If ever there was a wonder drug, aspirin might be it. Originally derived from the leaves of the willow tree, this mainstay of the family medicine cabinet has been used successfully for generations to treat conditions ranging from arthritis to fever, as well as to prevent strokes, heart attacks and even some types of cancer, among other ills. In deed, the drug is so popular that annual consumption worldwide totals about 120 billion tablets.
In recent years scientists have discovered another possible use for aspirin: stopping the spread of cancer cells in the body after an initial tumor has already formed. The research is still developing, but the findings hint that the drug could one day form the basis for a powerful addition to current cancer therapies.
Not everyone responds equally well to the drug, however, and for some people it can be downright dangerous. Investigators are thus trying to develop genetic tests to determine who is most likely to benefit from long-term use of aspirin. The latest research into the drug’s cancer-inhibiting activity is generating findings that could possibly guide those efforts.
MYRIAD MECHANISMS
During the past century researchers demonstrated that aspirin inhibits the production of certain hormonelike substances called prostaglandins. Depending on where in the body these prostaglandins are produced, they may trigger pain, inflammation, fever or blood clotting.
Obviously no one wants to block these natural responses all the time—particularly as they help the body to heal from cuts, bruises, infections and other injuries. But sometimes they linger for too long, causing more harm than good. Long-lasting, or chronic, inflammation, for example, increases the risk of developing heart disease and cancer by causing repeated damage to otherwise normal tissue. Eventually the damaged tissue, depending on where it is located and a host of other factors, may become a vessel-clogging plaque in a coronary artery or a tiny tumor hidden deep within the body. By turning down the prostaglandin spigot, aspirin prevents thousands of heart attacks every year and probably stops a significant number of tumors from forming in the first place.
In 2000 scientists discovered a second major major mechanism of action for aspirin in the body. The drug boosts the production of molecules called resolvins, which also helps to quench the fires of inflammation.
More recently, investigators have started to elucidate a third way that aspirin works—one that interferes with the ability of cancer cells to spread, or metastasize, through the body. Intriguingly, in this case, the drug’s anti-inflammatory properties do not appear to play the starring role.
Metastasis is a complex process that, somewhat counterintuitively, requires a certain amount of cooperation between tumor cells and their host. Some number of malignant cells must break away from the original tumor, cross the walls of a nearby blood vessel to enter the bloodstream and avoid getting detected by immune system defenders as they travel about the body. Those that survive this gauntlet must then cross the walls of another blood vessel at a different location in the body, nestle into surrounding tissue that is completely different from their original birthplace and start to grow.
Elisabeth Battinelli, a hematologist at Brigham and Women’s Hospital in Boston, has shown that cells called platelets, which are better known for their ability to trigger blood clots, also have an important part in allowing tumor cells to spread. First malignant cells coopt certain chemical signals from the platelets that collect along the blood vessel wall. Instead of directing the repair of a potential breach in the wall, however, these repurposed signals help the cancer cells break through the barrier and sneak into the bloodstream. Then the cancer cells cloak themselves in a protective
layer of platelets to hide from the patrolling sentries of the immune system. Once the tumor cells leave the bloodstream at some distant location, they instruct the platelets that have come along with them to produce so-called growth factors that trigger the development of new blood vessels, essential avenues that carry nutrients and oxygen to the now thriving secondary tumor.
Researchers often inject tumor cells into the bloodstream of mice to approximate what happens during metastasis when cancer cells must navigate the bloodstream to find a new home in the body. When Battinelli and her team fed aspirin to certain strains of mice and then injected them with malignant cells, the investigators discovered that the platelets did not shield breakaway cancer cells from the immune system or produce the necessary growth factors that allow cancer cells to grow and divide in a new location. Thus, aspirin appears to fight cancer in two ways: its anti-inflammatory action prevents some tumors from forming, and its antiplatelet properties interfere with some cancer cells’ ability to spread.
