How ancient viruses hidden in your genome could open up a new way to fight cancer
About half of your genome is made up of remnants of ancient viruses that hopped into your ancestors’ egg and sperm cells and have been passed on over generations.
While many of these viral remnants remain silent in our cells today, emerging evidence suggests that they can become active at the early stages of cancer development and targeting them may represent a powerful new approach to fight or even prevent cancer.
Dr. Laszlo Radvanyi, senior scientist at The Ottawa Hospital and professor at the University of Ottawa, has been studying ancient viral DNA in our genomes (called endogenous retroelements) for more than 20 years.
In a new research study published in Cell Reports, Dr. Radvanyi and colleagues, including Dr. Valentina Evdokimova, examined this viral DNA in an aggressive kind of childhood cancer called Ewing sarcoma. They show that it is highly active, producing fragments of the original viruses and spreading them to surrounding cells and across the body.
They also show that drugs developed to fight the human immunodeficiency virus (HIV) can be repurposed to silence these ancient viruses, suggesting a possible new approach to fight cancer.
“For decades, we’ve viewed these ancient viral elements as passive remnants in our DNA,” says Dr. Radvanyi. “We’re now discovering that they can actively shape how cancers grow, interact with the immune system and communicate throughout the body.”
Why do ancient viruses become active in cancer cells and what is their impact?
Cancer cells typically have multiple genetic mutations that allow them to grow uncontrollably, evade the immune system and activate genes that would normally be silent. In this chaotic environment, ancient viral DNA embedded in a cancer cell’s genome can become activated and produce fragments of the original virus (RNA and protein).
As Dr. Radvanyi explains, these viral fragments are like a double-edged sword:
“Initially, the body’s immune system recognizes and attacks these ancient reactivated viral pieces, along with the cancer cells that produce them,” he says. “At first glance this seem to be a good thing, but the problem is that it persists uncontrollably causing a state of so-called ‘chronic inflammation’, which is like a never-ending war.”
In this state, the immune system continues to send attack cells to the tumour, while also sending in repair cells that see the tumour as a wound to be healed. Eventually, the attacking cells become exhausted and the tumour learns to take advantage of the repair cells and enhanced supply lines to grow even faster.
“Paradoxically, the inflammation that was supposed to fight the cancer results in signals that help the cancer survive and grow faster,” says Dr. Radvanyi.
Dr. Radvanyi’s team and others have also found that tumours can spread fragments of these ancient viruses around the body in tiny bubbles called extracellular vesicles, causing more widespread inflammation and potentially more cancer.
Ewing sarcoma tissue viewed under a microscope. New research suggests that ancient viral DNA embedded in our genome may play an important role in how this cancer develops and grows. Photo: Nephron/Wikimedia Commons (CC BY-SA 3.0).
What could this mean for treating cancer?
Researchers are still trying to understand how this ancient viral reactivation affects cancer cells and how it can be manipulated. The answer will likely depend on the kind of cancer and the immune response within each person.
Dr. Radvanyi’s new research suggests that in Ewing sarcoma, ancient viruses are doing more harm then good and shutting them down may help fight the cancer. His team also shows that drugs originally developed to treat HIV (called reverse transcriptase inhibitors) can silence ancient viruses in laboratory models of Ewing sarcoma.
In a parallel project, Dr. Radvanyi’s team also showed that reverse transcriptase inhibitors can curtail early cancer development in a rodent model of spontaneous breast cancer that has similar ancient viral remnants.
Other groups have made similar findings in colorectal cancer and an early-phase clinical trial of an anti-HIV drug has shown promising results in people with colorectal cancer.
“For decades, we’ve viewed these ancient viral elements as passive remnants in our DNA,” says Dr. Radvanyi. “We’re now discovering that they can actively shape how cancers grow, interact with the immune system and communicate throughout the body. This opens up an entirely new set of opportunities to treat cancer and possibly other diseases.”
Authors:
Evdokimova V, Ruzanov P, Gassmann H, Hung M, Zhang Z, Senff-Ribeiro A, Khoshgoo N, Zheng S, Pachva MC, Ringwalt EM, Cripe TP, Roberts RD, Sorensen PH, Burdach SEG, Stein LD, Radvanyi L.
Funding:
Government of Ontario (OICR Investigator Award to L. Radvanyi), Cura Placida Children’s Cancer Research Foundation, National Cancer Institute, Research Institute at Nationwide Children's Hospital, Du musst kämpfen” Wohltätigkeitsinitiative, Dr. Robert Pfleger Foundation.
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