Limiting blood circulation can cause premature aging in the bone marrow, thereby diminishing the immune system’s capacity to combat cancer, as revealed by recent research conducted at NYU Langone Health.
The study, which appeared online on August 19 in JACC-CardioOncology, demonstrated that peripheral ischemia—characterized by constrained blood flow in the leg arteries—resulted in breast tumors growing twice as rapidly in mice compared to those without such restrictions. These results expand upon a 2020 investigation by the same researchers, which observed similar effects from ischemia during a heart attack.
Ischemia arises when fatty substances like cholesterol build up in artery walls, sparking inflammation and clot formation that hinder the delivery of oxygen-rich blood. In the legs, this condition leads to peripheral artery disease, impacting millions of people across the United States and heightening the chances of heart attacks or strokes.
“Our research indicates that compromised blood flow promotes cancer progression irrespective of its location in the body,” states lead author Kathryn J. Moore, PhD, who holds the Jean and David Blechman Professorship in Cardiology within the Department of Medicine at NYU Grossman School of Medicine’s Leon H. Charney Division of Cardiology. “The connection between peripheral artery disease and accelerated breast cancer growth emphasizes the vital need to manage metabolic and vascular risk factors within a holistic approach to cancer care.”
A key discovery from the study was that restricted blood flow prompts a transformation in immune cell types, favoring populations less effective at combating infections and tumors—a pattern akin to that observed during natural aging processes.
Systemic Immune Imbalance
In exploring the underlying connections between cardiovascular conditions and tumor expansion, the investigators created a mouse model featuring breast tumors and introduced transient ischemia in one hind leg. They subsequently assessed tumor development in these animals versus those with unimpeded blood flow.
This work elaborates on the immune system’s fundamental design, which has evolved to target pathogenic bacteria and viruses while, under typical circumstances, identifying and destroying malignant cells. Such defensive mechanisms depend on replenishable stem cell pools in the bone marrow, which generate essential white blood cell types as required over an individual’s lifetime.
In standard operations, the immune response to trauma or pathogens involves intensifying inflammation to neutralize dangers, followed by a deliberate reduction to safeguard surrounding healthy tissues. This delicate equilibrium is upheld by diverse immune cell factions that either promote or inhibit inflammatory activities. The scientists determined that diminished blood perfusion upsets this balance, redirecting bone marrow stem cells to prioritize “myeloid” immune cells—such as monocytes, macrophages, and neutrophils—that suppress robust immune activity, at the expense of lymphocytes, including T cells, which are crucial for potent anti-cancer defenses.
Within the tumor microenvironment, a parallel alteration occurred, with an influx of immune-suppressing elements like Ly6Chi monocytes, M2-like F4/80+ MHCIIlo macrophages, and regulatory T cells, all of which protect tumors from immunological assault.
Additional analyses confirmed the enduring nature of these immunological shifts. Ischemia not only modified the activity of numerous genes, steering immune cells toward a state more permissive of cancer, but also restructured chromatin—the architectural framework regulating DNA accessibility—thereby impeding the activation of cancer-fighting genetic pathways in immune cells.
“Our findings uncover a precise pathway through which ischemia fuels cancer advancement by altering stem cell programming in a manner that echoes aging and fosters immune evasion,” explains primary author Alexandra Newman, PhD, a postdoctoral researcher in Dr. Moore’s laboratory. “These insights pave the way for innovative approaches in cancer prophylaxis and therapy, such as proactive screening for malignancies in individuals with peripheral artery disease and the deployment of therapies that modulate inflammation to mitigate these impacts.”
Looking ahead, the research group aims to facilitate the development of clinical trials assessing whether current anti-inflammatory treatments can counteract the ischemia-induced modifications that propel tumor proliferation.
In addition to Drs. Newman and Moore, contributors from the Cardiovascular Research Center and the Leon H. Charney Division of Cardiology—both part of the Department of Medicine at NYU Grossman School of Medicine—include Jose Gabriel Barcia Duran, Richard Von Itter, Jessie Dalman, Brian Lim, Morgane Gourvest, Tarik Zahr, Kristin Wang, Tracy Zhang, Noah Albarracin, Whitney Rubin, Fazli K. Bozal, Chiara Giannarelli, Michael Gildea, and Coen van Solingen. Kory Lavine from the Department of Pathology and Immunology at Washington University School of Medicine in Saint Louis also participated as an author.
Funding for the study came from American Heart Association grants 915560, 25CDA1437452, 23POST1029885, 25PRE1373174, and 23SCEFIA1153739; National Institutes of Health grants T32GM136542, F30HL167568, T32HL098129, R01 HL151078, R01 HL161185, R35 HL161185, R01HL153712, R01HL172335, R01HL172365, and P01HL131481; as well as support from the Sarnoff Cardiovascular Research Foundation, the LeDucq Foundation Network, and the Laura and Isaac Perlmutter Cancer Center grant P30CA016087.
