In a novel study published today, (Monday 18 January), in Nature Communications, researchers at The Institute of Cancer Research, London, have discovered that more aggressive breast cancers secrete a protein called Wnt7a which drives the recruitment of surrounding cells and promotes the spread of the disease.
Examining the amount of Wnt7a in hundreds of breast cancer samples, the team found that women who had a high level of Wnt7a expression were much more likely to develop secondary disease and had a reduced chance of survival.
In order to effectively spread to other parts of the body, breast tumours need to trigger surrounding normal (non-cancer) cells called fibroblasts to help them invade into neighbouring tissue, enter the bloodstream and, finally, colonise distant tissue.
These activated fibroblasts, known as carcinoma-associated fibroblasts (CAFs), have long been known to help tumours grow and spread, but it has so far been unclear how tumours activate and harness them.
Led by Professor Isacke at the Breast Cancer Now Toby Robins Research Centre at The Institute of Cancer Research, the team have now found that the secretion of Wnt7a by tumours could be such a message, providing a ‘rallying call’ to recruit normal fibroblasts to further their growth.
By comparing non-aggressive and aggressive breast cancers in mice, the researchers first investigated why some tumours are able to recruit fibroblasts to further their invasion while others cannot. They demonstrated that the key difference between aggressive and non-aggressive tumours was that the aggressive tumours secreted more Wnt7a.
Subsequent studies showed that blocking the production of Wnt7a in aggressive tumours reduced the likelihood of metastasis to the lung, while increasing Wnt7a production in less-aggressive tumour cells promoted invasion and spread.
Crucially, the team confirmed the clinical importance of Wnt7a in human breast cancer. Studying nearly 900 breast tumour samples – sourced from both an independent cohort and The Cancer Genome Atlas – they found that high levels of Wnt7a expression in breast tumours were associated with more aggressive breast cancer types, an increased risk of breast cancer spreading and reduced chances of survival for patients.
While this research is at an early stage, it is hoped that Wnt7a might be used in the future as a marker to help identify which patients’ breast cancers might be more aggressive and therefore be more likely to spread – the point at which it becomes incurable. The cross-talk between tumours and their surrounding environment is also a mechanism that could eventually be used as a therapeutic target.
Further studies will now be required to understand precisely how activated fibroblasts promote tumour metastasis, by illuminating the full two-way communication between breast tumours and CAFs.
Professor Clare Isacke, Professor of Molecular Cell Biology and Academic Dean at The Institute of Cancer Research, London, said:
“Our research showed that women whose breast cancers secreted a greater amount of Wnt7a were much more likely to see their disease spread to other parts of the body, at which point it unfortunately becomes incurable.
“We urgently need to stop tumours recruiting and activating non-cancer cells by secreting this Wnt7a protein, It is now clear that effective anti-cancer strategies will also need to target the cross-talk between cancer cells and normal cells, and we believe this could be a particularly promising avenue for new treatments in the future.”
Dr Richard Berks, Senior Research Communications Officer at Breast Cancer Now, said:
“This is a significant discovery that confirms the secretion of Wnt7a as a way in which breast tumours issue a “rallying call” to surrounding non-cancer cells to help them spread.
“This finding could underpin future studies into secondary breast cancer, a disease that still kills nearly 12,000 women in the UK each year. The next step will now be to understand what signals these radicalised cells send back to tumours to help them grow.
“Ultimately, by finding out what messages a tumour sends to its surrounding tissue to recruit cells to its cause, Professor Isacke hopes to find ways to make tumours less aggressive and treatments more effective.”
The study, which has been published today in Nature Communications, was funded by Breast Cancer Now and Cancer Research UK. Breast Cancer Now thanks Walk the Walk for their generous support towards this project.