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Sympathetic and parasympathetic innervation in cancer: therapeutic implications

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Abstract

Purpose

The autonomic nervous system, consisting of sympathetic and parasympathetic/vagal nerves, is known to control the functions of any organ, maintaining whole-body homeostasis under physiological conditions. Recently, there has been increasing evidence linking sympathetic and parasympathetic/vagal nerves to cancers. The present review aimed to summarize recent developments from studies addressing the relationship between sympathetic and parasympathetic/vagal nerves and cancer behavior.

Methods

Literature review.

Results

Human and animal studies have revealed that sympathetic and parasympathetic/vagal nerves innervate the cancer microenvironment and alter cancer behavior. The sympathetic nerves have cancer-promoting effects on prostate cancer, breast cancer, and melanoma. On the other hand, while the parasympathetic/vagal nerves have cancer-promoting effects on prostate, gastric, and colorectal cancers, they have cancer-suppressing effects on breast and pancreatic cancers. These neural effects may be mediated by β-adrenergic or muscarinic receptors and can be explained by changes in cancer cell behavior, angiogenesis, tumor-associated macrophages, and adaptive antitumor immunity.

Conclusions

Sympathetic nerves innervating the tumor microenvironment promote cancer progression and are related to stress-induced cancer behavior. The parasympathetic/vagal nerves have variable (promoting or suppressing) effects on different cancer types. Approaches directed toward the sympathetic and parasympathetic/vagal nerves can be developed as a new cancer therapy. In addition to existing pharmacological, surgical, and electrical approaches, a recently developed virus vector-based genetic local neuroengineering technology is a powerful approach that selectively manipulates specific types of nerve fibers innervating the cancer microenvironment and leads to the suppression of cancer progression. This technology will enable the creation of "cancer neural therapy" individually tailored to different cancer types.

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Acknowledgements

This study was supported by Grants-in-Aid for Scientific Research promoted by the Ministry of Education, Culture, Sports, Science, and Technology in Japan (17H04365, 18K19950, 18H04707, 20H00666, and 20K21897), the Japan Agency for Medical Research and Development (AMED) under Grant Number JP20cm0106271, the Canon Foundation and the Takeda Science Foundation.

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  1. Department of Cellular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan

    Atsunori Kamiya, Takeshi Hiyama, Atsushi Fujimura & Soichiro Yoshikawa

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  1. Atsunori Kamiya
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  3. Atsushi Fujimura
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Correspondence to Atsunori Kamiya.

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The authors declare no competing interests except for a patent (applicant and inventor: Atsunori Kamiya; number: PCT/JP2017/25468; specific aspect of the manuscript covered in the patent application: the genetic engineering of local nerves for the treatment of cancers).

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This review article cites previous human and animal studies that were approved by the appropriate ethics committees in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

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Kamiya, A., Hiyama, T., Fujimura, A. et al. Sympathetic and parasympathetic innervation in cancer: therapeutic implications. Clin Auton Res 31, 165–178 (2021). https://doi.org/10.1007/s10286-020-00724-y

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