Aspirin does a remarkable number of things in the body, enough that it’s said it would never win approval today from the Food and Drug Administration as an over-the-counter drug.
But among those functions are some that may explain something that doctors have recognized for some time: patients with cancer who have been taking aspirin tend to have better outcomes.
Coming to resolution
“Chronic inflammation underlies many diseases, and the links between cancer and inflammation were first identified in the 1860s,” says Panigrahy, who will soon open his own laboratory at Beth Israel Deaconess Medical Center. “There is growing body of evidence linking pathologic inflammation of the kind associated with cancer to a failure in resolution.”
The resolution Panigrahy refers to has nothing to do with New Year’s, but rather with what should happen after an inflammatory response. After an injury and infection, inflammation is a good thing, but over time it should start to resolve—swelling should go down, inflammatory immune cells called neutrophils should die off and other immune cells called macrophages should digest the debris. Panigrahy believes that a failure of inflammation to resolve could be a significant factor in cancer development.
The resolution process relies on a new family of fatty molecules (lipids) called resolvins that the body produces to tamp down the acute inflammatory response. Together with Charles Serhan, PhD, at Brigham and Women’s Hospital (BWH)—one of resolvins’ discoverers in 2002—Panigrahy has been studying how these molecules act in the contexts of both inflammation and cancer, and how aspirin may manipulate those actions. Their work was funded last year by the National Cancer Institute’s Provocative Questions initiative, an effort to answer 24 questions raised by the cancer research community that address the broad scope of cancer biology, control, treatment and prevention.
“Aspirin triggers specific resolvin pathways,” Panigrahy explains. “We know resolvins keep white blood cells from being recruited in excess to sites of inflammation. They also counteract cytokines and chemokines, two kinds of immune system signaling proteins, which promote inflammation.
“So it could be,” he continues, “that aspirin’s anti-tumor capabilities are in part a product of its capability to reduce inflammation and activate resolution.”
There’s another route by which aspirin could impact cancer: coagulation (aka clotting), which depends largely on platelets. “Aspirin irreversibly inhibits platelets,” says Elisabeth Battinelli, MD, PhD, a BWH researcher associated with our Vascular Biology Program. “That is why surgeons tell you not to take aspirin before surgery, so you don’t affect your ability to clot.”
With BCH’s Joseph Italiano, PhD, Battinelli is investigating links between platelets and cancer progression. “Tumor cells in the bloodstream hide from the immune system and migrate to metastatic sites in part by coating themselves with platelets,” she says.
Batinelli explains that platelets also carry factors that affect blood vessel growth, or angiogenesis, important in cancer growth. The factors, both pro- and anti-angiogenic, are packaged in bundles called alpha granules; platelets release these granules when activated.
“The question is,” she asks, “are there different triggers for platelets to release either set of factors?”
Evidence suggests the answer is yes. Two years ago, Battinelli and Italiano showed in the journal Blood that platelets do indeed respond to different triggers by releasing granules containing different factors. Platelets exposed to an activating molecule called ADP or to breast cancer cells release VEGF, one of the original and most potent pro-angiogenic factors known. However, those exposed to a different platelet activator, thromboxane, release endostatin, a peptide that the late Judah Folkman, MD, found to be a potent blocker of angiogenesis.
More intriguing, Battinelli and Italiano found that treating platelets with aspirin before exposing them to ADP or breast cancer cells stopped them from releasing VEGF. Battinelli was also part of a team that, in 2012, reported in Cancer Discovery that aspirin could interrupt chemical crosstalk between platelets and breast cancer cells. She now wants to see whether other anticoagulants can have similar effects on platelets’ angiogenic potential as well as on tumor progression in patients.
A note of caution: We are not suggesting that patients with cancer, or healthy people trying to avoid cancer, should start taking aspirin as a preventive measure. This research is all in its early days, and because cancer knocks the blood’s clotting capabilities off kilter, it likely wouldn’t be safe to self-medicate with what really is a powerful anticoagulant.
But both these lines of research add credence to the idea that to better treat and maybe prevent cancer, we have to look beyond tumor cells to the environments they set up for themselves.