03:08pm Sunday 12 July 2020

Sylvester/AIDS Researcher Unifies Theory on Human Viral Oncogenesis

A study led by Enrique A. Mesri, Ph.D., associate professor of microbiology and immunology, sheds light on this group of cancers and may help develop new targeted therapies.

For the study, “Human Viral Oncogenesis: A Cancer Hallmarks Analysis,” published March 12 in a special issue of the Cell Press journal Cell Host and Microbe devoted to microbes and cancer, Mesri and his team used the comprehensive Hallmarks of Cancer model to dissect the viral, host and environmental co-factors that contribute to the biology of multistep oncogenesis mediated by established human oncoviruses.

“Cancers caused by viruses are little understood due to lack of animal models, the very different nature of the cancer the viruses cause, but fundamentally, because understanding the biology of viral cancers has been difficult, as they are at the crossroad of virology, infectious disease and oncology,” said Mesri, who also is a member of the Viral Oncology Program at Sylvester Comprehensive Cancer Center, Director of the AIDS Malignancies Program at the Miami Center for AIDS Research and Director of the Graduate Program in Microbiology and Immunology. “Human viral cancers have intriguing features. Not all people who are infected with a cancer-causing virus develop the cancer, and when they do, it tends to be either after long periods of time or after the onset of another infection or disease, such as HIV/AIDS.”

This happens, Mesri says, because infection with an oncovirus is generally not sufficient to cause cancer. Therefore, other carcinogenic risk factors also are involved in the process. In some cases, the immune system helps prevent viral cancers while a form of immune response — inflammation — promotes their development, such as with hepatocellular carcinomas after viral hepatitis.

“These facts and current experimental limitations of viral oncology have led to many misconceptions and confusions about this important aspect of infectious disease and cancer for the public, for researchers and for health professionals,” Mesri said.

To definitively understand human viral oncogenesis, Mesri and his team analyzed the six viruses that cause cancer in humans – Epstein-Barr virus (EBV), high-risk human papillomaviruses (HPVs), hepatitis B and C (HBV and HCV), human T cell lymphotropic virus-1 (HTLV-1), and Kaposi’s sarcoma herpesvirus (KSHV). They also reviewed current literature to answer these key questions:

Why is this virus able to cause cancer? What is unique about its biology and genes that allows it to dysregulate cell control pathways and cause cancer? If this virus is equipped to cause cancer, why doesn’t it cause cancer in all the infected individuals?

After careful analysis, a unifying picture emerged: Human oncoviruses are a group of highly evolved pathogens that depend on chronic infection of the human host for their survival and transmission to other hosts. To survive the immune system, the viruses carry powerful genes that help them replicate inside cells and persist by evading cell-killing mechanism and the immune response.

“What is really fascinating about these viruses is that these powerful viral genes they carry are able to usurp and dysregulate cell survival and cell proliferation mechanisms,” Mesri said. “Thus, they are able to convey characteristics or hallmarks of the cancer cell to the infected cell.”

Fortunately for most people, since human carcinogenesis requires the dysregulation of many growth regulatory pathways to achieve full transformation, and, in healthy individuals, viral infections are generally counteracted by the immune system, oncoviral infection is insufficient to provide all the cancer hallmarks. However, the delicate balance can be broken and the carcinogenic process accelerated by cancer co-factors, such as environmental mutagens, which can convey the missing cancer hallmarks, and immunosuppression, which allows the oncogenically infected cell to survive and thrive leading to the development of cancer.

“If we could understand the epidemiology of the infection with these cancer-causing viruses, we could develop vaccines to prevent the infection and thus, the cancer these agents cause,” said Mesri.

Successful examples are the hepatitis B vaccines that prevented millions of hepatocellular cancer cases in Asia and the novel HPV vaccines that prevent HPV-related cervical carcinomas.

Understanding the key host pathways deregulated by the viral proteins in viral cancers could lead to the development of promising new therapies, Mesri says, but he also stressed the importance of these findings to create awareness about treating viral cancers.

“It is clear that these viruses did not evolve to cause cancer but cancer is an active consequence of viral biology,” he said. “In treating viral cancers, it is essential to consider that although these cancers allow for host and viral targeting, the biology of the virus and the infected cancer cell are so intimately intertwined that they can both counteract therapeutic interventions and create additional sources of resistance to treatment.”

Mesri, an expert in Kaposi’s sarcoma herpesvirus, AIDS-associated cancers and viral lymphomas, enlisted world-recognized papillomavirus and hepatitis virus experts Karl Münger, Ph.D., from Harvard Medical School, and Mark Feitelson, Ph.D., from Temple University, to co-author the study.

University of Miami

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