Cytomegalovirus classed as an oncovirus by US researchers
MedWire News: US researchers believe they have sufficient evidence to confirm that human cytomegalovirus (hCMV) is an oncovirus.
The team, led by Michale Melnick (University of Southern California, Los Angeles, USA), reports that hCMV is the cause of salivary gland mucoepidermoid carcinoma (SG MEC).
"Although still controversial, there is growing evidence that active hCMV infection is associated with a variety of malignancies, including brain, breast, lung, colon, and prostate," explain Melnick et al in the journal Experimental and Molecular Pathology.
"Given that hCMV is frequently resident in SG ductal epithelium, we hypothesized that hCMV would be important to the pathogenesis of SG MEC," they add.
The researchers had previously carried out a series of experiments in mice and showed that purified CMV induces malignant transformation in SG cells using the pathogenic COX/AREG/EGFR/ERK signaling pathway previously reported to be involved in human MEC.
In the present study, Melnick and team used histologic and molecular techniques to investigate the presence of hCMV in 39 human SG MECs selected randomly from a repository of cases spanning 2004-2011.
They detected hCMV intermediate-early protein 1 (IE1) - an immediate early gene product of active viral expression - in 38 of the 39 MECs, but not in unaffected adjacent tumor regions or normal salivary glands (n=3).
IE1 immunostaining was positive in all tumor grades, specifically in epidermoid and intermediate tumor cells and the perinuclear cytoplasm, but not in mucous or stromal cells. The protein was frequently localized in the in nuclei of dysplastic cells and in viral inclusion bodies, which "is indicative of active infection," say the researchers.
Furthermore, the degree of IE1 immunostaining increased with increasing tumor grade.
Similar results were observed for a second hCMV protein, pp65, Melnick et al note.
The researchers also demonstrated that the proteins of the pathogenic COX/AREG/EGFR/ERK signaling pathway colocalized in epidermoid and intermediate tumor cells, which are also areas of IE1 localization. By contrast, these proteins were mostly absent in normal salivary glands and unaffected tumor-adjacent regions.
"If we are to propose that hCMV is etiologically related to MEC, then we must show evidence that the revised and relevant [for viruses and cancer] Koch's Postulates are operative," the researchers remark.
They say that they believe all four prospective causal criteria for viruses and cancer have been fully satisfied, namely because: protein markers for active hCMV are present in 97% of MECs; markers of active hCMV are absent in non-neoplastic SG tissues; hCMV-specific proteins (IE1, pp65) are in specific cell types and expression is positively correlated with severity; and hCMV correlates and colocalizes with an upregulation and activation of an established oncogenic signaling pathway (COX/AREG/EGFR/ERK).
"Importantly, these findings are corroborated by the prior satisfaction of the fifth causal criterion, namely the ability of purified virus to induce malignant transformation of SG cells in an in vitro animal model, using a similar oncogenic signaling pathway," they add.
Therefore, "in the absence of any contrary evidence, hCMV can reasonably be designated an 'oncovirus'," Malnick and co-authors conclude.
By Laura Dean