Scientists have discovered the mechanism that viruses use to produce cancer

Viral infections are thought to be a major cause of 10 to 20% of cancers worldwide, representing a significant portion of the global cancer burden.

A recent discovery could help us better understand how viruses cause this disease.

Cleveland Clinic researchers have discovered one of the mechanisms that a type of virus called Kaposi’s sarcoma-associated herpesvirus (KSHV) uses to induce cancer.

The study, published last month in Nature Communications, found that the KSHV virus activates a specific pathway responsible for cellular metabolism and how cells grow and multiply.

Using current breast cancer drugs approved by the US Food and Drug Administration (FDA), they were able to reduce virus replication, halt lymphoma progression and shrink existing tumors in preclinical models.

Jun Zhao, of the Cleveland Clinic Florida Research and Innovation Center, who holds a PhD in genetic, molecular and cellular biology, is the lead author of the study.

“Our findings have significant implications: viruses cause between 10% and 20% of cancers worldwide, a number that is constantly increasing as new discoveries are made. Treating virus-induced cancers with standard cancer therapies can help shrink existing tumors , but it doesn’t solve the underlying problem of the virus,” Zhao explained in a press release. “Understanding how pathogens turn a healthy cell into a cancer cell reveals exploitable vulnerabilities and allows us to engineer and retool existing drugs that can effectively treat virus-associated malignancies.”

Kaposi’s sarcoma-associated herpesvirus

Kaposi’s sarcoma-associated herpesvirus, also known as human herpesvirus 8 (HHV8), is “A type of virus that causes Kaposi’s sarcoma (a rare cancer in which lesions develop in the skin, lymph nodes, lining of the mouth, nose and throat and in other body tissues).

KSVH also causes certain types of lymphoma (cancer that starts in the cells of the immune system),” according to the National Cancer Institute.

According to the press release, KSVH is similar to other herpesviruses in that it is often asymptomatic and remains latent in the body after primary infection. However, when the immune system becomes weakened or compromised, as is the case in many elderly people, transplant recipients, or those with HIV or AIDS (acquired immunodeficiency syndrome), the virus can reactivate. In these high-risk immunocompromised groups, the reactivated virus “can trigger aggressive cancers”.

Cancer cells replicate rapidly and reprogram the body’s metabolism to help them grow and spread. Most viruses do not produce their own energy or the molecules they need and therefore capture the body’s cells to make them perform tasks that advance the cancer. However, the researchers discovered that the KSHV virus takes control of two host proteins (CDK6 and CAD), which causes the virus to replicate faster and the cells to multiply and spread uncontrollably.

The press release also states that these KSHV-induced cancers are “fast-acting, aggressive and difficult to treat” and that it is estimated that approximately 10 percent of people in North America and Northern Europe and 50 percent of people in Africa have KSHV, although the numbers are thought to be much higher, as the virus can be asymptomatic and often goes undiagnosed.

A University of Pittsburgh article on KSHV states, “It is highly likely that over 95% of healthy people infected with KSHV have no symptoms and never will” and that problems occur once a person’s immune system is compromised.

Viruses and cancer

In addition to KSHV, several other viruses are known to cause cancers in humans. According to the American Cancer Society, the following viruses can cause cancer in humans:

• Human papillomavirus
• Epstein-Barr virus
• Hepatitis B virus and hepatitis C virus
• Human immunodeficiency virus (HIV, which causes AIDS)
• Human T-lymphotropic virus-1
• Merkel cell polyomavirus

The American Society for Microbiology states that “viruses can lead to cancer by associating with host proteins, by proliferating when the human immune system is weakened, and by hijacking human cells to proliferate. Compared to other viruses, human tumor viruses are unusual in that they infect , but they don’t kill, the host cells.”

This process allows human tumor viruses to initiate persistent infections.

The research team found that a combination of Palbociclib – an FDA-approved drug to treat breast cancer that works by blocking CDK6 – and a compound that blocks CAD (the two host proteins that are hijacked by the virus) caused a substantial reduction of tumor size and improvements in cancer survival rates in preclinical models.

According to the press release, “The majority of tumors virtually disappeared after about a month of treatment, and the remaining tumors shrank by about 80%. Survival increased to 100% for the selected lymphoma cell lines.”

Future impact

The findings could lead to new options for the treatment of KSHV-associated cancers, which include Kaposi’s sarcoma, primary effusion lymphoma and HHV8-associated multicentric Castleman disease. Likewise, they could also extend beyond KSHV-associated cancers to other cancer-causing viruses using the same or similar mechanisms.

As for what these findings mean for the future, Zhao says, “Cellular metabolism could be hijacked by both viruses and cancers for pathogenesis. By investigating these mechanisms of metabolic reconfiguration, we aim to find the Achilles heel of viruses of cancer-causing and non-viral cancers. I’m excited to see what the future holds for this work.”