Infection of Tumor Cells with Xenotropic MLVs Promotes the Formation of Immature Blood Vessels.

Xenotropic Murine leukemia virus-Related Virus (XMRV) is a -retrovirus initially reported to be present within familial human prostate tumors and the blood of patients with chronic fatigue syndrome. However, subsequent studies were unable to replicate these findings, and there is now compelling evidence that detection of XMRV in human tissue represented laboratory contamination. Subsequent studies demonstrated that the virus evolved through a series of recombination events in human tumor cell lines generated through xenograft experiments, which would be of major potential concern but is mitigated by the fact that it was thought to be an extraordinarily rare event, and since as yet there is no direct evidence that XMRV infection has any functional effects that might contribute to tumor pathogenesis. Herein we describe a second xenotropic MLV, termed "B4rv", which appears to have arisen separately from XMRV through xenograft experiments with the human prostate cancer LNCaP cell line. LNCaP cells infected with XMRV or B4rv formed markedly larger tumors when injected subcutaneously into nude mice. Moreover, these tumors were highly hemorrhagic and displayed poor pericyte/smooth muscle cell (SMC) investment, which are markers of an increased metastatic potential. Conditioned media derived from LNCaPs infected with XMRV or B4rv, but not from an amphotropic MLV control virus, profoundly decreased the expression of marker genes in cultured SMC, consistent with inhibition of SMC differentiation and maturation. Similar effects were seen with a chimeric virus consisting of the MLV control virus containing the XMRV env gene, but not with an XMRV virus containing the MLV III IV env gene indicating that xenotropic envelope proteins are sufficient to induce tumor cells to produce factors that suppress differentiation of vascular SMC. Taken together, results provide evidence for a novel mechanism by which xenotropic MLVs might alter tumor pathogenesis. Although it is highly unlikely that either XMRV or B4Rv themselves infect humans and are pathogenic, results suggest that xenograft approaches commonly used in the study of human cancer promote the evolution of novel retroviruses, and raise the possibility that at least some of these might be capable of infecting humans and have pathological consequences. Dedication I dedicate this dissertation to my mom, for her love and support, and for teaching me to approach life with humor, strength, grace and optimism.

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