Breast tumors may be able to turn part of the body’s immune system into a tool for building their own nerve supply.
A new University of Oklahoma study has uncovered a chain of signals that may help explain why nerves are often found growing through solid tumors.
The discovery came from research on triple-negative breast cancer. This cancer is especially challenging because it does not carry the estrogen receptor, progesterone receptor or HER2 protein that can be targeted by several widely used breast cancer medicines.
That does not mean triple-negative breast cancer cannot be treated. Surgery, radiation, chemotherapy and some immune treatments can be effective, but doctors continue to search for additional targets because the cancer can grow quickly and return after treatment.
One emerging area of cancer research looks beyond cancer cells themselves. A tumor is actually a complicated community containing blood vessels, immune cells, connective tissue and, in many cases, nerve fibers.
These surrounding cells can strongly influence whether a tumor grows, spreads or responds to treatment. Scientists sometimes describe this neighborhood as the tumor environment, but in simple terms it is everything living around and within the cancer.
Researchers have been particularly curious about nerves. Tumors in several organs can become heavily supplied with nerve fibers, and higher nerve levels have sometimes been associated with more aggressive disease.
The mystery has been how a tumor persuades nerves to grow toward it. Maureen Cox and colleagues at the University of Oklahoma found that macrophages, a common type of immune cell, may act as the middleman.
Macrophages are usually helpful. They swallow germs and damaged material, help control inflammation and play an important role when the body repairs wounds.
Cancer can change their behavior, however. Once macrophages enter a breast tumor, the new study suggests they can begin producing a substance called BDNF, short for brain-derived neurotrophic factor.
BDNF is better known for its work in the nervous system. It supports nerve cells and helps promote nerve growth, which is useful in normal biology but potentially harmful when the same signal is produced inside a cancer.
The researchers found that macrophage-produced BDNF acted like an invitation to nearby nerves. Nerve fibers grew toward the tumor and entered it, potentially changing the conditions in which cancer and immune cells were living.
To test whether this signal mattered, the scientists blocked BDNF activity with a drug in mice. Nerves stopped growing into the tumors as they had before, and tumor growth was significantly reduced.
This experiment is important because it moves the research beyond a simple observation. The scientists did not merely notice that nerves and BDNF were present together; disrupting the signal also changed nerve growth and the behavior of the tumors.
Why would nerves help cancer? One possibility is that they weaken the immune attack that would otherwise damage cancer cells, allowing tumors to create a more protected environment.
Nerves may also encourage new blood vessels to form. A growing tumor needs a steady supply of oxygen and nutrients, so gaining more blood vessels can make it easier for cancer cells to survive and expand.
Another possibility involves cancer spread. Evidence from other research suggests that some cancer cells can travel alongside nerves, potentially giving them another route into surrounding tissue and eventually other parts of the body.
The Oklahoma team also searched for signs of the same process in human triple-negative breast cancer. Higher levels of both macrophages and BDNF in tumors were associated with worse survival.
That human evidence strengthens the study, but it does not prove that BDNF-driven nerve growth causes poorer survival. Patients with more aggressive cancers may differ in many ways, and observational patient data cannot establish cause and effect by itself.
The mouse experiments provide stronger evidence that the pathway can influence tumor growth, yet mice are still not people. Before the approach could become a treatment, researchers would need clinical studies showing that blocking this signal benefits patients without causing unacceptable side effects.
BDNF has normal roles in nerve health, so researchers will also need to understand what happens when its signaling is blocked elsewhere in the body. A cancer therapy must do more than slow tumors in an experiment; it must offer a meaningful benefit while remaining reasonably safe.
The researchers now plan to explore how tumor nerves affect immunity and to test the strategy in high-grade ovarian cancer. If the findings hold up, targeting the conversation between immune cells and nerves could become a new way to make aggressive cancers more vulnerable to the body’s defenses.
The study was published in Cell Death & Differentiation. Its key contribution is a clearer explanation of how nerves may be recruited into tumors, while the central unanswered question is whether stopping that process can improve survival in people with cancer.
Source: University of Oklahoma.
