The Emerging Field of Cancer Neuroscience

                                                                    By Lingyi Wang 

It’s well known that the nervous system plays an important role in maintaining health and wellbeing for vertebrate organisms. Just like blood vessels distributed throughout the body, in most animals, all tissues and organs (except for cartilages and lens) are surrounded by a network of nerves, namely the peripheral nervous system (PNS). The PNS connects these tissues and organs to the central nervous system (CNS) which consists of the brain and spinal cord, allowing internal communication between different parts of the body: when the sensory receptors in a tissue or organ receive a stimulus (such as touch, light, variations in temperature and blood sugar levels) they send signals in the form of electrical and chemical transmissions along the PNS network to report these changes to the CNS (Boilly et al., 2017; Faulkner et al., 2019).  After the information is integrated and processed by the CNS, signals will be sent back via the PNS to the corresponding tissue or organ, where adjustments will be made according to the CNS’ “command”. 

Looking at the classification of the nervous system, PNS is further divided into the somatic nervous system which controls the voluntary movements of the skeletal muscle, and the autonomic nervous system which is associated with involuntary body processes, such as blood pressure, heartbeat, breathing. The autonomic nervous system is subdivided into sympathetic or parasympathetic systems. In general, the sympathetic system works during stressful situations, and it initiates the “fight-or-flight” responses, whereas the parasympathetic system is responsible for “calming down” and resetting the body to relaxing states when the stress is over. Taken together, despite the complex compositions and functional specificities,  the nervous system allows the body to respond to changes in the internal and external environment and helps maintain optimal tissue and organ functions (Zahalka & Frentte, 2020; Monje et al., 2020). 

Alongside involvement in adaptation to its surrounding environment, the nervous system has an impact on cancer progression (Zahalka & Frenette, 2020). Although surgeons in the 19th century had attempted to treat cancers via neuron transection (Jobert, 1840), exploring the relationships between the nervous system and cancer has only gained wide attention in the past decade as greater evidence has been found to demonstrate the nerve-tumour crosstalk (Zahalka & Frenette, 2020).  In 2008, Ayala and colleagues observed an increase in the number of neurons during tumorigenesis of prostate cancer. The nerve density had nearly doubled in tumour tissues compared to the age-matched healthy tissues (Ayala et al., 2008). This increase in nerve density had later been found in other cancer types as well, such as colorectal (Albo et al., 2014) breast (Huang et al., 2014) and lung (Shao et al., 2016) cancers, and often shows a positive correlation with the aggressiveness of the tumour behaviours.  Moreover, neurotrophic growth factor and axon guidance molecules were found to be secreted by tumour cells to the tumour microenvironment (TME). Considering their roles in promoting axonogenesis (the outgrowth of nerve endings during embryonic development and tissue regeneration), this discovery has provided a molecular explanation of the increased nerve density and demonstrated that cancer cells actively recruit nerves to their TME to promote their development (Faulkner et al., 2019; Wang et al., 2020) 

With technological advances allowing precise neuron transection, gene editing and cell imaging, a lot of research has recently been focused on the molecular mechanisms behind the nerve-cancer crosstalk (Zahalka & Frenette, 2020). In gastric cancer, denervation experiments using mouse models have demonstrated that the parasympathetic nerve system has a promoting effect in tumorigenesis, as interruption of these nerves has resulted in reduced tumour size and decreased number of cancer stem cells. Incubating gastric organoids with different substrates and antagonists of various signalling receptors has suggested that this relationship is likely to be established through muscarinic receptors and its downstream YAP and WNT pathways (Zhao et al., 2014). A similar relationship has also been observed in prostate cancer via denervation studies (Magnon et al., 2013). Interestingly, in pancreatic cancer, the parasympathetic nerves showed an opposite effect on tumorigenesis. Denervation of the parasympathetic system unexpectedly stimulated the tumour development rather than inhibiting development (Renz et al., 2018). This was later explained by a mechanism involving another muscarinic receptor called CHRM1. CHRM1 is activated by acetylcholine (a chemical transmitted specifically by the parasympathetic nerve system). Since CHRM1 exerts inhibitory effects on tumour growth, denervation of the parasympathetic nerves indirectly blocks this CHRM1 receptor, accelerating the tumour growth (Renz et al., 2018). Overall, these findings illustrate the complexity of the nerve-tumour relationship and outline that the impact of a specific nerve on tumour development needs to be analysed on a case-by-case basis. 

