‘Eureka’ moment as University of Cambridge scientists uncover mechanism that enables aspirin to prevent spread of some cancers

University of Cambridge scientists have described the “Eureka moment” when they discovered the mechanism behind how aspirin could stop the spread of some cancers.

They learned how it reduce the metastasis of some cancers by stimulating the immune system - a finding that will support clinical trials that are already under way.

It could lead to the targeted use of aspirin to prevent the spread of susceptible types of cancer, and to the development of more effective drugs to prevent cancer metastasis.

Earlier studies that prompted the existing trials have shown some patients taking daily low-dose aspirin benefit from a reduction in the spread of some cancers, including breast, bowel, and prostate cancers. But not until now was it understood how aspirin could prevent metastases.

However, the researchers warn that, in some people, aspirin can have serious side-effects so the results of the studies are needed to determine how to use it safely and effectively to prevent cancer spread. Patients should consult their doctor before starting to take it, they say.

Prof Rahul Roychoudhuri, of the Department of Pathology at the University of Cambridge, who led the work, said: “Despite advances in cancer treatment, many patients with early stage cancers receive treatments, such as surgical removal of the tumour, which have the potential to be curative, but later relapse due to the eventual growth of micrometastases – cancer cells that have seeded other parts of the body but remain in a latent state.

“Most immunotherapies are developed to treat patients with established metastatic cancer, but when cancer first spreads there’s a unique therapeutic window of opportunity when cancer cells are particularly vulnerable to immune attack. We hope that therapies that target this window of vulnerability will have tremendous scope in preventing recurrence in patients with early cancer at risk of recurrence.”

The researchers say their latest discovery was serendipitous. They were investigating the process of metastasis because 90 per cent of cancer deaths occur when cancer spreads to other parts of the body from where it started.

They were seeking to understand how the immune system responds to metastasis, because individual cancer cells breaking away from their originating tumour and spreading elsewhere 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.

They previously screened 810 genes in mice and found 15 had an effect on cancer metastasis. In particular, mice lacking a gene that produces a protein called ARHGEF1 had less metastasis of various primary cancers to the lungs and liver.

They found that ARHGEF1 suppresses T cell, an immune cell that can recognise and kill metastatic cancer cells.

In seeking to develop treatments to take advantage of this discovery, they looked for a way for drugs to target it. The researchers 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).

But this was a revelation - because TXA2 is already well-known and linked to how aspirin works.

Produced by platelets, the blood stream cells that help blood clot, TXA2 prevents wounds from bleeding but occasionally causes heart attacks and strokes.

Aspirin reduces the production of TXA2, leading to anti-clotting, which is the reason it has an ability to prevent heart attacks and strokes.

The new study, published in Nature, found aspirin prevents cancers from spreading by decreasing TXA2 and releasing T cells from suppression.

A mouse model of melanoma showed 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.

First author Dr Jie Yang, from the Department of Pathology at Cambridge, said: “It was a Eureka moment when we found TXA2 was the molecular signal that activates this suppressive effect on T cells.

“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.”

Researchers plan to collaborate 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.

Prof Langley, who was not involved in this study, 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.

“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.”

The research was principally funded by the Medical Research Council, with additional funding from the Wellcome Trust and European Research Council.

The Add-Aspirin clinical trial is funded by Cancer Research UK, the National Institute for Health and Care Research, the Medical Research Council and the Tata Memorial Foundation of India.