| This dissertation explores the pathology of two simple retroviruses: Jaagsiekte Sheep Retrovirus (JSRV) and Xenotropic Murine Leukemia Virus-Related Virus (XMRV).;JSRV, a beta-retrovirus, is the etiological agent of ovine pulmonary adenocarcinoma, a form of non-small cell lung cancer in sheep and goats. It has been shown that the envelope protein alone is sufficient to induce tumorigenesis in the lungs of mice when delivered via an adeno-associated viral vector. Herein we attempted to determine whether JSRV envelope-induced tumors were maintained by a small population of tumor-initiating cells, termed cancer stem cells. In order to test this hypothesis, dissociated cancer cells were sorted based on putative stem cells markers and reporter vectors. No association with increased tumor-initiating capacity was found with any of the tested cell surface markers. Additionally, we were unable to detect any evidence of Oct4 expression in tumor-bearing mouse lung. However, tumor cells possessing an active Wnt-signaling pathway did show a significant correlation with increased tumor formation upon transplantation. Limiting dilution transplant analysis demonstrated a large fraction of cells are capable of tumor re-initiation. These results show that JSRV envelope-induced cancer is not maintained by a small subset of cancer stem cells but that individual tumor cells do vary in their tumor initiation potential in a fashion that correlates with the presence of Wnt signaling.;XMRV is a gamma-retrovirus initially discovered in prostate cancer biopsies. Several studies have shown a significant correlation between the presence of XMRV and related viral sequences with prostate cancer and chronic fatigue syndrome. We found that XMRV could induce apoptosis in a human neuroblastoma cell line (SH-SY5Y) in a cAMP-dependent fashion. Overexpression of XMRV's cellular receptor, Xpr1, was shown to increase intracellular cAMP levels as well as to bind to the Gbeta subunit of the large G-protein heterotrimer. Treatment of SY5Y cells with forskolin partially rescued the cells from XMRV toxicity. Moreover, expression of truncated forms of Xpr1 imparted similar protection. These results suggest that Xpr1 is a novel, atypical G-protein coupled receptor and that XMRV binding can disrupt the normal signaling function of Xpr1, leading to apoptosis of infected cells. |
