Aspirin could prevent some cancers from spreading

Scientists have discovered how aspirin could reduce the metastasis of some cancers by stimulating the immune system. Their work could lead to the targeted use of aspirin to prevent the spread of susceptible types of cancer, as well as the development of more effective drugs to prevent cancer metastasis.

Studies of people with cancer have previously observed that those taking daily low-dose aspirin have a reduction in the spread of some cancers, such as breast, bowel and prostate cancers. This is significant as, while cancer starts out in one location, 90% of cancer deaths occur when cancer spreads to other parts of the body. However, it wasn’t known exactly how aspirin could prevent metastases.

In this study, led by the University of Cambridge and published in the journal Nature, the scientists wanted to better understand how the immune system responds to metastasis as, when individual cancer cells break away from their originating tumour and spread to another part of the body, they are particularly vulnerable to immune attack. The immune system can recognise and kill these lone cancer cells more effectively than cancer cells within larger originating tumours, which have often developed an environment that suppresses the immune system.

The researchers previously screened 810 genes in mice and found 15 that had an effect on cancer metastasis. In particular, they found that mice lacking a gene that produces a protein called ARHGEF1 had less metastasis of various primary cancers to the lungs and liver. The researchers determined that ARHGEF1 suppresses a type of immune cell called a T cell, which can recognise and kill metastatic cancer cells.

To develop treatments to take advantage of this discovery, the team needed to find a way for drugs to target it. The scientists traced signals in the cell to determine that ARHGEF1 is switched on when T cells are exposed to a clotting factor called thromboxane A₂ (TXA₂). This was an unexpected revelation for the scientists, because TXA₂ is already well-known and linked to how aspirin works.

Produced by platelets, TXA₂ helps blood clot and prevents wounds from bleeding, but occasionally this causes heart attacks and strokes. Aspirin reduces the production of TXA₂, leading to the anti-clotting effects, which underlies its ability to prevent heart attacks and strokes.

The researchers found that aspirin prevents cancers from spreading by decreasing TXA₂ and releasing T cells from suppression. They used a mouse model of melanoma to show that in mice given aspirin, the frequency of metastases was reduced compared to control mice, and this was dependent on releasing T cells from suppression by TXA₂.

“It was a Eureka moment when we found TXA₂ was the molecular signal that activates this suppressive effect on T cells,” said Dr Jie Yang, who carried out the research at the University of Cambridge.

“Before this, we had not been aware of the implication of our findings in understanding the anti-metastatic activity of aspirin. It was an entirely unexpected finding which sent us down quite a different path of enquiry than we had anticipated.

“Aspirin, or other drugs that could target this pathway, have the potential to be less expensive than antibody-based therapies, and therefore more accessible globally.”

In the future, the researchers plan to help the translation of their work into potential clinical practice by collaborating with Professor Ruth Langley of the MRC Clinical Trials Unit at University College London, who is leading the Add-Aspirin clinical trial, to find out if aspirin can stop or delay early stage cancers from coming back.

Commenting on the study, Langley said, “This is an important discovery. It will enable us to interpret the results of ongoing clinical trials and work out who is most likely to benefit from aspirin after a cancer diagnosis.”

Langley also acknowledged that, in a small proportion of people, aspirin can cause serious side effects, including bleeding or stomach ulcers. “Therefore, it is important to understand which people with cancer are likely to benefit and always talk to your doctor before starting aspirin,” she said.

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