Study Reveals how Cancer Protein Increases Lung Metastasis Risk by Making Blood Vessels Leakier

A protein carried by tiny particles released by tumour cells makes blood vessels in the lungs more permeable, allowing metastatic tumours to establish more easily, according to a study led by researchers at Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center.

Published in Nature Cancer, the findings provide new insight into how cancer spreads to the lungs and could help researchers develop new ways to assess and reduce the risk of metastasis.

Researchers investigated how some tumours increase their ability to spread by releasing extracellular vesicles and particles (EVPs), which carry proteins, DNA, and other molecules that influence surrounding tissues. Although EVPs are produced naturally by almost all cells for communication, tumour cells exploit them to prepare distant organs for metastasis.

The team identified a protein called integrin alpha-5 as a key component of tumour-derived EVPs that increases the permeability of blood vessels in the lungs, promoting metastasis across several cancer types.

“These findings help us understand one of the mechanisms underlying lung metastasis, so that we can start to think about ways to detect and block it to improve outcomes for patients,” said study senior author Dr David Lyden, the Stavros S. Niarchos Professor in Pediatric Cardiology and a member of the Gale and Ira Drukier Institute for Children’s Health and the Sandra and Edward Meyer Cancer Center at Weill Cornell.

Over the past two decades, researchers have shown that tumours use EVPs to reshape their surroundings and prepare distant organs for cancer spread. As a result, scientists increasingly view EVPs and their molecular cargo as promising targets for new cancer therapies and liquid biopsies, which analyse blood samples for signs of disease.

Previous research from the Lyden laboratory showed that tumour-derived EVPs increase the permeability of blood vessels in the lungs, making it easier for circulating tumour cells to enter lung tissue. In the new study, the researchers identified the specific EVP cargo responsible for this effect.

In animal studies, tumours including melanoma, osteosarcoma, and colorectal cancer caused marked increases in the permeability of lung blood vessels through the release of tumour-derived EVPs. The researchers also found that injecting these EVPs into healthy, tumour-free mice produced the same effect, demonstrating that the particles alone were sufficient to increase blood vessel permeability.

Further experiments revealed that the EVPs did not act directly on the endothelial cells lining blood vessels. Instead, they targeted lung macrophages carrying integrin alpha-5, triggering the release of the inflammatory protein IL-6, which loosened the lining of blood vessels.

“This effect on lung vessels is surprisingly rapid, as we could measure it just an hour or two after injecting the EVPs,” said study first author Dr Shani Dror, a research associate in the Lyden.

The researchers also found that a breast tumour model not normally prone to metastasis spread readily after the introduction of EVPs containing integrin alpha-5.

To determine whether the findings extended beyond animal models, the researchers analysed a large dataset of gene expression from human tumours. They found that high integrin alpha-5 expression in several tumour types, including colorectal cancer, was associated with poorer overall survival.

Tumour samples from patients with intermediate to advanced colorectal cancer also released EVPs containing integrin alpha-5 and were able to increase the permeability of blood vessels.

“One possibility is that we could try to detect these integrin alpha-5-containing EVPs during cancer surgery to assess the risk of metastasis,” said study co-corresponding author Dr Jacqueline Bromberg, a breast oncologist at Memorial Sloan Kettering and an associate professor of medicine at Weill Cornell.

“If we had a good drug for blocking integrin alpha-5, we could give this at the time of surgery to potentially reduce the risk of metastasis.”