Expression of the Jaagsiekte Sheep Retrovirus Envelope Glycoprotein Is Sufficient To Induce Lung Tumors in Sheep

Institute of Comparative Medicine, University of Glasgow Veterinary School, 464 Bearsden Road, Glasgow G61 1QH, Scotland.
Journal of Virology (Impact Factor: 4.44). 09/2006; 80(16):8030-7. DOI: 10.1128/JVI.00474-06
Source: PubMed


Jaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary adenocarcinoma (OPA). The expression of the JSRV envelope (Env) alone is sufficient to transform a variety of cell lines in vitro and induce lung cancer in immunodeficient mice. In order to determine the role of the JSRV Env in OPA tumorigenesis in sheep, we derived a JSRV replication-defective virus (JS-RD) which expresses env under the control of its own long terminal repeat (LTR). JS-RD was produced by transiently transfecting 293T cells with a two plasmid system, involving (i) a packaging plasmid, with the putative JSRV packaging signal deleted, expressing the structural and enzymatic proteins Gag, Pro, and Pol, and (ii) a plasmid which expresses env in trans for JS-RD particles and provides the genomes necessary to deliver JSRV env upon infection. During the optimization of the JS-RD system we determined that both R-U5 (in the viral 5' LTR) and the env region are important for JSRV particle production. Two independent experimental transmission studies were carried out with newborn lambs. Four of five lambs inoculated with JS-RD showed OPA lesions in the lungs at various times between 4 and 12 months postinoculation. Abundant expression of JSRV Env was detected in tumor cells of JS-RD-infected animals and PCR assays confirmed the presence of the deleted JS-RD genome. These data strongly suggest that the JSRV Env functions as a dominant oncoprotein in the natural immunocompetent host and that JSRV can induce OPA in the absence of viral spread.