REWIRING PLATELETS
How does aspirin stop tumor cells from hijacking platelets to do their bidding? Instead of blocking a single compound (a prostaglandin, for example), in this case the drug seems to turn entire groups of genes on or off in the nuclei of certain blood cells.
To try to better understand this previously unknown effect of aspirin, cardiologist Deepak Voora of Duke University and his colleagues looked at cells called megakaryocytes, which give rise to platelets. Using complex mathematical and pharmacological tools, they identified about 60 genes that are either turned on or off in the megakaryocytes in response to aspirin. The end result of all this genetic manipulation: the platelets produced by the megakaryocytes did not clump together, which presumably prevented them from camouflaging cancer cells. Thus, in addition to blocking prostaglandins, aspirin basically “rewires the platelets” so that they do not serve as inadvertent accomplices to metastasis.
There is still a lot of basic research that must be conducted, Voora says, before the feasibility of an aspirin-based therapy to prevent metastasis can be determined. The next steps are to confirm these experiments in larger, more diverse groups of people and to better understand the normal functions of these aspirinsensitive genes. In the meantime, investigators hope to learn enough to create a genetic test that will make it possible to tell whether a patient might benefit from taking aspirin. Ideally, such a test would determine not only the most effective dose of the drug but also whether or not the person’s body is reacting to the medication as predicted.
Much of aspirin’s cardiovascular benefit, for example, stems from its ability—at a dose as low as 81 milligrams—to prevent clots from forming in the bloodstream. And yet one study of 325 people found that aspirin has no effect on the clotting processes of 5 percent of patients who consume the drug, with another 24 percent having a reduced effect. Furthermore, some people may experience severe side effects—such as bleeding. Thus, no responsible clinician would advise everyone to take the drug on a daily basis.
Investigators have identified about 60 genes that are turned on or off in response to aspirin.
To date, the only way to know for sure that a patient is resistant to aspirin’s anticlotting effects is to test the person’s blood after several weeks of therapy to see if it takes longer to form clots than it once did—an expensive proposition that is not very practical. Genetic tests would presumably be less expensive, but they are a long way off. “It’s challenging to develop a single molecular test that will tell you if someone will respond [to aspirin] or not because it’s become clear that there is no single pathway by which aspirin works,” says Andrew Chan, an epidemiologist at Harvard Medical School. In other words, researchers and physicians will have to look at many different genes—and their complex interactions— to determine how likely a patient is to benefit from aspirin treatment, whether for cardiovascular disease or cancer.
Until then, the U.S. Preventive Services Task Force, a national panel of independent health experts, recommends low-dose aspirin to prevent cardiovascular disease and colorectal cancer in only a very select group of people. Those who may benefit the most, according to the available evidence, are adults aged 50 to 59 years who are likely to live at least another decade, have a 10 percent or greater risk of having a heart attack or stroke in that time, are not at increased risk for bleeding (because of other medications, for example) and are willing to take low-dose aspirin daily for at least 10 years. For adults aged 60 to 69 years, the task force recommends selectively offering aspirin treatment depending on individual circumstances. It has determined that there is not enough evidence to weigh the potential benefits against possible harms for daily aspirin use in adults younger than 50 years or older than 70.
Most patients who have already suffered a heart attack or stroke, however, seem to benefit from regular aspirin therapy regardless of age, says Paul Gurbel, director of the Inova Center for Thrombosis Research and Translational Medicine in Falls Church, Va. And if you think you are currently suffering a heart attack, many doctors recommend chewing a 325-milligram tablet of aspirin immediately after you have called 911 to minimize the damage from any potential clot.
Nevertheless, aspirin cannot make up for a lifetime of bad habits. Quitting smoking—or better yet, never starting—eating moderately, keeping your body lean and remaining physically active may be as effective as—or even more effective than—taking aspirin on a daily basis for keeping lots of health problems, including heart disease and cancer, at bay. Aspirin may well be an amazing drug, but it is still not a cure for everything that ails you.