USC University of Southern California

Common Virus Conclusively Identified as Cancer-Causing Oncovirus

Cytomegalovirus (CMV) is a cause of the most common salivary gland cancers according to a new study from the Laboratory for Developmental Genetics at the Herman Ostrow School of Dentistry of USC.

The findings, published online in the journal Experimental and Molecular Pathology on November 12, is the latest in a series of studies that together demonstrate CMV’s role as an oncovirus, a virus that can either trigger cancer in healthy cells or exploit mutant cell weaknesses to enhance tumor formation. CMV is the latest addition to a group of fewer than 10 identified oncoviruses.

Professor and lead author Michael Melnick said the conclusion that CMV is an oncovirus came after rigorous study of both human salivary gland tumors and salivary glands of postnatal mice.

This study illustrates not only that the CMV in the tumors is active but also that the amount of virus-created proteins found is positively correlated with the severity of the cancer, Melnick said.

Previous work with mice satisfied other important criteria needed to link CMV to cancer. After salivary glands obtained from newborn mice were exposed to purified CMV, cancer developed; in addition, efforts to stop the cancer’s progression identified how the virus was acting upon the cells to spark the disease.

Thus, the team not only uncovered the connection between CMV and mucoepidermoid carcinoma, the most common type of salivary gland cancer, but also identified a specific molecular signaling pathway exploited by the virus to create tumors, being the same in humans and mice.

“Typically, this pathway is only active during embryonic growth and development,” Melnick said, “but when CMV turns it back on, the resulting growth is a malignant tumor that supports production of more and more of the virus.”

The study, published by Melnick along with Ostrow colleagues Professor Tina Jaskoll and Assistant Professor Parish Sedghizadeh and Ohio State collaborator Professor Carl Allen, explains how the collective work clearly satisfies all of Koch’s Postulates for viruses and cancer, an established set of causal criteria that must be demonstrated before a virus can truly be designated an oncovirus.

CMV’s classification as an oncovirus has important implications for human health. The virus, which has an extremely high prevalence in humans, can cause severe illness and death in patients with compromised immune systems and can cause birth defects if a woman is exposed to CMV for the first time while pregnant. It may also be connected to other cancers besides salivary gland cancer, Melnick added.

“CMV is incredibly common; most of us likely carry it because of our exposure to it,” he said. “In healthy patients with normal immune systems, it becomes dormant and resides inactive in the salivary glands. No one knows what reactivates it.”

Jaskoll said salivary gland cancers can be particularly problematic because they often go undiagnosed until they reach a late stage. And since the affected area is near the face, surgical treatment can be quite extensive and seriously detrimental to a patient’s quality of life.

However, with the new information about CMV’s connection to cancer comes hope for new prevention and treatment methods, perhaps akin to the development of measures to mitigate human papilloma virus (HPV) after its connection to cervical cancer was established. Jaskoll added that the mouse salivary gland model created to connect CMV to cancer might also be used to design more effective treatments.

“This could allow us to have more rational design of drugs used to treat these tumors,” she said.

Melnick said that in the not too distant future, he expects much more information about viruses and their connections to cancer and other health issues seemingly unrelated to viral infection to emerge.

“This should be a most fruitful area of investigation for a long time to come,” he said. “This is just the tip of the iceberg with viruses.”

The study, “Human Cytomegalovirus and Mucoepidermoid Carcinoma of Salivary Glands: Cell-Specific Localization of Active Viral and Oncogenic Signaling Proteins is Confirmatory of a Causal Relationship,” was funded by the Oral Biology Fund of the Herman Ostrow School of Dentistry of USC.