Apart from directly regulating tumour growth via different signalling pathways, the nervous system also plays an important role in other stages of cancer progression. In terms of angiogenesis, a necessary  event during tumour development is to grow blood vessels and provide the tumour with essential nutrients. A key study by Zahalka and colleagues using prostate cancer models has demonstrated that the sympathetic nerves can stimulate angiogenesis via a process called “angiometabolic switch”. The sympathetic nerves release a chemical called noradrenaline to the TME, which subsequently activates the expression of Adrβ2 receptor in endothelial cells (which is a component of blood vessels) . With greater expression of the Adrβ2 receptor, the endothelial cell metabolism shifts to favour aerobic glycolysis, which in turn stimulates angiogenesis.  On the other hand, this study also provided an explanation of the better survival rate observed in cancer patients who also have cardiovascular diseases and anxiety disorders, because drugs prescribed for these disease often work as β2 receptor blockers (Zahalka et al., 2017). For cancer metastasis, tumour invasion along the nerve networks has been recognised as a new pathological feature and becomes another hallmark indicating severe malignancies (Amit, Na’ara & Gil, 2016). 

The discovery of the driving roles of the nervous system in cancer has brought new opportunities for developing new diagnostic methods and cancer therapies. As the nerve density is closely related to cancer aggressiveness, quantifying the nerve growth in cancer patients can be used to predict the disease outcomes (Faulkner et al., 2019). Such examples can be seen in developing neuroproteins as cancer biomarkers (Li et al., 2018). For cancer treatment, developing denervation technologies to disable particular nerves and suppress tumour growth has gained a lot of research interest in recent years.  In addition, components downstream of the neural pathways have also provided new drug targets for cancer therapies (Zahalka & Frenette, 2020). 

In summary, investigating the impact of the nerve system in cancer progression has recently become a new hot-topic in cancer research. Mounting evidence has suggested that there is an intricate relationship between tumour cells and the nerve system. Although several mechanisms have been proposed to describe this nerve-tumour crosstalk, more research is still needed to complete the detailed molecular pathways for different cancer types. It is hoped that the emerging field of cancer neuroscience will provide promising angles for developing further treatments and help patients win their arduous battle against tumour cells. 

References: 

Boilly B., Faulkner S., Jobling P., et al. (2017) Nerve Dependence: From Regeneration to Cancer. Cell. 31(3): 342-354. 

Faulkner S., Jobling P., March B., et al. (2019) Tumor Neurobiology and the War of Nerves in Cancer. Cancer Discov. 9(6): 702-710. 

Zahalka A. H., Frenette P. S. (2020) Nerves in Cancer. Nature Rev Cancer. 20(3): 143-157. 

Monje M., Borniger J. C., Silva N. J. D. et al. (2020) Roadmap for the Emerging Field of Cancer Neuroscience. Cell. 181 (2): 219-222. 

Jobert M. (1840) New treatment of cancer. Lancet. 34, 112.

Ayala G. E., Dai H., Powell M., et al. (2008) Cancer related axonogenesis and neurogenesis in prostate cancer. Clin Cancer Res. 14:7593–603.

Albo, D., Catherine L., Akay M.D., et al. (2011) Neurogenesis in colorectal cancer is a marker of aggressive tumor behavior and poor outcomes. Cancer. 117, 4834–4845.

Huang, D., Su S., Cui X. et al. (2014) Nerve fibers in breast cancer tissues indicate aggressive tumor progression. Medicine. 93, e172. 

Shao, J. X., Wang B., Yao Y-N., et al. (2016) Autonomic nervous infiltration positively correlates with pathological risk grading and poor prognosis in patients with lung adenocarcinoma. Thorac. Cance.r 7, 588–598. 

Wang J., Li L., Chen N., et al. (2020) Nerves in the Tumor Microenvironment: Origin and Effects. Front Cell Dev Biol. 8: 601738. 

Zhao C. M., Hayakawa Y., Kodama Y., et al. (2014) Denervation suppresses gastric tumorigenesis. Sci Transl Med. 6:250ra115

Magnon C.,  Hall S. J. , Lin J., et al. (2013) Autonomic nerve development contributes to prostate cancer progression. Science. 341:1236361. 

Renz B. W., Takahashi R., Tanaka T., et al. Beta2 Adrenergic-neurotrophin Feedforward Loop promotes Pancreatic Cancer. Cancer Cell. 2018;33:75–90 e7.

Zahalka A. H., Arnal-Estape A. , Maryanovich M., et al. (2017) Adrenergic nerves activate an angio-metabolic switch in prostate cancer. Science. 358:321–6.

Amit A., Na’ara S., Gil Z. (2016) Mechanisms of cancer dissemination along nerves. Nature Rev Caner. 16: 399-408. 

Li X. , Dun M.D., Faulkner S, et al. (2018) Neuroproteins in cancer: assumed bystanders become culprits. Proteomics. 18:e1800049.

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