Cancer Neuroscience: Managing Cancer by Getting on its Nerves

By Charlotte Hutchings

Cancer is the second most common cause of death globally. Responsible for 9.6 million deaths in 2018, this global health problem is becoming an increasing burden upon all societies (Bray et al., 2018). Unfortunately, commonly applied treatment modalities, namely radiotherapy and chemotherapy, suffer from undesirable side-effects due to lack of specificity. That is, such treatments kill healthy cells as well as cancer cells, thus leading to toxicity and tissue damage. Additionally, chemotherapy is often limited in its time of effectiveness following the onset of drug resistance. Consequently, there are still substantial advances needed in cancer management, from the early stages of diagnosis, to advanced treatment of the disease.

One novel therapeutic target to emerge is the nervous system. It has long been known that cancer cells can use nerves as a ‘pathway’ to disseminate from the primary tumour. This process, referred to as ‘perineural invasion’, contributes to metastasis, the main cause of cancer deaths and, therefore, is a negative prognostic factor (Amit et al., 2016). More recently, it has become clear that tumours themselves are physically innervated. Indeed, the complex tumour microenvironment consists of not only cancer cells but also fibroblasts, endothelial cells, immune cells and neurons (Boilly et al., 2017). Such innervation has been shown to provide active inputs to the tumorigenesis process (Hutchings et al., 2020). The best clinical evidence for the role of nerves in cancer comes from patients with spinal cord injuries who have up to 65% lower risk of developing prostate cancer compared to age-matched healthy individuals (Barbonetti et al., 2018). Hence the field of “Cancer Neuroscience” was born.

The nerve input to tumours involves the release of neurotransmitters, peptides and hormones. Signals from the sympathetic nervous system (SNS) are mediated by epinephrine/norepinephrine acting on adrenergic receptors. The parasympathetic nervous system (PNS) predominantly releases acetylcholine which signals through muscarinic and nicotinic cholinergic receptors. In particular, the vagus nerve, the largest of the cranial nerves and primary nerve of the PNS, appears to play a key role in regulating tumorigenesis (Hutchings et al., 2020). 

Early work on prostate cancer implicated SNS in primary tumorigenesis (proliferation) and PNS in secondary tumorigenesis (invasion and metastasis) (Magnon et al., 2013). Using a mouse model, Magnon and colleagues demonstrated that inhibiting SNS nerve input, either by physical severing or chemical blockade, resulted in a significant decrease in cancer cell proliferation (Magnon et al., 2013). Consistently, patients treated with β-adrenergic receptor antagonists, or clinical ‘beta-blockers’, have lower prostate cancer incidence and improved prognosis (Zahalka et al., 2020). As regards the PNS, chemical blockade or genetic ablation of M1-type muscarinic receptors led to significantly reduced dissemination and prolonged survival (Magnon et al., 2013). Similar effects have been recorded in a number of carcinomas including cancers of the: breast, colon, rectum, lung, stomach and pancreas. Importantly, the strength, impact, and timing of SNS and PNS inputs varies from cancer-to-cancer and organ-to-organ, likely in line with the basal nerve inputs to each site (Hutchings et al., 2020). 

It remains unclear how and why the mechanisms behind the nerve-tumour interaction evolved. Is this an attempt by the body to control tumorigenesis? Has the body simply mistaken the tumour for an organ and is now trying to innervate it? Interestingly, the interaction is not one-way but rather bidirectional. Cancer cells themselves produce and release axon guidance molecules, nerve growth factor and neurotransmitters to enhance their own innervation and promote neuronal activity (Boilly et al., 2017). In gastric cancer, for example, nerve growth factor released by cancer cells stimulates neurogenesis. In turn, acetylcholine released by PNS nerve fibres infiltrating the tumour acts on the cancer cells to promote production of nerve growth factor (Hayakawa et al., 2017). Indeed, positive feedback is emerging as a common feature of the nerve-tumour interaction. Perhaps cancer is co-opting the body’s neuronal pathways as a way to accelerate its own progress. 

