Viruses and Cancer: XMRV and Prostate Cancer

Way back in 1908, two Danish vets called Vilhelm Ellerman and Oluf Bang who were searching for an infectious cause for leukaemia succeed in transferring the disease from one chicken to another using cell-free tissue filtrates (Ellerman C. Bang O. Centralbl.Bakteriol. 46: 595609). In 1909, fresh out of medical school and with only two years of research under his belt, Peyton Rous joined the Rockefeller Institute and was put in charge of the laboratory for cancer research. One year later Rous was able to transmit solid tumours of chickens by transplanting tissue, which he followed up by isolating the infectious agent responsible for the tumour, Rous Sarcoma Virus (Rous P. J.Exp.Med. 12:696705; Rous P. J.Exp.Med. 13:397411). Now, I like my Kentucky fried science as much as the next guy, but what really drove these early researchers was the idea that human cancers might be infectious. Once it was shown that some (but by no means all) animal tumours were caused by viruses, it seemed like it might be a short step to translating that discovery into human medicine. Although a wide range of oncogenic viruses were shown to cause cancers in animals, it wasn’t until 1981 and the discovery of human T-cell leukaemia virus (HTLV) that the first pathogenic human retrovirus was found.

Subscribe to podcasts (free):
[iTunes] Enhanced podcasts
[RSS] mp3 podcasts (audio only)
Download this podcast (free):
Enhanced version
mp3 version (audio only)

It is currently estimated that 20-25% of human cancers are caused by viruses, although, because of the complicated nature of carcinogenesis, other factors also contribute to tumour formation in many cases. Some viruses directly promote tumours through the actions of viral protein(s) which alter the growth properties of transformed cells. The E6 and E7 proteins of oncogenic human papillomaviruses (HPV) do this by binding to and inactivating cellular tumour suppressor proteins. That’s why it would be a good idea to prevent this by vaccinating against the most dangerous types of HPV. Other human tumour viruses cause cancer indirectly and the tumour cells themselves may not express the virus. Hepatitis B (HBV) and hepatitis C (HCV) viruses are believed to cause liver cancer by inducing chronic damage to hepatocytes; continual hepatocyte division to replace the damaged liver tissue may establish a cellular environment where other genetic changes result in cancer. Human immunodeficiency virus (HIV) causes cancer indirectly by compromising the immune system and allowing cancers induced by Kaposi’s sarcoma herpes virus (HHV-8), Epstein-Barr virus (EBV), and other viruses to develop.

In the majority of human tumours, it is not possible to identify any virus involvement, but genetic studies of rare families with predispositions to certain cancers have led to the identification of tumour suppressor genes which negatively regulate cell replication or growth and whose functions are lost in tumour cells. The classic example of this is the Rb tumour suppressor gene which was identified by studies of individuals with familial retinoblastoma (Human retinoblastoma susceptibility gene: cloning, identification, and sequence. 1987 Science 235: 1394-1399).

A less well known example is the familial susceptibility locus Hpc1 which is caused by mutations in the gene for RNase L (Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. 2002 Nature Genetics 30: 181-184). RNase L helps mediate the interferon-induced innate antiviral response. In Hpc1 families, a single amino acid substitution in RNase L leads to reduced enzyme activity, and individuals with this common genotype (~11% of the population) have been reported to have a 2-fold elevated risk for development of prostate cancer. Because of the known role of RNase L in fighting virus infections, it was suggested that this defect in this enzyme might allow infection with an oncogenic virus, leading to prostate cancer. A research paper published at the end of last year showed that 40% of prostate cancers from patients with the defective RNase L gene showed evidence of infection with xenotropic endogenous murine leukaemia retrovirus (XMRV), whereas less than 2% of sporadic prostate cancers showed evidence of this virus (Identification of a Novel Gammaretrovirus in Prostate Tumors of Patients Homozygous for R462Q RNASEL Variant. 2006 PLoS Pathog 2, e25).

Although this was a tantalizing discovery, the initial results were based on PCR, which raised the possibility of laboratory contamination, and retrovirus was actually found in stromal and haematopoietic cells within the tumour rather than in the cancer cells themselves.
In January, a new paper provided crucial additional support for the original findings (An infectious retrovirus susceptible to an IFN antiviral pathway from human prostate tumours. Proc Natl Acad Sci USA. 2007 104: 1655-1660). The researchers assembled a complete XMRV genome from two cDNA clones and obtained infectious virus by transfecting human prostate cancer cell lines. They also showed that XMRV is sensitive to interferon, which is supports the fact that it is found in tumours from patients with defective RNase L genes. By cloning the junctions between XMRV DNA and human cellular DNA from two primary human prostate cancers, they confirmed XMRV infection of the tumour cells and ruled out the possibility that initial identification of the virus was a PCR artifact. At present it is not known whether XMRV integration affects gene expression directly or whether the integrations might have indirect effects on the aetiology or progression of prostate cancer.

Some big questions still remain. Is XMRV infection involved in nonfamilial cases of prostate cancer? What is the exact mechanism of tumourigenesis? What is the origin of XMRV- is it a zoonotic infection, transmitted from mice to humans? How widely distributed is XMRV infection in humans? Is XMRV associated with any other human cancers? And how many other human tumours involve infections by viruses?

• A new human retrovirus associated with prostate cancer. Proc Natl Acad Sci USA. 2007 104: 1449-1450

---

Possibly related posts: (automatically generated)

• Viruses and Human Cancer « MicrobiologyBytes
• Measle’s Spread Doesn’t Depend on Airways