Disruption of blood flow can lead to premature aging of bone marrow, weakening the immune system’s ability to fight cancer, according to a new study from NYU Langone Health. The study, published in JACC-CardioOncology, showed that peripheral ischemia – a restriction of blood flow in the arteries of the legs – led to twice as rapid growth of breast tumors in mice as in mice without blood flow restriction. These findings build on a 2020 study by the same team, which found that ischemia during a heart attack has the same effect.
Link Between Cardiovascular Disease and Cancer Growth
Ischemia occurs when fatty deposits such as cholesterol build up in the artery walls, leading to inflammation and clots that restrict the flow of oxygen-rich blood. When this happens in the legs, it causes peripheral artery disease, which can increase the risk of a heart attack or stroke. “Our study shows that impaired blood flow promotes cancer growth regardless of where in the body it happens, says corresponding author Kathryn J. Moore, PhD, Jean and David Blechman Professor of Cardiology in the Department of Medicine, Leon H.Charney Division of Cardiology, NYU Grossman School of Medicine. ” This association between peripheral arterial disease and breast cancer growth underscores the importance of addressing metabolic and vascular risk factors as part of a comprehensive cancer treatment strategy. Importantly, the research team found that impaired blood flow triggers a shift toward immune cell populations that cannot efficiently fight infection and cancer, consistent with the changes that occur with age.
To investigate the mechanisms behind the link between cardiovascular disease and cancer growth, the study authors developed a mouse model with mammary tumors and induced transient ischemia in a hind leg. The team then compared cancer growth in mice with and without circulatory disorders. Their findings are based on the nature of the immune system, which has evolved to attack invading bacteria and viruses and to recognize and eliminate cancer cells under normal conditions. These protective functions rely on stem cell reserves in the bone marrow that can be activated when needed to produce important populations of white blood cells throughout life.
New Strategies for Cancer Prevention and Treatment
Normally, the immune system responds to injury or infection by ramping up inflammation to eliminate threats and then dialing it back to prevent damage to healthy tissue. This balance is maintained by a mixture of immune cells that either activate or suppress inflammation. The researchers found that reduced blood flow disrupts this balance. It reprograms the stem cells in the bone marrow to preferentially produce “myeloid” immune cells (monocytes, macrophages, neutrophils), which dampen the immune response, while reducing the production of lymphocytes such as T cells, which contribute to a strong anti-tumor response. The local environment within tumors showed a similar change, accumulating more immunosuppressive cells – including Ly6Chi monocytes, M2-like F4/80+ MHCIIlo macrophages and regulatory T cells – that protect the cancer from immune attack.
Further experiments showed that these immune changes were long-lasting. Ischemia not only altered the expression of hundreds of genes and shifted immune cells to a more cancer-tolerant state, but also reorganized the structure of chromatin – the protein scaffold that controls access to DNA – making it more difficult for immune cells to activate the genes involved in fighting cancer. “Our results reveal a direct mechanism by which ischemia promotes cancer growth by reprogramming stem cells in a way that resembles the aging process and promotes immune tolerance,” says first author Alexandra Newman, PhD, a postdoctoral fellow in Dr. Moore’s lab. These findings open up new strategies for cancer prevention and treatment, such as earlier cancer screening for patients with peripheral artery disease and the use of inflammation-modulating therapies to counteract these effects. In the future, the research team hopes to be involved in the design of clinical trials investigating whether existing inflammation-targeted therapies can counteract the post-ischemic changes that promote tumor growth.