As evidence accumulates for a pro-tumour role of nerves, it has become conceivable that neuronal inputs could be targeted as a novel way of controlling cancer. One potential approach is the use of drugs that target neuronal pathways. Beta-blockers, for instance, could be used to completely or partially inhibit SNS inputs. Encouragingly, a meta-study demonstrated that non-small cell lung cancer patients prescribed beta-blockers had better disease-free survival than those undergoing traditional therapies (Coelho et al., 2019). Alternatively, cholinergic inhibitors, such as M3 receptor antagonist darifenacin, could be used to target the PNS (Schuller, 2019).

Whilst pharmaceutical approaches could re-purpose nerve blocking agents already in use, other methods of controlling the nerve-tumour crosstalk are also being considered. Electroceuticals is a term used to describe the manipulation of bioelectrical signalling with the aim, ultimately, to control downstream signalling pathways and cellular activity (Mishra, 2017). Bioelectronic devices with the capacity to provide electrical stimulation already exist, pacemakers being the most common. As the fields of biomaterials, bioelectronics and neurobiology advance there is every possibility that a device could be designed to activate or inhibit the activity of cancer-associated neurons based on the use of electrical stimulation.

The field of Cancer Neuroscience is undoubtedly growing. There is still much work to be done to determine the precise neuronal pathways involved in cancer and such investigation must be carried out on a cancer-by-cancer basis with all variables considered. Even so, just the thought of how much potential rests on this upcoming field is enough to excite the brain. 

References:

Amit, M., Na’ara, S. & Gil, Z. (2016) Mechanisms of cancer dissemination along nerves. Nat Rev Cancer. 16, 399-408. doi: 10.1038/nrc.2016.38.

Barbonetti, A., D’Andrea, S., Martorella, A., Felzani, G., Francavilla, S. & Francavilla, F. (2018) Risk of prostate cancer in men with spinal cord injury: A systematic review and meta-analysis. Asian Journal of Andrology. 20, 555-560. doi: 10.4103/aja.aja_31_18. 

Boilly, B., Faulkner, S., Jobling, P. & Hondermarck, H. (2017) Nerve dependence: From regeneration to cancer. Cancer Cell. 31, 342-354. doi: 10.1016/j.ccell.2017.02.005. 

Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A. & Jemal, A. (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 68, 394-424. doi: 10.3322/caac.21492.

Coelho, M., Squizzato, A., Cassina, N., Marino, F., Ribeiro, L. V. & Cosentino, M. (2019). Effect of beta-blockers on survival of lung cancer patients: A systematic review and meta-analysis. European Journal of Cancer Prevention: The Official Journal of the European Cancer Prevention Organisation (ECP). doi:10.1097/CEJ.0000000000000544.

Hayakawa, Y., Sakitani, K., Konishi, M., Asfaha, S., Niikura, R., Tomita, H., Renz, B. W., Tailor, Y., Macchini, M., Middelhoff, M., Jiang, Z., Tanaka, T., Dubeykovskaya, Z. A., Kim, W., Chen, X., Chen, D., Urbanska, A. M., Nagar, K., Westphalen, C. B., Quante, M., Lin, C., Gershon, M. D., Hara, A., Zhao, C., Worthley, D. L., Koike, K. & Wang, T. C. (2017) Nerve growth factor promotes gastric tumorigenesis through aberrant cholinergic signaling. Cancer Cell. 31, 21-34. doi: 10.1016/j.ccell.2016.11.005. 

Hutchings, C., Phillips, J. A. & Djamgoz, M. B. A. (2020) Nerve input to tumours: Pathophysiological consequences of a dynamic relationship. BBA Reviews on Cancer. 188411. doi: 10.1016/j.bbcan.2020.188411.

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, 1236361. doi:10.1126/science.1236361

Mishra, S. (2017) Electroceuticals in medicine – The brave new future. Indian Heart Journal. 69, 685-686. doi: 10.1016/j.ihj.2017.10.001. 

Schuller, H. M. (2019). The neuro-psychological axis of smoking-associated cancer. Journal of Immunological Sciences. 3, 1-5. doi:10.29245/2578-3009/2019/2.1166

Zahalka, A. H., Fram, E., Lin, W., Mohn, L., Frenette, P. S., Agalliu, I. & Watts, K. L. (2020) Use of beta-blocker types and risk of incident prostate cancer in a multiethnic population. Urologic Oncology.  doi: 10.1016/j.urolonc.2020.03.024. 

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