BERKELEY, CA (UroToday.com) - The presence of xenotropic murine leukemia virus-related virus (XMRV) in tumor tissue of patients with a familial form of prostate cancer was originally reported in 2006 by Urisman et al.[1]
Three years later, Lombardi et al. [2] reported a higher prevalence of XMRV in patients suffering myalgic encephalomyelitis (also known as chronic fatigue syndrome), in comparison with the healthy population. Although these reports attracted a lot of attention on XMRV, the relevance and significance of those findings in human disease remain unclear and have been questioned in subsequent studies.
While discussing the available data supporting and questioning the relationship between XMRV infection and disease, this review provides a general overview of the molecular biology of XMRV, including its genomic organization, cellular receptors, restriction factors in the host cell that provide innate immunity to XMRV, and potential mechanisms of oncogenesis, as well as available data on the characterization of XMRV integration sites in prostate cancer cells. A number of sections were also dedicated to antiretroviral drugs found to be effective on XMRV in vitro.
XMRV is a gammaretrovirus related to the murine leukemia virus (MLV) that has been used for many years as a model to study RNA tumor viruses (i.e. retroviruses). The association of prostate cancer with polymorphisms in RNASEL,[1] a gene involved in interferon-mediated antiviral response, gave credibility to the association between XMRV and prostate cancer. The higher prevalence of XMRV in prostate cancer tumors compared with tissue from healthy patients was reported by several labs in the U.S. (e.g. Cleveland Clinic, Emory University, etc…) but not in studies carried out with samples collected in Europe, Korea, Mexico and a few other sites in the U.S. (e.g. John Hopkins University in Baltimore, several hospitals in New York City, and the Dan L. Duncan Cancer Center in Houston, Texas, etc.). Although the discordant results were initially attributed to geographic variation, justified concerns appeared as different groups in the U.S. failed to show any XMRV in prostate cancer tissues, suggesting that detection of XMRV in prostate cancer was the result of different types of experimental artifacts. Since the publication of our review at the end of November 2010, a number of papers on this subject have been published, and my overall impression is that they have shifted the balance towards the lack of significance of XMRV in prostate cancer.
Several reported findings are compatible with a role of XMRV in human disease:
- XMRV belongs to the xenotropic/polytropic subgroup of MLV and has a broad host range and for example, XMRV can infect human blood cells in vitro, [3]
- retroviruses are vectors or promoters of oncogenic processes, and XMRV has been shown to integrate into the DNA of prostate cancer cells,
- XMRV replication can be stimulated by androgens and inhibited by androgen inhibitors, and
- the inoculation of macaques intravenously with XMRV leads to persistent chronic disseminated infection where XMRV replication in the prostate has been observed during the acute phase of infection.[4]
On the other hand, in the original study of Urisman et al.,[1] XMRV was detected in 1% of stromal cells, but not in tumor cells - suggesting an indirect effect on the transformation process. Still, XMRV could induce cancer by low-frequency insertional activation or by generation of highly active transforming viruses. In principle, insertional mutagenesis (commonly observed in gammaretroviruses, such as XMRV) should render tumors in which all the cells are infected. Infection of a minor fraction of prostate cancer cells would be incompatible with a causal role of XMRV in prostate tumorigenesis.
Recently published studies illustrating the extreme care needed to exclude DNA or RNA contamination in PCR analyses of XMRV raised important concerns on the significance of the association between XMRV and human disease. Thus, MLV-encoding nucleic acids were found in commercial PCR reagents. Amplifiable levels of mouse mitochondrial DNA or intracisternal A particle sequences (derived from expression of retrotransposons) can be found in human blood and tissue samples due to handling problems, and human tumor cell lines propagated by xenografting in mice could be infected with XMRV (see ref.[5] for a summary of available data). It should be noted that a millionth of a microliter of mouse blood is a potential source of a positive signal in a PCR assay for MLV. In addition, false positives obtained by immunohistochemical detection of XMRV in tumors using specific antisera could be explained by insufficient purity of the antigen raised against the virus.[6]
Surprisingly, phylogenetic analysis of XMRV sequences isolated from the prostate cancer cell line 22Rv1 showed higher diversity than those obtained from cancer patients.[7] Based on these findings and the sequence similarity of the XMRV clones obtained from both sources, authors concluded that the human tumor cell line was probably infected during 22Rv1 xenografting in mice. Recently, these authors also reported that 2 out of 14 XMRV integration sites in DNA from prostate tumor tissues were identical to sites cloned in the same laboratory from experimentally infected DU145 cells (a human prostate cancer cell).[8] These results suggested a contamination of the patient-derived tumor tissue by XMRV present in the DU145 cells, although the reverse contamination cannot be ruled out. Evidence suggesting a contamination of human samples with XMRV originating from the 22Rv1 cell line during in vivo passages of a prostate tumor xenograft, by a mechanism of recombination, has been recently presented in the 18th Conference on Retroviruses and Opportunistic Infections, held in Boston a few weeks ago.[9] These results provide strong support for the disappointing possibility of XMRV being nothing else but a laboratory contaminant. In this scenario, XMRV infection would be devoid of any clinical significance.
Acknowledgment:
I thank Alan Rein for valuable comments and discussion.
References:
- Urisman A, et al. Identification of a novel gammaretrovirus in prostate tumors of patients homozygous for R462Q. RNASEL variant. PLoS Pathog 2006; 2: e25.
- Lombardi VC, et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 2009; 326: 585-589.
- Hohn O, et al. No evidence for XMRV in German CFS and MS patients with fatigue despite the ability of the virus to infect human blood cells in vitro. PLoS One 2010; 5: e15632.
- Onlamoon N, et al. Infection, viral dissemination and antibody responses of Rhesus macaques exposed to the human gammaretrovirus XMRV. J. Virol. 2011: doi :10.1128/JVI.02411-10
- Smith RA. Contamination of clinical specimens with MLV-encoding nucleic acids: implications for XMRV and other candidate human retrovirus. Retrovirology 2010; 7: 112.
- Aloia AL, et al. XMRV: A new virus in prostate cancer? Cancer Res. 2010; 70: 10028-10033.
- Hué S, et al. Disease-associated XMRV sequences are consistent with laboratory contamination. Retrovirology 2010; 7: 111.
- Garson JA et al. Analysis of XMRV integration sites from human prostate cancer tissues suggests PCR contamination rather than genuine human infection. Retrovirology 2011; 8: 13.
- Paprotka T et al. XMRV probably originated through recombination between 2 endogenous murine retroviruses during in vivo passage of a human prostate cancer xenograft. 18th Conference on Retroviruses and Opportunistic Infections, Boston, Feb 27 – Mar 2, 2011; Abstract 91LB.
Written by:
Luis Menéndez-Arias as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Evidence and controversies on the role of XMRV in prostate cancer and chronic fatigue syndrome - Abstract
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