Cutting off blood flow can prematurely age the bone marrow, weakening the immune system’s ability to fight cancer, according to a new study from NYU Langone Health.

Published online August 19 in JACC-CardioOncology, the study showed that peripheral ischaemia–restricted blood flow in the arteries in the legs–caused breast tumours in mice to grow at double the rate seen in mice without restricted flow.

These findings build on a 2020 study from the same team that found ischaemia during a heart attack to have the same effect.

Ischaemia occurs when fatty deposits, such as cholesterol, accumulate in artery walls, leading to inflammation and clotting that restrict the flow of oxygen-rich blood.

When this happens in the legs, it causes peripheral artery disease, which affects millions of Americans, and can increase the risk of heart attack or stroke. 

“Our study shows that impaired blood flow drives cancer growth regardless of where it happens in the body,” says corresponding author Kathryn J. Moore, PhD, the Jean and David Blechman Professor of Cardiology in the Department of Medicine, Leon H. Charney Division of Cardiology, NYU Grossman School of Medicine.

“This link between peripheral artery disease and breast cancer growth underscores the critical importance of addressing metabolic and vascular risk factors as part of a comprehensive cancer treatment strategy.” 

Importantly, the research team found that restricted blood flow triggers a shift toward immune cell populations that cannot efficiently fight infections and cancer, mirroring changes seen with ageing. 

Systemic Skewing

To examine the mechanisms behind the link between cardiovascular disease and cancer growth, the study authors developed a mouse model with breast tumours and induced temporary ischaemia in one hind limb.

The team then compared cancer growth in mice with and without impaired blood flow.

Their findings build on the nature of the immune system, which evolved to attack invading bacteria and viruses, and under normal conditions, to detect and eliminate cancer cells.

These protective functions rely on stem cell reserves in the bone marrow, which can be activated as needed to produce key white blood cell populations throughout life.

Normally, the immune system responds to injury or infection by ramping up inflammation to eliminate threats, then scaling back to avoid harm to healthy tissue.

This balance is maintained by a mix of immune cells that either activate or suppress inflammation.

The researchers found that reduced blood flow disrupts this equilibrium.

It reprograms stem cells in the bone marrow to favour the production of “myeloid” immune cells (monocytes, macrophages, neutrophils) that dampen immune responses, while reducing output of lymphocytes like T cells that help to mount strong anti-tumour responses.

The local environment within tumours showed a similar shift, accumulating more immune-suppressive cells– including Ly6Chi monocytes, M2-like F4/80+ MHCIIlo macrophages, and regulatory T cells – that shield cancer from immune attack. 

Further experiments showed that these immune changes were long-lasting.

Ischaemia not only altered the expression of hundreds of genes, shifting immune cells into a more cancer-tolerant state, but also reorganised the structure of chromatin–the protein scaffolding that controls access to DNA–making it harder for immune cells to activate genes involved in fighting cancer.

“Our results reveal a direct mechanism by which ischaemia drives cancer growth, reprogramming stem cells in ways that resemble ageing and promote immune tolerance,” says first author Alexandra Newman, PhD, a postdoctoral scholar in Dr. Moore’s lab.

“These findings open the door to new strategies in cancer prevention and treatment, like earlier cancer screening for patients with peripheral artery disease and using inflammation-modulating therapies, to counter these effects.”

Moving forward, the research team hopes to help design clinical studies that evaluate whether existing inflammation-targeted therapies can counter postischemic changes driving tumour growth.

Source: NYU Langone Health