New insight into the anti-cancer effect of aspirin

12/15/16  Portland, Ore.

Acetylsalicylic acid, a.k.a. aspirin.For reasons that remain uncertain, people who take aspirin on a regular basis have a reduced risk of colorectal cancer and certain other malignancies.

Now researchers have identified a previously unknown way that aspirin could achieve this result: "The benefit of aspirin may be due to its effect on blood cells called platelets rather than acting directly on tumor cells," says Owen McCarty, Ph.D., a professor in the Department of Biomedical Engineering at Oregon Health &Science University.

When tumor cells break off and enter the blood stream, their interactions with platelets can promote tumor cell survival by turning on genes such as c-MYC, a master regulator that is implicated in driving tumor growth in colon, pancreas, breast, lung, prostate and other cancers. In a series of experiments with cells grown in lab dishes, McCarty and colleagues showed that inhibition of platelets with low doses of aspirin cuts the signaling link between platelets and cancer cells, which in turn knocks back cancer growth.

"Of course there are many caveats," says McCarty, senior author of the paper describing the results in the American Journal of Physiology—Cell Physiology. It's not yet known, for instance, whether the cascade of effects observed in cell cultures works the same way in people. The new findings aren't sufficient to justify taking aspirin solely to help prevent cancer.

But the research helps explain how aspirin can be protective at doses too low to directly curb tumor cell growth. "Aspirin has an effect mediated by platelets," McCarty says. The effect may work in concert with aspirin's anti-inflammatory properties to oppose malignant cell growth.

The researchers began by growing human tumor cells in cultures with or without blood platelets to look for effects on tumor cell proliferation in three tumor cell lines: two derived from colon cancer and one from pancreatic cancer. The addition of platelets significantly increased the proliferation rate of all three tumor cell types.

To find out if the regulator protein c-MYC was involved, the researchers added a drug to inhibit c-MYC in cultures of colon cancer cells. As suspected, when the action of c-MYC was blocked, platelets no longer drove the proliferation of colon cancer cells, providing evidence that platelets act by triggering the increased production of c-MYC.

Platelets pre-treated with a low dose of aspirin lost the ability to promote tumor cell proliferation in two of the three cancer cell lines. The exception was an aggressive, metastatic colon cancer cell line.

A third set of experiments provided further evidence that aspirin achieved its effect via c-MYC signaling. The researchers incubated platelets with aspirin for 24 hours, added the platelets to cancer cell cultures, and then measured the production of c-MYC by cancer cells. In the two non-metastatic cancer cell lines, platelets that would otherwise drive increased c-MYC production ceased to do so when treated with aspirin.

First author Annachiara Mitrugno, Ph.D., a postdoctoral fellow in the Division of Hematology and Medical Oncology at OHSU, designed the project and performed much of the research.The researchers say the findings might have implications for aspirin therapy in conditions in which platelet activation is important, such as during the journey of the cancer cells in the circulation. Because the interaction between platelets and cancer cells can begin early following the invasion of cancer cells into the blood stream, low doses of aspirin might eventually prove safe and effective way to prevent cancer in patients at risk.

The research was supported by grants from the Altarum Institute (to McCarty and Craig Williams, a professor in the OSU/OHSU College of Pharmacy), the National Institutes of Health (to McCarty and Rosalie Sears, Ph.D., an associate professor in the Department of Molecular and Medical Genetics at OHSU), and the American Heart Association (to McCarty).



Aspirin therapy reduces the ability of platelets to promote colon and pancreatic cancer cell proliferation: implications for the oncoprotein c-MYC by Annachiara Mitrugno, Joanna L. Sylman, Anh T.P. Ngo, Jiaqing Pang, Rosalie C. Sears, Craig Williams, Owen J.T. McCarty. American Journal of Physiology –Cell Physiology (November 2016)

Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomized trials by Peter M. Rothwell, F. Gerald R. Fowkes, Jill F.F. Belch, Hisao Ogawa, Charles P. Warlow and Tom W. Meade. Lancet (January 2011)