‘Silent’ Cytomegalovirus Can Cause Intestinal Cancers in Mice: Significance in Humans Still Unclear

Figure 1. The CMV virus, which occurs in up to 90% of the worlds' population

Human Cytomelagovirus (CMV), which infects millions of people worldwide usually without any symptoms, appears to cause gastrointestinal cancers in mice, the significance in humans is not clear.

Up to 90% of the worldwide population are silently infected with CMV (Fig. 1), which generally is not associated with any symptoms, but is a persistent little blighter nonetheless. CMV infection can cause severe disease particularly in people with a weakened immune system such as transplant patients, and AIDS patients, and  developing fetuses. People with a healthy immune system can mount a vigorous immune response to keep the virus at bay; however, in people with a weakened immune system, the virus can rage out of control and cause severe disease which can be life threatening.

 Unlike other organisms, viruses do not replicate through cell division; instead they invade and exploit host cells to do their replication for them. To do this, they must first bind to a host cell, enter it, and then hijack the hosts’ cells machinery to replicate and produce more viruses in the so called ‘primary infection’ stage. CMV viral replication is typical amongst viruses in that during the hijack of a host cell, viral DNA integrates into host cell DNA resulting in the production of various genes needed for viral replication. There are several phases of gene expression: immediate-early, delayed early and late, based on the time from initial viral infection. Following primary infection, CMV can also enter into a latent phase when the virus enters a dormant state during which viral replication does not occur. However, CMV can be later be reactivated back to a replicative state which can occur in people with a weakened immune system.

During the immediate-early gene and latent phases  of a CMV infection a gene called US28 is produced. As CMV infection had previously been detected in the cells that line the gastrointestinal tract and since the role of US28 has only been investigated in in vitro studies, Bongers et al., chose to examine the role of US28 in tumor formation in cells lining the gastrointestinal tract of mice, as reported in this months’ issue of the Journal of Clinical Investigation. To do this, they created transgenic mice─ mice where extra genes are added to the genome (Fig. 2)─ in this case the US28 gene was specifically targeted to cells in the lining layer of the mouse gut [Fig. 3]) and the lining layer of the gut was examined to see if there were any cancerous changes.

Figure 2. Creation of US28 transgenic mice

Figure 3. US28 expression in the gastrointestinal lining layer of US28 transgenic mice

In US28 transgenic mice, they found that US28 had the ability to induce cancer by increasing cell proliferation in the cells lining the gut through activating of specific intracellular signaling molecules (wnt and MAPK). US28 transgenic mice also went on to develop intestinal cancers.

As patients with inflammatory bowel disease have an increased risk of developing colon cancer, they examined whether CCL2, which is expressed in many inflammatory conditions and inflammatory bowel disease, increased the ability of US28 to induce cancer which it did.

The authors conclude that US28 produced by CMV promotes the development of cancer in transgenic mice and suggest that CMV infection may facilitate the development of gastrointestinal cancers in humans. In addition, inflammatory factors such as CCL2 can increase the oncogenic activity of US28. Although this is the first in vivo study of it’s type and builds on previous in vitro studies which have implicated US28 and CMV in the development of cancer, it falls way short of drawing any firm conclusions that CMV could cause cancer in humans. In fact, drawing any such conclusions would be unwise as this is more of a hypothesis-generating study which could form the basis of further research to analyse the association between CMV and intestinal cancer in humans.

Reference: http://www.jci.org/articles/view/42563/pdf

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