the JSRV capsid protein cross-reacts with 30% of human pulmonary adenocarcinoma samples but not with nontumorous lung lesions, normal lung tissue, or many adenoc...