University of Oklahoma researchers have discovered that immune cells called macrophages encourage nerve fibers to grow inside triple-negative breast cancer tumors. The finding provides a potential explanation for how solid tumors recruit nerves into their tissue during disease progression.
The study, published in the journal Cell Death & Differentiation, highlights a previously unclarified biological mechanism. Scientists found that macrophages entering the tumor produce brain-derived neurotrophic factor, or BDNF, a protein that normally aids nerve cell development but instead draws nerve fibers into cancerous growth.
Triple-negative breast cancer is an aggressive form of the disease that lacks receptors for estrogen and progesterone, and does not produce the HER2 protein. Because it lacks these specific targets, standard hormone therapies and HER2-targeted treatments used in other breast cancers are ineffective against it.
Although medical researchers have known for years that many solid tumors contain nerve fibers, the process by which those nerves infiltrate tumor tissue had remained unclear. Macrophages typically serve as defense cells that fight infections and repair damaged tissue in the body, but inside tumors, their release of BDNF alters their function.
Experimental results and drug inhibition
Maureen Cox, an assistant professor in the Department of Microbiology and Immunology at the University of Oklahoma College of Medicine and a researcher at the OU Health Stephenson Cancer Center, described macrophages as the critical source drawing nerves into tumors. She noted that while macrophages normally play a beneficial role in human health, they facilitate a harmful process in breast cancer.
To examine what happens when the BDNF signal is blocked, researchers conducted laboratory experiments on mice using an existing drug that inhibits BDNF activity. The treatment restricted the growth of nerve fibers inside the tumors and significantly slowed overall tumor growth.
Cox described the findings as promising, noting that an existing commercial drug already available on the market could potentially be repurposed to target BDNF in cancer patients.
The research team also hypothesized that tumor-infiltrating nerves may suppress the body's natural anti-cancer defenses. Cox explained that if nerves act as immunosuppressors, blocking their growth from the start might strengthen the immune system and allow the body to combat cancer more effectively.
Patient survival data and future applications
Beyond animal models, the Oklahoma team analyzed clinical data from human patients diagnosed with triple-negative breast cancer. Patient tumors containing higher levels of macrophages and BDNF were associated with lower overall survival rates, supporting the hypothesis that the mechanism carries biological significance in humans.
Scientists are now investigating the precise activities of nerve fibers once they establish themselves within tumor tissue. One key area of study is angiogenesis, the formation of new blood vessels that supply tumors with essential oxygen and nutrients. Other research has also indicated that cancer cells may travel along nerve fibers to spread away from primary tumor sites.
The research team plans to evaluate the same therapeutic approach in high-grade ovarian cancer to determine whether the macrophage-driven mechanism occurs in other aggressive cancers. Cox said the ultimate goal of the research is to reactivate anti-cancer immunity so a patient's own immune system can reject tumors.
