Our five senses provide us with the crucial information we need to interact with the world. On a physiological level, the sights, smells, sounds, tastes, and sensations we experience can help shape our personalities, connect us with loved ones, and alert us to potential threats.
On a biochemical level, the process of sensing begins when sensory nerves detect a stimulus from outside the body. The nerves translate this stimulus into electrical signals that are sent to the brain, which decodes the signals into meaningful information about our surroundings. As you read this sentence, the sensory nerves in your eyes allow you to visualize the words. Your skin feels the texture of a mouse, screen, or touchpad as you scroll, and your ears translate sound waves into the soundtrack of your day.
Somewhere in the body, sensory nerves are firing nearly all the time. Given that one role of our senses is to protect us from danger, that should be a benefit. But can the activity of sensory nerves contribute to cancer development?
In recent years, scientists have discovered a variety of mechanisms linking sensory nerve activity to the development and growth of various cancers. While this research is quite preliminary from a translational standpoint, some researchers suggest that the molecular mechanisms discovered in these studies could pave the way to new treatments.
The Interplay Between Sensory Nerves and Cancer
While some tumors, such as those that develop in the brain and spinal cord, arise from nervous tissue, nerves can also signal to other tissue types via electrical currents, secreted molecules, or extracellular vesicles. The complex scope of these interactions was discussed during the symposium session “Nerves, Cancer, and Immunity,” at the AACR Annual Meeting 2022, held in New Orleans April 8-13.
One particular talk highlighted the communication between peripheral nerves and cancer cells. Moran Amit, MD, PhD, an assistant professor in the department of Head and Neck Surgery at The University of Texas MD Anderson Cancer Center, explained that tumors with more nerve involvement typically correlate with worse patient outcomes.
A few mechanisms underlying that connection have been known for a while, Amit said. Nerves can promote the growth of blood vessels, which provide the tumor with oxygen, nutrients, and a potential route for metastatic spread. Nerves themselves can also serve as “highways for dissemination,” Amit continued.
Nerves can also secrete certain factors, such as norepinephrine, which promote cell growth and help hide the tumor from the immune system. As Amit and colleagues discovered, this signaling may be part of a larger feedback loop, in which cancer cells promote these tumorigenic secretions.
The researchers found that tumors lacking p53, including premalignant lesions, had more nerve involvement than p53 wild type tumors. They observed that p53 deficient tumor cells secrete extracellular vesicles containing cargo that, when taken up by nerve cells, can promote redifferentiation into adrenergic nerves, which secrete norepinephrine.
Amit and colleagues are using this knowledge to develop potential new cancer treatments. They have preliminary data showing that different compositions of nerves surrounding head and neck tumors correlate with patient morbidity and quality of life. Amit also showed that boosting the nerve-tumor adrenergic signaling may promote antitumor immune responses.
“We are in a great time now to develop or target the nervous system in order to affect not only patient survival, but patient quality of life as well,” Amit said. “In the next decade, we would hopefully like to see more clinical trials targeting the nerves.”
As sensory nerves are a prevalent type of peripheral nerve, they likely play a role in this crosstalk in a variety of ways. Are there organ-specific mechanisms by which sensory nerves contribute to tumor development and progression?
Many of Amit’s data about p53 loss and adrenergic nerve differentiation were published in a 2020 study in Nature, in which he and his colleagues pieced together the mechanisms underlying this feedback loop in oral cancer. One crucial discovery was that the adrenergic nerves feeding the tumor were not adrenergic nerves before the cancer developed.
Amit and colleagues depleted the adrenergic nerves of mice before introducing human oral cancer cells and found that the removal of adrenergic nerves prior to tumor engraftment had no effect on the number of adrenergic nerves associated with the tumor at the time of harvest. This suggested that the adrenergic nerves must be differentiating from another source.
As the oral cavity contains a high density of sensory nerves, the researchers sought to determine if sensory nerves played a role in this redifferentiation process. Before tumor cell engraftment into mice, the researchers deadened touch and taste perception across much of the oral cavity. Compared with control mice, mice with impaired sensation had virtually no tumor-associated adrenergic neurons and significantly smaller tumors after 21 days.
These findings position sensory nerves as key precursors of tumorigenic nerve activity in oral cancer. While more research is needed to understand why sensory nerves are the nerves of choice and how redifferentiation might be prevented, the study highlights one way nerves and tumors communicate.
Nerve cells and tumor cells do not interact in an isolated setting, but rather in the midst of other cell types that form a complex microenvironment. Therefore, the interactions between nerve cells and tumor cells can affect other players that contribute to tumor growth and metastasis.
In melanoma, the ability of immune cells to infiltrate the tumor and target cancer cells is crucial to mount a response to immunotherapy, a common pillar of melanoma treatment. According to a recent study in Cancer Immunology Research, a journal of the American Association for Cancer Research (AACR), sensory nerves in the skin can decrease immune cell infiltration and contribute to tumor progression.
The authors of the study found that melanoma cells engrafted into denervated areas of mouse skin grew more slowly than those engrafted into control mice. These tumors also contained more B cells, CD8+ T cells, and CD4+ T cells, and fewer regulatory T cells, than tumors from control mice.
