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The Epstein Barr virus (EBV) infects over 90% of the adult population in the world and causes the disease commonly known as “mono” or mononucleosis. In children, mono often does not cause symptoms. When mono does cause symptoms, they are usually similar to the flu. In adults, the symptoms appear slowly.

Even after any symptoms have subsided, the virus is able to stay inside the body. During this period, the virus is considered latent, cannot be spread to others, and does not cause you to feel sick. It simply settles in the surface cells that line your body cavities, called epithelial cells, and will stay there for the remainder of your life. These can be found lining the stomach, intestines, throat, etc. 

The mono virus was the first human virus linked to the development of tumors or cancerous growths. In some cases, the dormant mono virus can cause dysfunction in the surrounding cells, leading to the development of cancer. In a March 2022 study, researchers have shown how the Epstein Barr virus allows cancer cells to hide from the body’s immune system.

When cells have something wrong with them, the immune system works to get rid of those cells to prevent risk of it affecting other cells. When the immune system targets abnormal cells, it sets off a domino effect of steps to get rid of them. In this domino effect, two of the cell types released are platelets and “natural killer” cells. As the name implies, natural killer cells are responsible for killing cells that have been infected with viruses. Platelets are blood cells that, when triggered, start to form clots, or clumps, to limit the spread of the virus through the bloodstream. This is also used to stop external bleeding.

Although the mononucleosis virus can promote the formation of epithelial cancer, it also allows cancer cells to escape being targeted by natural killer cells. Mono does this by secreting an enzyme known as F3. The F3 enzyme is what causes natural killer cells to overlook infected cancer cells. 

In the study, conducted at Sun Yat-sen University Cancer Center in China, scientists looked at tumors of people who had mono in the past. They gathered biopsies from patients who tested positive for mono as well as patients who tested negative. These samples were treated with a stain that would show how much F3 was present. They found that tumors of those who had mono in the past had an increased amount of F3 present in them. 

Chemical reactions in the body are called pathways, which can be thought of as different “roads” the body can take where molecules react with one another in a specific order. Mono can cause cells to activate a specific biochemical pathway that increases the amount of F3 secreted. This pathway, the AKT pathway, will cause the body to overlook the cancer cells, as well as make the cancer cells divide. 

In normal cells, a signal is needed in order for the cell to replicate. The defining feature of cancerous cells is that they don’t need this signal in order for the cell to divide. Scientists have known that the AKT pathway promotes cell proliferation for decades. They showed that this AKT pathway was active using a western blot analysis, where a chemical glows when it reacts with one of the byproducts of the pathway.

The more light showing in the sample, the more active the pathway. The scientists found that when there was more F3 enzyme, cancer cells had an active AKT pathway. In a kind of circular reinforcement, an active AKT pathway ultimately leads to even more F3 being secreted. 

The scientist knew from previous studies that mono also increases the likelihood of cancer by activating, or “turning on,” blood cells known as platelets. When platelets are activated, they will circle around cancer cells, preventing natural killer cells from reaching them. Natural killer cells have a harder time crossing this thick wall of platelets. 

When scientists inhibited the secretion of F3 experimentally, they saw that tumors grew at a much slower rate. When F3 was inhibited, platelets created a smaller, less dense circle around the cancer cells, this gave natural killer cells more of an opportunity to reach and kill the cancer cells. Therefore, scientists concluded that F3 secretion was necessary for platelets to become activated and inhibit natural killer cells from being able to reach the cancerous cells. 

The Epstein Barr Virus is one of the most common viruses in the world. Because of this, understanding its relationship to epithelial cancer is important for screening high risk patients. Knowing that F3 can be a marker for latent mono infection is a starting point on how to prevent epithelial cancers in people who have had mono previously in their lives. 

Study Information

Original study: EBV Infection in Epithelial Malignancies Induces Resistance to Antitumor Natural Killer Cells via F3-Mediated Platelet Aggregation

Study published on: March 15, 2022

Study author(s): Xiaobing Duan, Haiwen Chen, Xiang Zhou, Pingjuan Liu, Xiao Zhang, Qian Zhu, Ling Zhong, Wanlin Zhang, Shanshan Zhang, Xinyu Zhang, Yanhong Chen, Yan Zhou, Chaopin Yang, Qisheng Feng, Yi-Xin Zeng, Miao Xu, Tong Xiang

The study was done at: Sun Yat-sen University Cancer Center (China)

The study was funded by: American Association of Cancer Research

Raw data availability: Raw data is in the Research Data Deposit public platform (www.researchdata.org.cn), with the approval RDD number RDDB2022251242. The transcriptome has been deposited in the NCBI SRA database (NCBI SRA, RRID:SCR_004891) under the accession number SRP118175 (https://trace.ncbi.nlm.nih.gov/Traces/sra/?study=SRP118175) or SRP354343 (https://trace.ncbi.nlm.nih.gov/Traces/sra/?study=SRP354343)

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