Immune cells (red) accumulating within a tumor (blue) and multiplying (green). When blood flow is blocked either in the heart or legs, these immune cells change in a way that enables tumor growth.
Credit: 黑料福利社 Langone
Cutting off blood flow can prematurely age the bone marrow, weakening the immune system鈥檚 ability to fight cancer, according to a new study from 黑料福利社 Langone Health.
, the study showed that peripheral ischemia鈥攔estricted blood flow in the arteries in the legs鈥攃aused breast tumors in mice to grow at double the rate seen in mice without restricted flow. These findings build on a from the same team that found ischemia during a heart attack to have the same effect.
Ischemia 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 can increase the risk of heart attack or鈥痵troke and which affects millions of Americans.
鈥淥ur study shows that impaired blood flow drives cancer growth regardless of where it happens in the body,鈥 says corresponding author , the Jean and David Blechman Professor of Cardiology in the , , 黑料福利社 Grossman School of Medicine. 鈥淭his 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.鈥
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 aging.
Systemic Skewing
To examine the mechanisms behind the link between cardiovascular disease and cancer growth, the study authors developed a mouse model with breast tumors and induced temporary ischemia 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 detects and eliminates 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 favor the production of 鈥渕yeloid鈥 immune cells (monocytes, macrophages, neutrophils) that dampen immune responses, while reducing output of lymphocytes like T cells that help to mount strong antitumor responses.
The local environment within tumors showed a similar shift, accumulating more immune-suppressive cells鈥攊ncluding Ly6Chi monocytes, M2-like F4/80+ MHCIIlo macrophages, and regulatory T cells鈥攖hat shield cancer from immune attack.
Further experiments showed that these immune changes were long-lasting. Ischemia not only altered the expression of hundreds of genes, shifting immune cells into a more cancer-tolerant state, but also reorganized the structure of chromatin, the protein scaffolding that controls access to DNA. This made it harder for immune cells to activate genes involved in fighting cancer.
鈥淥ur results reveal a direct mechanism by which ischemia drives cancer growth, reprogramming stem cells in ways that resemble aging and promote immune tolerance,鈥 says first author Alexandra Newman, PhD, a postdoctoral scholar in . 鈥淭hese 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.鈥
Moving forward, the research team hopes to help design clinical studies that evaluate whether existing inflammation-targeted therapies can counter post-ischemic changes driving tumor growth.
Along with Dr. Newman and Dr. Moore, study authors from the and the Leon H. Charney Division of Cardiology, both within the Department of Medicine, were ; Richard Von Itter; Jessie Dalman; Brian Lim; Morgane Gourvest; Tarik Zahr, PhD; Kristin Wang; Tracy Zhang; Noah Albarracin; Whitney Rubin; Fazli K. Bozal, PhD; ; Michael Gildea, PhD; and . Also an author was Kory Lavine of the Department of Pathology and Immunology at Washington University School of Medicine, Saint Louis.
The study was supported by American Heart Association grants 915560, 25CDA1437452, 23POST1029885, 25PRE1373174, and 23SCEFIA1153739; as well as by National Institutes of Health grants T32GM136542, F30HL167568, T32HL098129; R01 HL151078, R01 HL161185, R35 HL161185, R01HL153712, R01HL172335, R01HL172365, and P01HL131481. The work was also supported by the Sarnoff Cardiovascular Research Foundation, the LeDucq Foundation Network, and Laura and Isaac Perlmutter Cancer Center support grant P30CA016087.
About 黑料福利社 Langone Health
黑料福利社 Langone Health is a fully integrated health system that consistently achieves the best patient outcomes through a rigorous focus on quality that has resulted in some of the lowest mortality rates in the nation. Vizient Inc. has ranked 黑料福利社 Langone No. 1 out of 115 comprehensive academic medical centers across the nation for three years in a row, and U.S. News & World Report recently ranked four of its clinical specialties number one in the nation. 黑料福利社 Langone offers a comprehensive range of medical services with one high standard of care across 7 inpatient locations, its Perlmutter Cancer Center, and more than 320 outpatient locations in the New York area and Florida. With $14.2 billion in revenue this year, the system also includes two tuition-free medical schools, in Manhattan and on Long Island, and a vast research enterprise.