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Available from: Chris Cousens, Dec 23, 2013
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    • "Jaagsiekte Sheep RetroVirus envelope has been demonstrated in various cell lines in vitro, e.g., human bronchial epithelial cells BEAS- 2B (Danilkovitch-Miagkova et al., 2003), rat fibroblasts 208F (Hofacre and Fan, 2004), canine kidney epithelial cells MDCK (Liu and Miller, 2005), rat kidney epithelial cells RK3E (Maeda et al., 2005) or mouse fibroblasts NIH3T3 (Maeda et al., 2001; Palmarini et al., 2001). In vivo, oncogenic properties of the envelope have been reported in sheep and mice, using viral vectors bearing Jaagsiekte Sheep RetroVirus-envelope (Wootton et al., 2005; Caporale et al., 2006). Similarly, Enzootic Nasal Tumour Virus-1 is able to transform fibroblastic and epithelial cell lines (Alberti et al., 2002; Dirks et al., 2002; Liu et al., 2003a) and to induce pulmonary tumours in mice (Wootton et al., 2006). "
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    ABSTRACT: Sheep and goats are widely infected by oncogenic retroviruses, namely Jaagsiekte Sheep RetroVirus (JSRV) and Enzootic Nasal Tumour Virus (ENTV). Under field conditions, these viruses induce transformation of differentiated epithelial cells in the lungs for Jaagsiekte Sheep RetroVirus or the nasal cavities for Enzootic Nasal Tumour Virus. As in other vertebrates, a family of endogenous retroviruses named endogenous Jaagsiekte Sheep RetroVirus (enJSRV) and closely related to exogenous Jaagsiekte Sheep RetroVirus is present in domestic and wild small ruminants. Interestingly, Jaagsiekte Sheep RetroVirus and Enzootic Nasal Tumour Virus are able to promote cell transformation, leading to cancer through their envelope glycoproteins. In vitro, it has been demonstrated that the envelope is able to deregulate some of the important signaling pathways that control cell proliferation. The role of the retroviral envelope in cell transformation has attracted considerable attention in the past years, but it appears to be highly dependent of the nature and origin of the cells used. Aside from its health impact in animals, it has been reported for many years that the Jaagsiekte Sheep RetroVirus-induced lung cancer is analogous to a rare, peculiar form of lung adenocarcinoma in humans, namely lepidic pulmonary adenocarcinoma. The implication of a retrovirus related to Jaagsiekte Sheep RetroVirus is still controversial and under investigation, but the identification of an infectious agent associated with the development of lepidic pulmonary adenocarcinomas might help us to understand cancer development. This review explores the mechanisms of induction of respiratory cancers in small ruminants and the possible link between retrovirus and lepidic pulmonary adenocarcinomas in humans.
    Veterinary Microbiology 09/2015; DOI:10.1016/j.vetmic.2015.08.008 · 2.51 Impact Factor
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    • "The ability of JSRV to cause lung tumors in sheep that are histologically and phenotypically similar to those frequently found in humans, particularly that of never smokers, make it an attractive model for understanding the etiology and carcinogenesis of human lung cancer [2]–[4]. Unlike most replication-competent retroviruses, which cause cancer by insertional activation of cellular oncogenes or by acquisition of cellular oncogenes, the envelope protein of JSRV is itself a potent oncogene that when expressed in mouse [5] or sheep lungs [6] is sufficient to induce lung cancer. We have developed a tractable mouse model to study lung cancer induced by the JSRV envelope protein (Jenv) that involves delivering the Jenv gene to the mouse respiratory tract using a replication defective adeno-associated virus (AAV) vector. "
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    ABSTRACT: The phosphatidylinositol 3-kinase-regulated protein kinase, Akt, plays an important role in the initiation and progression of human cancer. Mammalian cells express three Akt isoforms (Akt1-3), which are encoded by distinct genes. Despite sharing a high degree of amino acid identity, phenotypes observed in knockout mice suggest that Akt isoforms are not functionally redundant. The relative contributions of the different Akt isoforms to oncogenesis, and the effect of their deficiencies on tumor development, are not well understood. Here we demonstrate that Akt isoforms have non-overlapping and sometimes opposing functions in tumor initiation and progression using a viral oncogene-induced mouse model of lung cancer and Akt isoform-specific knockout mice. Akt1 ablation significantly delays initiation of lung tumor growth, whereas Akt2 deficiency dramatically accelerates tumorigenesis in this mouse model. Ablation of Akt3 had a small, not statistically significant, stimulatory effect on tumor induction and growth by the viral oncogene. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Ki67 immunostaining of lung tissue sections revealed that the delayed tumor induction in Akt1-/- mice was due to the inhibitory effects of Akt1 ablation on cell growth and survival. Conversely, the accelerated growth rate of lung tumors in Akt2-/- and Akt3-/- mice was due to increased cell proliferation and reduced tumor cell apoptosis. Investigation of Akt signaling in tumors from Akt knockout mice revealed that the lack of Akt1 interrupted the propagation of signaling in tumors to the critical downstream targets, GSK-3α/β and mTOR. These results demonstrate that the degree of functional redundancy between Akt isoforms in the context of lung tumor initiation is minimal. Given that this mouse model exhibits considerable similarities to human lung cancer, these findings have important implications for the design and use of Akt inhibitors for the treatment of lung cancer.
    PLoS ONE 04/2014; 9(4):e94595. DOI:10.1371/journal.pone.0094595 · 3.23 Impact Factor
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    • "Hyal2 homologues from a variety of different species, including humans, have been shown to mediate entry of JSRV Env pseudotyped retroviral particles [17]. JSRV induces lung tumors in sheep through expression of the envelope (Env) protein [18]. Several studies have shown that the JSRV Env protein has the ability to transform a variety of cell types in vitro [19-21], including human cells [22], and can induce lung tumors in mice [23,24]. "
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    ABSTRACT: Adenocarcinoma is the most common type of non-small cell lung cancer and is frequently observed in non-smoking patients. Adenocarcinoma in-situ (formerly referred to as bronchioloalveolar carcinoma) is a subset of lung adenocarcinoma characterized by growth along alveolar septae without evidence of stromal, vascular, or pleural invasion, that disproportionately affects never-smokers, women, and Asians. Adenocarcinoma in-situ is morphologically and histologically similar to a contagious lung neoplasm of sheep called ovine pulmonary adenocarcinoma (OPA). OPA is caused by infection with the exogenous betaretrovirus, jaagsiekte sheep retrovirus (JSRV), whose envelope protein (Env) is a potent oncogene. Several studies have reported that a proportion of human lung adenocarcinomas are immunopositive for an antigen related to the Gag protein of JSRV, however other groups have been unable to verify these observations by PCR. Here we examine human lung cancer tissue arrays (TA) for evidence of JSRV Env protein and DNA by immunohistochemical staining and PCR, respectively. Our results reveal that a subset of human lung cancers express an antigen that reacts with a JSRV Env-specific monoclonal antibody in immunohistochemistry and that exogenous JSRV-like env and gag sequences can be amplified from TA tumor samples, albeit inefficiently. While a causative role has not been established, these data suggest that a JSRV-like virus might infect humans. With next generation sequencing approaches, a JSRV-like virus in human lung cancers may be identified which could have profound implications for prevention, diagnosis and therapy.
    BMC Research Notes 03/2014; 7(1):160. DOI:10.1186/1756-0500-7-160
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