New research from the University of Oklahoma has revealed how an aggressive type of breast cancer can manipulate the immune system to attract nerves to tumors, creating conditions that can help the cancer grow.
Scientists have known for years that many solid tumors contain extensive nerve networks. What has been less clear is how those nerves enter the tumor in the first place. The new study, published in Cell death and differentiationexplains this process in triple negative breast cancer, a form of disease that is especially difficult to treat.
Immune cells help attract nerves to tumors
Researchers found that tumors attract macrophages, a type of immune cell that normally helps the body fight infections and repair damaged tissue. After entering the tumor, these macrophages release brain-derived neurotrophic factor (BDNF), a protein that stimulates nearby nerves to grow toward and into the cancer.
BDNF is best known for supporting the growth and survival of nerve cells in the brain. However, in breast cancer, researchers discovered that tumors can take advantage of this same biological signal. By causing nerve growth within the tumor, the process can contribute to cancer progression and resistance to treatment.
“Macrophages are the critical source of attracting nerves to the tumor. Although macrophages normally play a positive role in the body, they facilitate a negative function in this breast cancer scenario,” said Maureen Cox, Ph.D., assistant professor in the Department of Microbiology and Immunology at the OU School of Medicine and a research member at the Stephenson Cancer Center at OU Health.
Blocking the signal slowed tumor growth
The discovery could open the door to a different way of treating cancer. Instead of focusing solely on destroying cancer cells, future therapies could disrupt signaling between macrophages and nerves that appear to support tumor growth.
Cox and his colleagues tested this strategy in mice. They used a drug that blocks BDNF signaling and found that nerves no longer grew in the tumors. Tumor growth was also significantly reduced.
“It looks really promising that we can use this drug, which is already on the market, to target BDNF,” Cox said. “We think nerves are immunosuppressive, so if we can stop nerve growth in the first place, maybe we can stimulate the immune response to help fight cancer.”
Evidence from patients with triple negative breast cancer
The researchers also examined data from people with triple-negative breast cancer to determine whether the same biological pattern could occur in humans. Tumors containing higher levels of macrophages and BDNF were associated with worse survival, providing evidence that the mechanism seen in mice could also be relevant to patients.
Cox and his team now want to better understand exactly how nerves contribute to tumor growth. Some evidence indicates that nerves can stimulate the formation of blood vessels, which can supply oxygen and nutrients to tumors. Other research suggests that cancer cells can move along nerves as they leave the original tumor and metastasize.
The researchers also plan to test the same intervention in high-grade ovarian cancer, another aggressive cancer that can be difficult to treat.
“Ultimately, we want to turn anti-tumor immunity back on in cancer patients so that their own immune systems can reject tumors,” he said.
Research support
The research was supported by the NIH National Institute of General Medical Sciences (award numbers P20GM103447 and P20GM103639). This project was also supported by the Tobacco Settlement Endowment Trust (TSET) of Oklahoma, a major funder of the Stephenson Cancer Center and the TSET Health Promotion Research Center at the University of Oklahoma, and by Oklahoma Shared Clinical and Translational Resources through an institutional development award from the National Institute of General Medical Sciences (grant no. U54GM104938).