An aggressive form of breast cancer may use immune cells to attract nerves into tumors, creating an environment that helps the cancer grow.
Researchers at the University of Oklahoma say the discovery reveals an unusual relationship between cancer, the immune system and the nervous system.
The study focused on triple-negative breast cancer, one of the more difficult forms of breast cancer to treat.
It is called “triple-negative” because its cells lack three common targets that doctors can use to guide several major breast cancer treatments.
Because those targets are missing, patients often have fewer treatment choices than people with some other breast cancer types. Chemotherapy and newer immune-based treatments can help, but the disease can still be aggressive and has a greater tendency to spread in some patients.
Scientists have known that many solid tumors contain nerves. These nerve fibers are not simply innocent structures trapped inside a growing tumor; research increasingly suggests they can influence cancer behavior.
Until now, however, scientists have not fully understood how nerves are encouraged to grow into some tumors. The University of Oklahoma team found that immune cells called macrophages may provide an important part of the answer.
Macrophages normally protect the body by removing damaged cells, fighting infection and helping injured tissue heal. Inside a tumor, however, cancer can change the local environment and push these otherwise useful cells into supporting tumor growth.
The researchers found that macrophages inside triple-negative breast tumors release a protein called brain-derived neurotrophic factor, or BDNF. This protein is normally important for supporting nerve cells and encouraging their growth and survival.
In the brain and nervous system, BDNF performs useful jobs. But inside breast tumors, the researchers found that cancer appears to take advantage of this same nerve-growing signal.
BDNF released by macrophages encouraged nearby nerves to grow toward and into tumors. This creates a possible chain of events in which cancer attracts immune cells, the immune cells produce BDNF, and BDNF then helps bring nerves into the tumor.
Assistant professor Maureen Cox and her colleagues wanted to know whether interrupting this process could affect the cancer. They tested a drug that blocks BDNF signaling in mice with breast tumors.
When the BDNF signal was blocked, nerve growth into the tumors was reduced. The tumors also grew significantly more slowly, suggesting that the nerves or the biological conditions associated with them may be helping the cancer.
The finding raises an intriguing treatment possibility. Instead of attacking cancer cells directly, doctors might one day be able to weaken tumors by disrupting the support system they build around themselves.
Cox’s team suspects that nerves may also help cancer by suppressing immune responses. If nerves make immune cells less able to attack a tumor, preventing those nerves from entering could potentially allow the body’s natural defenses to work more effectively.
There may be other explanations as well. Previous research suggests nerves can encourage the growth of blood vessels, which tumors need to receive oxygen and nutrients as they become larger.
Scientists have also found evidence that cancer cells can sometimes use nerves as pathways when spreading away from the original tumor. Understanding which of these effects matters most in triple-negative breast cancer will require additional experiments.
The researchers also looked at information from people with triple-negative breast cancer. Patients whose tumors had higher levels of macrophages and BDNF tended to have poorer survival, supporting the idea that the pathway may be relevant in human disease and not only in laboratory animals.
Still, the results do not show that blocking BDNF will successfully treat breast cancer in people. Much of the experimental evidence came from mice, and human clinical trials would be needed to determine whether the approach is effective and safe.
One encouraging detail is that the researchers used a drug that is already available, which could potentially make future testing easier. But an existing drug is not automatically proven safe or effective for a new cancer treatment, and its effects would need careful study.
The team plans to investigate exactly how nerves support tumors and to test the strategy in high-grade ovarian cancer, another aggressive disease. The broader goal is to remove signals that help cancers hide from the immune system and allow patients’ own defenses to attack them more effectively.
The research was published in Cell Death & Differentiation. Overall, the study provides a compelling biological explanation for how nerves may enter tumors, but its greatest promise remains experimental until researchers show that interrupting this pathway improves outcomes in human patients.
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