The researchers further found that tumors from denervated mice were associated with significantly more tertiary lymphoid structures—specialized clusters of B and T cells that form within and around tumors and generally correlate with improved prognosis. The researchers also observed an increase in gene expression patterns associated with specialized capillaries known as high endothelial venules, which traffic lymphocytes into the tumor environment.
These data suggest that sensory nerves may inhibit immune cell infiltration into melanoma tumors. While the mechanisms remain to be determined, the authors speculate that topical and systemic agents that disrupt sensory nerves to treat cancer-associated pain may have a future role in cancer treatment as well.
While the examples above have focused primarily on effects mediated by the presence of sensory nerves, other researchers are finding that the activation of some sensory nerves can also affect cancer development.
In a 2022 study published in Nature, researchers used a mouse model of glioma development to study the interplay between nerves and tumor cells as gliomas emerge. They observed that all tumors emerged near the olfactory bulb—a region in the brain responsible for deciphering smells. This led the researchers to investigate whether olfactory nerves could affect gliomagenesis.
The researchers designed mouse models in which the olfactory neurons could be selectively activated or inhibited using a drug. Mice that experienced olfactory nerve activation developed larger gliomas than control mice, and mice that experienced olfactory nerve suppression developed smaller gliomas than control mice. The researchers also decreased the sensory experience of their mouse model by plugging one nostril of each mouse, which led to significantly smaller olfactory bulb tumors on the side of the brain matching the side of nostril occlusion.
The researchers performed RNA sequencing on tumors from mice with and without nostril occlusion and discovered that the growth factor IGF1 was significantly downregulated in tumors from mice with a decreased exposure to smells. They further found that IGF1 is secreted by mitral/tuft cells in the olfactory bulb in response to olfactory stimulation, and that knocking out IGF1 in these cells suppressed glioma formation.
The authors of the study emphasized that IGF1 signaling also plays a strong role in processing visual and auditory stimuli and suggested that further research into its role in the development of other sensory-related tumors be conducted. Regardless, these data suggest that some patients with glioma may benefit from the clinical development of IGF1 pathway inhibitors.
Gliomas can also be found in the optic nerve, which carries visual information from the eyes to the brain. In a 2021 paper published in Nature, researchers sought to determine whether optic nerve activity can influence the local development of gliomas.
Optic nerve gliomas are often driven by a single-allele germline mutation of neurofibromatosis 1 (NF1), which characterizes the genetic condition NF1 cancer predisposition syndrome. Mutation or deletion of the wild type allele in the glioma cell of origin drives malignant transformation and tumor growth. In this study, the researchers used an NF1 heterozygous mouse model, which reliably develops optic nerve gliomas during adolescence.
When the researchers stimulated the optic nerve using a fiberoptic implant, they observed an increase in tumor volume compared with control mice. To assess this in a physiological context, the researchers deprived adolescent mice of natural light, thereby reducing stimulation of retinal ganglion cells. Mice kept in darkness developed significantly fewer tumors than control mice, and they did not develop tumors after being returned to normal light conditions.
The researchers further found that neurons in the tumor microenvironment with heterozygous NF1 mutations shed more of a membrane-associated protein known as NLG3, which has been shown to contribute to glioma formation and progression. Using a small molecule inhibitor of the enzyme that releases NLG3 from the cell surface, the researchers recapitulated the antitumor effects of keeping mice in the dark.
Though much remains to be understood about the link between visual stimulation and glioma development, the researchers suggest that the identified mechanism holds promise for the future exploration of pharmacological agents targeting NLG3 expression and release.
At present, the link between auditory nerve excitation and the development of local tumors, such as vestibular schwannomas, is inconclusive. While some meta-analyses have found that chronic exposure to environmental noise—including recreational noise such as concerts, sporting events, and headphone usage—is associated with an increased risk of schwannoma, other studies have found no such correlation.
However, researchers are currently investigating other potential links between loud noise and cancer risk.
Because exposure to high levels of noise, especially traffic noise, has been linked to high blood pressure and heart disease, some studies have sought to understand the molecular mechanisms underlying vascular damage resulting from noise exposure. In one study, mice exposed to seven days of aircraft noise or to a drug that elevated blood pressure, or both, had increased levels of inflammatory immune cells and cytokines such as IL-6 in both the aorta and in cortical brain tissue—an effect that was most pronounced in mice exposed to both conditions. Both IL-6 signaling and chronic inflammation are known to contribute to cancer development and/or progression, and other oncogenic signaling molecules, such as MCP-1 and VCAM-1, were also increased in the aortas of mice exposed to both noise and hypertension.
In another study published in the journal Free Radical Research, the researchers exposed mice to four days of aircraft noise and found increased markers of oxidative stress in their vasculature, as well as in immune cells associated with the vascular tissue. Notably, increases in oxidative DNA damage were observed both in mice with a genetic DNA repair deficiency and mice with intact DNA repair systems. While the researchers stressed that their study did not examine cancer development, they suggest that the link to potentially cancer-causing mechanisms warrants further investigation.
The results in these studies, as well as in the studies examining all five senses, are preliminary, and their translational relevance remains to be seen. However, an improved understanding of the molecular interplay between nerves and cancer cells may give researchers insights into novel ways to target tumorigenesis.