The Story of Human Cytomegalovirus and Cancer: Increasing Evidence and Open Questions

Abstract

Although human cytomegalovirus (HCMV) is generally not regarded to be an oncogenic virus, HCMV infection has been implicated in malignant diseases from different cancer entities. On the basis of our experimental findings, we developed the concept of "oncomodulation" to better explain the role of HCMV in cancer. Oncomodulation means that HCMV infects tumor cells and increases their malignancy. By this concept, HCMV was proposed to be a therapeutic target in a fraction of cancer patients. However, the clinical relevance of HCMV-induced oncomodulation remains to be clarified. One central question that has to be definitively answered is if HCMV establishes persistent virus replication in tumor cells or not. In our eyes, recent clinical findings from different groups in glioblastoma patients and especially the detection of a correlation between the numbers of HCMV-infected glioblastoma cells and tumor stage (malignancy) strongly increase the evidence that HCMV may exert oncomodulatory effects. Here, we summarize the currently available knowledge about the molecular mechanisms that may contribute to oncomodulation by HCMV as well as the clinical findings that suggest that a fraction of tumors from different entities is indeed infected with HCMV.

How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?

“…However, CMV infection has been implicated in different malignant diseases and the term Boncomodulation^has been conied to better explain that CMV infects tumor cells and increases their malignancies (Michaelis et al 2009). Detection of CMV DNA, mRNA, and/or antigens in tumor tissues suggested a role of CMV infection in the etiology of several human malignancies.…”

“…CMV protects tumor cells from apoptosis through the induction of several intracellular signaling pathways such as AKT, mitogenactivated protein kinase, and c-Jun NH2-terminal kinase, following binding of CMV glycoproteins to PDGFR or virus coreceptors [reviewed in (Cinatl et al 2004;Michaelis et al 2009)].…”

Viral epigenomes in human tumorigenesis

“…Human cytomegalovirus (HCMV) is the largest herpesvirus (4230 kb) (Table 1) and it infects 50-100% of adults worldwide (Michaelis et al, 2009). Similar to all members of this family, it can remain latent within host cells for long periods.…”

“…Although HCMV is not considered to be oncogenic, its infection has been implicated in carcinogenesis by different pathways, and the concept of 'oncomodulation' emerged to explain the role of this virus in tumor progression (Cinatl et al, 1996(Cinatl et al, , 2004Michaelis et al, 2009).…”

Identification of human cytomegalovirus in tumour tissues of colorectal cancer and its association with the outcome of non-elderly patients

“…On the other hand, in healthy individuals, the primary asymptomatic infection is usually followed by lifelong latency. During latent infection, the virus is able to modulate multiple cellular functions and signal pathways through complex virus-host interactions, many of which are associated with oncomodulation (Michaelis et al, 2009). A number of human cancers are suggested to be associated with HCMV (Cobbs et al, 2002;Giraldo et al, 1980;Huang et al, 2002;Pacsa et al, 1975;Sanford et al, 1977).…”