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Xenotropic MLV envelope proteins induce tumor cells to secrete factors that promote the formation of immature blood vessels

Meera Murgai1, James Thomas2, Olga Cherepanova1, Krista Delviks-Frankenberry4, Paul Deeble3, Vinay K Pathak4, David Rekosh5 and Gary Owens1*

Author Affiliations

1 Robert M. Berne Cardiovascular Research Center, University of Virginia, School of Medicine Charlottesville, Charlottesville, VA 22908, USA

2 Department of Medicine, University of California, San Francisco, CA, 94143, USA

3 Department of Biology, Mary Baldwin College, Staunton, VA, 24401, USA

4 Viral Mutation Section, HIV Drug Resistance Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, 21702, USA

5 Myles H. Thaler Center for AIDS and Human Retrovirus Research and The Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, 22908, USA

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Retrovirology 2013, 10:34  doi:10.1186/1742-4690-10-34

Published: 27 March 2013

Abstract

Background

Xenotropic Murine leukemia virus-Related Virus (XMRV) is a γ-retrovirus initially reported to be present within familial human prostate tumors and the blood of patients with chronic fatigue syndrome. Subsequent studies however were unable to replicate these findings, and there is now compelling evidence that the virus evolved through rare retroviral recombination events in human tumor cell lines established through murine xenograft experiments. There is also no direct evidence that XMRV infection has any functional effects that contribute to tumor pathogenesis.

Results

Herein we describe an additional xenotropic MLV, “B4rv”, found in a cell line derived from xenograft experiments with the human prostate cancer LNCaP cell line. When injected subcutaneously in nude mice, LNCaP cells infected with XMRV or B4rv formed larger tumors that were highly hemorrhagic and displayed poor pericyte/smooth muscle cell (SMC) investment, markers of increased metastatic potential. Conditioned media derived from XMRV- or B4rv-infected LNCaPs, but not an amphotropic MLV control virus infected LNCaPs, profoundly decreased expression of marker genes in cultured SMC, consistent with inhibition of SMC differentiation/maturation. Similar effects were seen with a chimeric virus of the amphotropic MLV control virus containing the XMRV env gene, but not with an XMRV chimeric virus containing the amphotropic MLV env gene. UV-inactivated XMRV and pseudovirions that were pseudotyped with XMRV envelope protein also produce conditioned media that down-regulated SMC marker gene expression in vitro.

Conclusions

Together these results indicate that xenotropic MLV envelope proteins are sufficient to induce the production of factors by tumor cells that suppress vascular SMC differentiation, providing evidence for a novel mechanism by which xenotropic MLVs might alter tumor pathogenesis by disrupting tumor vascular maturation. Although it is highly unlikely that either XMRV or B4Rv themselves infect humans and are pathogenic, the results suggest that xenograft approaches commonly used in the study of human cancer promote the evolution of novel retroviruses with pathogenic properties.