Tel Aviv University study finds link between heart attacks and cancer growth
Researchers shows factor-rich microscopic particles escape from the healing heart and travel through the bloodstream to reach existing tumors
Renee Ghert-Zand is the health reporter and a feature writer for The Times of Israel.
Researchers at Tel Aviv University say they’ve discovered a mechanism that encourages the growth of cancerous tumors in people with heart disease.
The study done on mice, led by medical student Tal Caller, found that microscopic bubbles called small extracellular vesicles (sEVs) escape from the heart as it heals from a myocardial infarction (heart attack). They enter the bloodstream and end up “feeding” cancer tumors in other parts of the body.
Caller and his fellow researchers found that a drug commonly used to treat heart disease may be able to reduce or stop the sEVs’ ability to promote cancer.
The peer-reviewed study, overseen by Prof. Jonathan Leor, from TAU’s Neufeld Cardiac Research Institute and the Taman Institute at Sheba Medical Center’s Leviev Cardiovascular and Thoracic Treatment and Research Center, was published in March in Circulation.
Researchers and clinicians have long observed that people with heart disease also have a greater risk of developing cancer.
In 2019, researchers at the American Heart Association’s Scientific Sessions presented data from an evaluation of 12,712 people from the Framingham Heart Study, an ongoing, multi-generational study that began in 1948 seeking to identify common factors or characteristics that contribute to cardiovascular disease.
The study presented at the AHA conference followed the cohort, none of whom had heart problems at the start, for 15 years. It found that the people with elevated risk factors for heart disease over a 10-year period were three times more likely to be diagnosed with cancer during the 15 years of the study.
In addition, people in the study who later had a heart attack, heart failure or atrial fibrillation had a much greater chance of developing cancer compared with those who did not have any heart problems.
Most such studies are observational, and scientists are trying to understand the causal relationship between heart disease and cancer. Some think it has to do with the increased inflammation and changes in hormone levels heart problems cause in the body.
Could sEVs and their cargo explain the causal relationship?
“Most researchers looking at sEVs and heart disease focus on the potential for them to treat or even cure heart disease. We look at their pathophysiology,” Leor said.
“A few years ago we reported on the role of sEVs found in the fat around the heart and how they carry factors that have the potential to cause atrial fibrillation, the most common type of heart arrhythmia, or irregular heart rhythm,” he said.
In light of the increasing interest in looking into the possible connections between heart disease and cancer, the TAU team thought about researching how sEVs might be related. They thought that several existing reports claiming that single factors were behind the association between the two diseases didn’t make sense.
“We thought that a single factor was probably not enough. So we decided to look at sEVs, which contain multiple factors, including proteins, cytokines, micro-RNA, and RNA,” Leor said.
According to Caller, there continues to be debate about whether or not sEVs are reparative to the heart after a heart attack.
“But that is not what we were looking at. We were focused on the growth of cancer tumors and focused on the fact sEVs find their way into the blood’s circulation after a heart attack,” Caller said.
Unleashing growth factors and suppressing immunity
According to Caller, he and his colleagues saw these tiny bubbles, measuring 30-100 nanometers, reach cancer tumors. He wasn’t able to say that they target the tumors for a specific purpose, only that some end up in the tumors. They also end up in organs like the liver and kidneys.
Leor explained that some of the biological material inside the sEVs appear to fuel the cancer.
“sEVs 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,” he said.
So far, the researchers have found that the sEVs play a role in the progression of existing cancer. They didn’t focus on whether they contribute to cancer’s showing up in the first place.
“We don’t know this yet, but we can hypothesize that they do because pro-inflammatory and pro-fibrotic factors they carry are known to play a role in the initiation of cancer,” Caller explained.
The researchers found that in the mice there was a strong association between sEVs and the growth of lung cancer. At the same time, they found a weak association with the growth of triple-negative breast cancer, the most aggressive form of breast cancer.
When they looked at sEVs and cancer cell cultures in dishes in the lab, they again found a strong association with lung cancer progression. There was also a strong association with colon cancer growth. There was a weak association with the growth of melanoma, and again with triple-negative breast cancer.
“There are of course many other types of cancer, but we didn’t look into all of them for this study,” Caller said.
Targeting the secretion of sEVs
The researchers tried to think of a way to reduce the secretion of sEVs from the mice’s damaged hearts. They decided to give the animals spironolactone, a well-known, old and effective drug used to treat heart failure. They found that the hearts secreted 30 percent fewer sEVs and the cancerous tumors grew more slowly.
Despite the promising results of spironolactone, the researchers were concerned about the feasibility of using the drug in the clinical setting because of its negative side effects, such as gynecomastia (an imbalance of the hormones estrogen and testosterone causing an increase in the amount of breast gland tissue in boys or men).
Leor suggested that newer drugs currently used in clinical practice that are similar to spironolactone, but cause fewer adverse effects could be considered.
“The important point is that the damaged heart must be treated effectively to reduce the growth of cancer,” Caller said.
According to Leor, the emphasis should be on the prevention of illness through exercise and a healthy diet until the connection between sEVs and cancerous tumor growth is fully understood.
“Hopefully, in the future, we will have more specific pharmacological targets based on Tal’s research that we can use to target the connection between heart disease and different types of cancer,” he said.
