Researchers at Tel Aviv University (TAU) and the Leviev Cardiothoracic and Vascular Center at the Sheba Medical Center have found a mechanism responsible for increasing the risk of developing cancer among patients with heart disease. They say that small extracellular bubbles, or vesicles (sEVs), that are secreted from the sick heart to heal itself are released into the bloodstream and promote the growth of cancer cells throughout the body.

The discovery may improve the protocols for treating heart disease so that clinicians also consider the increased risk of cancer.

The research was conducted under the leadership of Professor Jonathan Leor from the Neufeld Cardiac Research Institute of TAU’s Faculty of Medical and Health Sciences and the Taman Institute at Sheba’s Leviev Center, and his student Tal Caller, a medical and research student at TAU’s School of Medicine. The research was published on March 15, 2024, in  Circulation.

“In 2013, the Israeli cardiologist Tal Hasin showed for the first time that there is a connection between heart failure and cancer,” Caller explains. “Patients with heart disease are at a higher risk of developing cancer, and since heart disease is already a leading cause of death, many people are at risk. Our research revealed that the diseased heart secretes a cancer-promoting factor, which we identified as small extracellular vesicles (sEVs). These are tiny particles wrapped in a simple membrane, which all cells secrete, but because of heart damage, these vesicles are released in greater quantities and contain factors related to inflammation, healing, growth, creation of new blood vessels, and changes in the immune system. These vesicles move through the circulatory system and eventually reach the tumor or the pre-cancerous tissue.

“Following an injury in the heart muscle and deterioration to heart failure, sEVs containing growth factors and small nucleic acid molecules that promote cell division are released,” Caller continues. “These sEVs contribute to the healing of the injured cardiac tissue. However, released from the injured heart, those vesicles move within the body’s circulatory system, eventually targeting cancerous growths.”

“Many theories have been proposed to explain the increased risk of cancer in heart patients,” says Professor Leor. “They started with shared risk factors such as smoking, diabetes, and obesity and ended with a single protein or molecule. We showed for the first time that the diseased heart secretes sEVs that contain thousands of different growth factors. These bubbles directly promote the growth of certain tumors and also modulate the immune system, making the body more vulnerable to tumor growth.”

To test their hypothesis, the TAU researchers inhibited the formation of sEVs in animal models with heart disease and found that the risk of cancer decreases along with the inhibition of vesicle production. However, this is not a viable therapeutic option, since inhibiting the production of the vesicles causes severe undesired side effects.

“When you systemically inhibit the formation of sEVs, you get less cancer but you cause collateral damage along the way,” Professor Leor says. “That is why we tried a different strategy: we treated the patient’s heart to reduce the damage to the cardiac tissue so that it secretes fewer sEVs. We used spironolactone, which is a well-known and effective drug used to treat heart failure.

“We treated the animals with spironolactone at a very early stage of the disease and found that the heart secreted 30% fewer sEVs and the cancerous tumors grew more slowly. Our experiment shows that it is possible to intervene in heart disease in a way that reduces the risk of cancer among heart patients.”

“It may be necessary to adjust the existing treatments for the heart so that they also consider the risk of cancer,” Caller concludes. “In addition, it is possible to find biomarkers among heart patients that will indicate an increased risk of cancer, since not all patients are at an increased risk. This is basic research, and much work is still required to unravel the connection between the two.”

The study was funded by the Israel Cancer Association and the Israel Science Foundation.