Early regions of JC virus and BK virus induce distinct and tissue-specific tumors in transgenic mice.

Abstract

JC virus and BK virus are ubiquitous human viruses that share sequence and structural homology with simian virus 40. To characterize tissue-specific expression of these viruses and to establish model systems for the study of human viral-induced disease, transgenic mice containing early regions of each of the viruses were produced. The viral sequences induced tumors in a distinct and tissue-specific manner that was similar to their tissue tropism in humans. Ten JC virus-containing founder mice were produced, of which 5 survived to maturity. Four of them developed adrenal neuroblastomas, which metastasized to several other tissues. JC virus tumor-antigen RNA was detected at high levels in the tumor tissues and at low levels in the normal tissues of these mice. One of the three BK virus-containing mice was abnormally shaped and died at 2 weeks of age. The other two BK virus-containing mice developed primary hepatocellular carcinomas and renal tumors and died at 8-10 months of age. BK virus tumor-antigen RNA was expressed in tumor tissues of both mice. Since each of the viruses retained the general tissue tropism that it exhibits in humans, these data suggest that transgenic mice harboring human viruses will be useful as animal models for viral-induced diseases.

Oncogenic transformation by BK virus and association with human tumors

“…Tumors induced by BKV in mice and rats were fibrosarcoma, liposarcoma, ostesarcoma, nephroblastoma, glioma and choroid plexus papilloma, the latter arising only in mice (Corallini et al, 1977;Noss et al, 1981;Noss and Stauch, 1984). Moreover, transgenic mice expressing BKV Tag developed hepatocellular carcinoma, renal tumors and lymphoproliferative disease (Small et al, 1986;Dalrymple and Beemon, 1990). Gardner's BKV strain seems to be more oncogenic than other isolates, such as MM, BKV-IR or RF (Costa et al, 1976;Dougherty, 1976;Caputo et al, 1983).…”

Detection and expression of human BK virus sequences in neoplastic prostate tissues

“…It resides in the kidneys in a latent or persistent state, but can be reactivated upon immunosuppression of the host and is associated with hemorrhagic cystitis and polyomavirus nephropathy (Arthur et al, 1986;Hiraoka et al, 1991;Pappo et al, 1996;Randhawa et al, 1999;Li et al, 2002). BKV oncogenically transforms rodent cells in culture, causes kidney tumors in transgenic mice, and transforms primary human cells in culture when coexpressed with an activated ras oncogene (Portolani et al, 1975;Pater and Pater, 1986;Small et al, 1986;Dalrymple and Beemon, 1990). BKV has been reported to be detected in a number of human tumors, including those in the urinary tract, brain, pancreatic islet, lung, eye, liver, Kaposi's sarcoma, and bone (reviewed in Imperiale, 2000Imperiale, , 2001Reploeg et al, 2001;Tognon et al, 2003).…”

Detection of polyomaviruses and herpesviruses in human adrenal tumors

“…They have been involved in the development of several human cancers and lymphomas, but their role in human adrenal tumors has never been investigated, although experimental evidences indicate that polyomaviruses can infect and transform cells of the adrenal cortex and the adrenal medulla (Small et al, 1986;Ressetar et al, 1993Ressetar et al, , 1997Tischler et al, 1993;Servenius et al, 1994;Flaegstad et al, 1999;Thomas et al, 2000;Hornsby et al, 2002). We have recently reported the case of a patient with a large NFA, which showed histological features consistent with HCMV infection, whose presence was confirmed by detection of HCMV DNA and proteins (Pomara et al, 2006).…”

“…Our finding of polyomaviruses in ACC and in malignant pheochromocytoma is intriguing, since these viruses have been associated with adrenal malignancy in experimental animal models, such as transgenic mice containing early regions of polyomaviruses, and in studies of human cancers. In particular, JCV-and SV40-containing mice have been shown to develop highly malignant adrenal neuroblastomas that metastasize to other tissues, whereas BKV-containing mice develop primary hepatocellular carcinomas and renal tumors (Small et al, 1986;Feigenbaum et al, 1992;Ressetar et al, 1993;Servenius et al, 1994). In humans, BKV sequences and large T-antigen expression were demonstrated in 18 out of 18 neuroblastomas, but not in normal adrenal medulla (Flaegstad et al, 1999).…”