The nervous system does more than transmit sensations, control movement, and coordinate stress responses. It may also play an active role in how tumors grow, adapt, and communicate with their surroundings. Today, cancer research is revealing that tumor cells do not act alone. They interact with blood vessels, immune cells, fibroblasts, inflammatory molecules, and even nerve fibers.

A tumor can behave as a complex biological ecosystem. Within this tumor microenvironment, nerves can release neurotransmitters and growth factors capable of influencing cell proliferation, inflammation, angiogenesis, and the invasive potential of cancer. In other words, nerves may be part of the signaling network that helps determine how a tumor behaves.

One of the most intriguing observations in recent years is that some tumors appear capable of attracting nerve fibers toward themselves. To achieve this, they produce molecules known as neurotrophic factors, including NGF (Nerve Growth Factor) and BDNF (Brain-Derived Neurotrophic Factor), whose normal function is to support the development and maintenance of nervous tissue. When these molecules are released by tumor cells, they can stimulate the growth of new nerve fibers within the tumor microenvironment, establishing an increasingly close communication between cancer and the nervous system.

Researchers have also discovered that certain cancer cells can respond directly to neuronal signals. In brain tumors such as gliomas, recent studies have shown that neurons can transmit signals that promote tumor growth. These findings have given rise to a new field of research known as Cancer Neuroscience, which seeks to understand how neural circuits can influence cancer progression.

 

The Sympathetic Nervous System: When the Stress Response Influences the Tumor Microenvironment

One of the key players in this story is the sympathetic nervous system, the branch of the autonomic nervous system responsible for preparing the body to respond to threats and challenges. When an individual faces danger, this system triggers the well-known “fight-or-flight” response, increasing heart rate, blood pressure, and the release of adrenaline and noradrenaline.

From an evolutionary perspective, this response is essential for survival. The challenge arises when it remains activated for prolonged periods due to chronic stress.

Numerous studies have found that many tumor cells express receptors capable of responding to adrenaline and noradrenaline. When these molecules bind to their receptors, they can activate cellular pathways involved in proliferation, angiogenesis, and tumor invasion. In addition, these signals may stimulate the production of factors such as VEGF, a key protein involved in the formation of new blood vessels that supply nutrients and oxygen to the tumor.

Sustained sympathetic activation may also influence the immune system. Some studies suggest that persistently elevated catecholamine levels can alter the activity of immune cells responsible for recognizing and eliminating cancer cells, creating a more permissive environment for tumor progression.

This does not mean that stress directly causes cancer. However, it does reinforce the idea that physiological processes associated with chronic stress can influence important biological mechanisms within the tumor microenvironment.

 

The Link Between the Nervous System and Immunity 

The nervous system and the immune system are in constant communication. For many years, these systems were thought to function relatively independently. Today, however, it is clear that a complex network of interactions exists between them.

Immune cells possess receptors for a variety of neurotransmitters, while neurons can respond to molecules produced by the immune system. This biological dialogue helps coordinate responses to infections, tissue injury, and inflammation.

In the context of cancer, this communication becomes particularly important. Neurotransmitters and stress hormones can influence the activity of T lymphocytes, dendritic cells, macrophages, and natural killer (NK) cells, all of which play critical roles in antitumor immunity. For this reason, some researchers believe that understanding the nervous system–immune system–cancer axis could help optimize future immunotherapeutic strategies.

Another particularly important phenomenon is perineural invasion. In some types of cancer, tumor cells can migrate around nerves and even use them as pathways to spread into surrounding tissues.

This phenomenon is frequently observed in pancreatic, prostate, head and neck, and several other cancers. In addition to being associated with greater tumor aggressiveness, it may also contribute to cancer-related pain experienced by some patients.

Current evidence indicates that perineural invasion is not a passive process. Instead, it involves active communication between cancer cells, nerve fibers, and supporting cells of the nervous system. These interactions create a microenvironment that facilitates tumor survival and migration.

 

Figure 1. Sympathetic signaling, neurotrophic factors, neuron–tumor communication, immune modulation, and perineural invasion represent key mechanisms linking the nervous system to cancer progression.

 

These discoveries are expanding our understanding of cancer beyond genetic mutations and immune responses alone. It is becoming increasingly clear that nerves are an integral component of the tumor microenvironment and may influence multiple aspects of disease progression.

Although much of this research is still evolving, the findings obtained so far suggest that communication between the nervous system and cancer could become an important therapeutic target in the future. Understanding how neurons, neurotransmitters, and nerve fibers interact with tumors may open the door to more precise and comprehensive approaches to cancer treatment.

 

Main reference:

Monje, M., Borniger, J. C., D’Silva, N. J., Deneen, B., Dirks, P. B., Fattahi, F., … & Winkler, F. (2020). Cancer neuroscience: State of the field, emerging directions. Cell, 181(2), 219–222. https://doi.org/10.1016/j.cell.2020.03.034 

 

Other reference:

Magnon, C., Hall, S. J., Lin, J., Xue, X., Gerber, L., Freedland, S. J., & Frenette, P. S. (2013). Autonomic nerve development contributes to prostate cancer progression. Science, 341(6142), 1236361. https://doi.org/10.1126/science.1236361 

AbuQeis, I., Zou, Y., Ba, Y. C., & Teeti, A. A. (2024). Neuroscience of cancer: Research progress and emerging of the field. Ibrain, 10(3), 305–322. https://doi.org/10.1002/ibra.12172