How can aspirin prevent the metastasis of some cancers?

BarcelonaScientists have been trying for some time to validate a clinical observation that some people with certain types of tumors, such as breast, bowel, and prostate cancers, who take low-dose aspirin every day have a lower risk of cancer metastasis. In fact, several clinical trials are underway to understand this effect. But can a drug designed to reduce pain, inflammation, and fever really prevent the spread of cancer? Until now, the exact mechanism by which this common medicine in the medicine cabinet can stimulate the immune system to stop the spread of cancer was unknown. journey tumor, but this Wednesday news was published in the magazine Nature from a study carried out in mice that has been directed by the University of Cambridge and funded by the public organisation of the United Kingdom, the Medical Research Council and the European Research Council.

This international team has described the capacity of aspirin (acetylsalicylic acid) to reduce the appearance of metastases in mice, since it favours the activation of T lymphocytes, a type of immune cell that in normal conditions is responsible for detecting and eliminating cells. The research suggests in several animal models – suffering from breast, colon or melanoma cancer – that treatment with aspirin results in a lower rate of metastasis in other organs, such as the lungs and liver, when compared with mice that have not received the medication. According to the authors, "the finding paves the way for the use of more effective antimetastatic immunotherapies".

The Cambridge researchers explain that they discovered by chance the relationship between aspirin and the spread of cancer. The group was investigating the process of metastasis and looking for answers to the question of why, although the disease begins in one organ, 90% of deaths occur when it has spread to other parts of the body. Specifically, they wanted to better understand how the immune system responds to metastasis and why tumor cells are especially vulnerable to defenses. "The immune system can recognize and kill these solitary cancer cells more effectively than those within larger original tumors, which have often developed an environment that suppresses the immune system," they explain in a statement.

A relatively unknown gene

In the study, they examined 810 genes and found that 15 had some influence on cancer metastasis. In particular, they found that mice that lacked a relatively unknown gene that produces a protein called ARHGEF1 had less metastasis from several primary cancers in the lungs and liver. By zooming in further and tracing cellular signals, they determined that ARHGEF1 is activated when T cells are exposed to a clotting factor called thromboxane A2 (TXA2). “It was a eureka moment to find that TXA2 was the molecular signal that triggers this suppressive effect on T cells. It was a totally unexpected finding that sent us down a very different research path than we had anticipated,” explains pathologist Jie Yang, from the same team.

TXA2 is produced by platelets – a cell in the bloodstream that helps blood clot, preventing wounds from bleeding – and aspirin reduces the production of these cells. That is, it has an anticoagulant effect. Therefore, the scientists' hypothesis is that aspirin prevents cancers from spreading by decreasing TXA2 and freeing T cells from suppression. "This phenomenon is especially relevant for tumor cells that enter the bloodstream with the risk of generating metastasis," explains Ignacio Melero, co-director of the department of immunology and immunotherapy at the Clínica Universidad de Navarra, to SMC Spain.

The head of the medical oncology service at the Catalan Institute of Oncology (ICO) in Hospitalet, Ramón Salazar, positively values both the methodology and the results of the study, although he emphasizes that this will not influence clinical recommendations for the time being. "The biggest limitation is the same as always: what happens in preclinical models does not necessarily happen later in the human body. In fact, in several randomized trials in adjuvant colon and breast cancer, aspirin has not improved the results of relapse-free survival or overall survival," he points out in statements to SMC.

According to Yang, aspirin has the potential to be less expensive than antibody-based therapies and therefore more widely available worldwide. Although the researchers themselves admit that more information is needed, they stress that the discovery will support ongoing clinical trials. However, they warn that, in some people, aspirin can have serious side effects and clinical trials are underway to determine how to use it safely and effectively.

"In a small proportion of people, it can cause serious side effects, such as bleeding or stomach ulcers. So it is important to understand which people with cancer can benefit," stresses Ruth Langley, from the MRC clinical trials unit at University College London. She is leading the Add-Aspirin clinical trial, to find out if aspirin can stop or delay the return of early-stage cancers, and the Cambridge group is already working together to expand the study published on Wednesday.

Future research could therefore explore combining aspirin with other immunotherapies to further enhance its anti-metastatic effects, the authors suggest. “Most immunotherapies are developed to treat patients with established metastatic cancer, but when cancer first spreads there is a unique therapeutic window of opportunity when cancer cells are especially vulnerable to immune attack,” says senior study author Professor Rahul Roychoud.