Researchers Discover How Tumors Enlist Nerves to Keep Growing

OKLAHOMA CITY – New research from the University of Oklahoma demonstrates how an aggressive form of breast cancer co-opts the body’s own immune system to attract nerves that fuel tumor growth.

Scientists have long known that many solid tumors contain networks of nerves, but they haven’t understood how those nerves get there. This study, published in Cell Death & Differentiation, explains how that happens in triple-negative breast cancer, a type of cancer that is difficult to treat.

Researchers found that tumors recruit macrophages, immune cells that normally help fight infection and heal wounds. Once inside the tumor, the macrophages release a protein called brain-derived neurotrophic factor (BDNF), which acts like a chemical beacon that encourages nearby nerves to grow into the tumor. Although BDNF is best known for helping nerve cells grow in the brain, the researchers found that breast tumors hijack this same signal to attract nerves that support tumor growth and treatment resistance.

“Macrophages are the critical source for drawing nerves into the tumor. Although macrophages typically play a positive role in the body, they are facilitating a negative function in this scenario of breast cancer,” said Maureen Cox, Ph.D., an assistant professor in the Department of Microbiology and Immunology at the OU College of Medicine and a research member of OU Health Stephenson Cancer Center.

The findings are important because they point to a potential new treatment strategy: Rather than targeting cancer cells directly, future therapies could block the communication between macrophages and the nerves that help tumors grow.

Cox and her team tested such an approach in mice. When they used a drug to block BDNF signaling, the nerves didn’t infiltrate the tumor and its growth was significantly reduced.

“It looks really promising that we can use this drug, which is already on the market, to target BDNF,” Cox said. “We believe that the nerves are immunosuppressive, so if we can stop the nerves from growing in the first place, maybe we can boost the immune response to help fight the cancer.”

To see whether these findings might apply to people, Cox’s team analyzed data from patients with triple-negative breast cancer. They found that tumors with higher levels of macrophages and BDNF were associated with poorer survival, suggesting that what occurs in mice may also take place in humans.

Cox’s next steps are to further understand how the nerves cause tumor growth. Some evidence suggests that the nerves encourage the growth of blood vessels that deliver oxygen and nutrients to the tumor. Other studies suggest that tumor cells can crawl along the nerves to escape the original site and metastasize. She also plans to test the intervention in high-grade ovarian cancer, which is similarly difficult to treat.

“Ultimately, we want to turn the anti-tumor immunity back on in cancer patients so their own immune systems can reject the tumors,” she said.

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About the project

The research was supported by the National Institute of General Medical Sciences of the NIH (award numbers P20GM103447 and P20GM103639). This project was also supported by Oklahoma's Tobacco Settlement Endowment Trust (TSET), a primary funder of the Stephenson Cancer Center and TSET Health Promotion Research Center at the University of Oklahoma and by the Oklahoma Shared Clinical and Translational Resources through an Institutional Development Award from the National Institute of General Medical Sciences (grant no. U54GM104938).

About the University of Oklahoma

Founded in 1890, the University of Oklahoma is a public research university with campuses in Norman, Oklahoma City and Tulsa. As the state’s flagship university, OU serves the educational, cultural, economic and healthcare needs of the state, region and nation. In Oklahoma City, the OU Health Campus is one of the nation’s few academic health centers with seven health profession colleges located on the same campus. The OU Health Campus serves approximately 4,000 students in more than 70 undergraduate and graduate degree programs spanning Oklahoma City and Tulsa and is the leading research institution in Oklahoma. For more information about the OU Health Campus, visit www.ouhsc.edu.