Scientists have uncovered a key mechanism that explains how aspirin may help prevent cancer metastasis, potentially leading to more targeted clinical applications. Their discovery could enhance ongoing clinical trials and contribute to the development of more effective drugs for preventing the spread of certain cancers. However, they caution that aspirin can have serious side effects in some individuals, and clinical trials are being conducted to determine the safest and most effective way to use it for cancer prevention. Previous studies have suggested that people with cancer who take daily low-dose aspirin experience reduced metastasis in cancers such as breast, bowel, and prostate cancer. However, until now, the precise mechanism by which aspirin prevents metastasis was unknown.
The research team was initially studying the process of metastasis, as cancer typically originates in one location but becomes life-threatening when it spreads to other parts of the body. Metastasis is responsible for 90% of cancer-related deaths, making it a critical area of study. Scientists focused on understanding how the immune system reacts to metastasis, as cancer cells that break away from a primary tumor and spread are particularly vulnerable to immune system attacks. The immune system is more effective at recognizing and eliminating these lone cancer cells compared to larger tumors, which often create a suppressive environment that weakens immune responses.
Professor Rahul Roychoudhuri in the Department of Pathology at the University of Cambridge, who led the work, stated: “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.”
To explore this further, researchers screened 810 genes in mice and identified 15 genes that influenced metastasis. Among these, the gene responsible for producing a protein called ARHGEF1 stood out. They found that mice lacking this gene exhibited significantly less metastasis in primary cancers affecting the lungs and liver. Further investigation revealed that ARHGEF1 plays a crucial role in suppressing a type of immune cell known as a T cell, which is responsible for recognizing and destroying metastatic cancer cells. This discovery suggested that inhibiting ARHGEF1 could enhance the immune system’s ability to combat cancer spread.
To develop treatments targeting this mechanism, the scientists examined how ARHGEF1 is activated in cells. They traced the signaling pathways and discovered that ARHGEF1 is switched on when T cells are exposed to thromboxane A2 (TXA2), a clotting factor. This revelation was unexpected, as TXA2 is already well known for its role in blood clotting and cardiovascular health. TXA2 is produced by platelets, which help blood clot to prevent excessive bleeding but can also contribute to heart attacks and strokes. Aspirin reduces TXA2 production, which explains its ability to prevent cardiovascular events.
Their new research demonstrated that aspirin also prevents cancer metastasis by lowering TXA2 levels, which in turn releases T cells from suppression. This allows T cells to function more effectively in eliminating metastatic cancer cells. Using a mouse model of melanoma, they found that mice treated with aspirin had significantly fewer metastases compared to those that did not receive aspirin. This effect was directly linked to the release of T cells from TXA2-induced suppression.
Dr Jie Yang in the Department of Pathology at the University of Cambridge, first author of the report, stated: “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.”
Looking ahead, the researchers plan to further investigate how their findings can be applied to clinical practice. They are collaborating with Professor Ruth Langley at the MRC Clinical Trials Unit at University College London, who is leading the Add-Aspirin clinical trial. This trial aims to determine whether aspirin can prevent or delay the recurrence of early-stage cancers. If successful, the research could lead to the integration of aspirin into cancer treatment protocols to help reduce the risk of metastasis in susceptible patients.
Professor Langley, who was not involved in this study, commented: “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 study received primary funding from the Medical Research Council, with additional financial support from the Wellcome Trust and the European Research Council. The Add-Aspirin clinical trial is supported by Cancer Research UK, the National Institute for Health and Care Research, the Medical Research Council, and the Tata Memorial Foundation of India. This collaborative effort underscores the importance of ongoing research in identifying safe and effective strategies to combat cancer metastasis using widely available medications like aspirin.
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