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Ana Isabel Castillo Orozco
“Cancer Neuroscience”: This is the name given to a novel and exciting field that aims to study the complex interactions between the nervous system and cancer development. In recent years, increasing evidence has come to light that neuronal activity is crucial in regulating cancer initiation and progression. At the same time, it has also been noted that cancer heavily influences and disrupts nervous system functions. Lastly, but not less critical, cancer therapy is well known to cause secondary and long-lasting effects on the nervous system of affected individuals. How all these processes occur at the cellular and systemic levels remains widely unexplored. These are some of the puzzles aimed to be illuminated by cancer neuroscience.
The beginnings of Cancer Neuroscience
The call to establish this emerging discipline came in late 2019 when a group of 35 experts from a wide range of scientific backgrounds, including cancer biology, developmental biology, neuroscience, and immunology, gathered at a breakthrough meeting held at Cold Spring Harbor Laboratory. At the conference, the need to better understand the complex interactions between cancer and the nervous system was recognized (Cold Spring Harbor, 2022). While individual researchers had previously made some efforts to elucidate these mechanisms, this gathering represented a unique opportunity to promote collaborative work and multidisciplinary approaches, thus, bringing life to “Cancer Neuroscience.”
Cross-communication between cancer cells and the nervous system
But how can neural activity influence the development of tumors that have started in or metastasized into the central nervous system? Although there are still many unknown mechanisms, previous research has shown the presence of synaptic communication between neurons and brain cancer cells. This crosstalk enables the regulation of cancer growth through neurotransmitter and voltage-regulated mechanisms [1].
This kind of communication exists in normal conditions, as the nervous system is highly involved in brain development. For example, neurons that produce excitatory neurotransmitters such as glutamate (glutamatergic neurons) stimulate the proliferation of cells that provide them with physical support and transport of nutrients and waste, known as glial cells or neuroglia. Similarly, brain cancer cells use this mechanism to increase proliferation as glutamatergic neuronal activity is involved in malignant glioma growth [tumors arising from cells that support the brain and spinal cord known as glial cells] [2]. Remarkably, this cancer-favoring effect through excitatory neurotransmitters has also been implicated in brain metastasis. For instance, breast cancer that metastasizes to the brain initiates up-regulation of neurotransmitter receptors that induce internal currents in the malignant cells, further promoting metastasis [3].
On the other side, cancer’s influence on nervous system function may also occur. Through bidirectional interactions, cancer cells shape and disturb neural circuits. This phenomenon may disrupt normal brain activity, leading to the appearance of clinical signs such as seizures. This effect is beneficial for cancer cells, as this increase in neuronal activity promotes tumor growth by activity-dependent signals. Likewise, it has been observed that cancers outside the central nervous system may disrupt normal brain functions such as sleep, but how these effects emerge is yet to be understood. Intriguingly, cancer cells have been observed to invade peripheral nerve fibers. Such incursion leads to the reconfiguration of peripheral nerves and, ultimately, the presence of chronic pain syndromes[1].
Challenges and Future venues
Another gap the field aims to address is the effects and mechanisms of cancer treatment on the nervous system. Radiation and chemotherapy can produce severe secondary effects on affected individuals, such as cognitive impairment (e.g., loss of memory), sensory loss, paralysis, pain, and even depression [4]. In the last few years, the underlying basis by which cancer therapy causes neural toxicity has started to shed some light. Accordingly, a few strategies for neuroprotection and neural regeneration have been proposed. However, the full impact and extent of how cancer therapy affects nerve-cancer interactions are still blurred.
To further tangle the landscape between cancer cells and the nervous system, this complex communication can also occur indirectly, intermediated by the immune system and other types of cells in the nervous system. In normal conditions, immune cells such as macrophages and cell components of the blood-brain barrier (BBB) [e.g., endothelial cells] are responsible for the defense from pathogens and restraining access from solutes in the blood, respectively. However, cancer cells can sometimes remodel the functions of these cells (e.g., tumor-associated macrophages) to their favor and establish a niche suitable for survival. These groups of non-cancer cells that benefit tumor growth are known as the tumor microenvironment. Thus, cancer-nervous system crosstalk may also be triggered by interactions from the tumor microenvironment [1]. Such interconnections represent one of the earliest and least researched topics in the realm of ‘Cancer Neuroscience”. Indeed, the dissection of these mechanisms will require a combination of neuroscience, oncology, and immunology.
Cancer Neuroscience hits entrepreneurship
Such is the need to understand these processes that even startups have emerged to develop therapeutic avenues based on the premises of Cancer Neuroscience. Following the Cold Spring Harbor meeting in 2019, Cygnal Therapeutics and Divide & Conquer were launched with $65 and $13 million budgets respectively to address the disruption of communication between nerves, cancer cells, and cells from the tumor microenvironment [5]. The development of candidate drugs to improve cancer treatment by targeting these crosstalks through these ventures and other academic efforts is still ongoing.
Cancer Neuroscience aims to combine the modern tools of neuroscience with cancer biology. Although there is still much left to be discovered about these intricate interaction mechanisms, the crosstalk between neuroscientists and cancer biologists has never been so crucial for consolidating this field. The clarification of how these complex relationships between cancer cells and the nervous system occur will be pivotal in providing new opportunities to find more effective and targeted cancer therapies.
Edited by Sushma Teegala
References:
[1]MONJE, M., BORNIGER, J. C., D’SILVA, N. J., DENEEN, B., DIRKS, P. B., FATTAHI, F., FRENETTE, P. S., GARZIA, L., GUTMANN, D. H. & HANAHAN, D. 2020. Roadmap for the emerging field of cancer neuroscience. Cell, 181, 219-222.
[2] VENKATESH, H. S., JOHUNG, T. B., CARETTI, V., NOLL, A., TANG, Y., NAGARAJA, S., GIBSON, E. M., MOUNT, C. W., POLEPALLI, J. & MITRA, S. S. 2015. Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell, 161, 803-816.
[3] ZENG, Q., MICHAEL, I. P., ZHANG, P., SAGHAFINIA, S., KNOTT, G., JIAO, W., MCCABE, B. D., GALVÁN, J. A., ROBINSON, H. P. & ZLOBEC, I. 2019. Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature, 573, 526-531.
[4]YANG, M. & MOON, C. 2013. Neurotoxicity of cancer chemotherapy. Neural regeneration research, 8, 1606.
[5]DOLGIN, E. 2020. Cancer-neuronal crosstalk and the startups working to silence it. Nature Biotechnology, 38, 115-118.
Websites:
Cold Spring Harbor Laboratory (2022). Charting a new field of cancer neuroscience. Available at: https://www.cshl.edu/charting-a-new-field-of-cancer-neuroscience/ (Accessed: 03 September 2022).
Images
Cover image by Alexander Neils Alcalde Yañez
DALL-E 2 https://openai.com/dall-e-2
Ramesh, A., Dhariwal, P., Nichol, A., Chu, C., & Chen, M. (2022). Hierarchical text-conditional image generation with clip latents. arXiv preprint arXiv:2204.06125.
Figure 1. Main mechanisms aimed to be studied by Cancer Neuroscience Scheme. Created with BioRender.com.”
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