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Tumor Innervation: History, Methodologies, and Significance
 
 
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Regulation of Carcinogenesis by Sensory Neurons and Neuromediators

1
Department of Medical Pharmacology, Immunopharmacology, and Immuno-Oncology Unit, School of Medicine, Akdeniz University, 07070 Antalya, Turkey
2
Department of Pathology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, 15213 PA, USA
3
Department of Neuroscience, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, 15213 PA, USA
4
Department of Immunology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, 15213 PA, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Izumi Horikawa
Cancers 2022, 14(9), 2333; https://doi.org/10.3390/cancers14092333
Received: 18 March 2022 / Revised: 26 April 2022 / Accepted: 5 May 2022 / Published: 9 May 2022
(This article belongs to the Special Issue The Tumor Neuroenvironment)
Sensory nerve fibers extensively innervate the entire body. They are the first to sense danger signals, including the ones coming from newly formed cancer cells. Various studies have demonstrated that the inactivation of sensory nerve fibers as well as the vagus nerve enhances tumor growth and spread in models including breast, pancreatic, and gastric cancer. On the other hand, there are also contradictory findings that show the opposite, namely that the inactivation of nerve fibers inhibits tumor growth. These discrepancies are likely caused by the stage and the level of aggressiveness of the tumor model used. Hence, further studies are required to determine the factors involved in neuro-immunological mechanisms of tumor growth and spread.
Interactions between the immune system and the nervous system are crucial in maintaining homeostasis, and disturbances of these neuro-immune interactions may participate in carcinogenesis and metastasis. Nerve endings have been identified within solid tumors in humans and experimental animals. Although the involvement of the efferent sympathetic and parasympathetic innervation in carcinogenesis has been extensively investigated, the role of the afferent sensory neurons and the neuropeptides in tumor development, growth, and progression is recently appreciated. Similarly, current findings point to the significant role of Schwann cells as part of neuro-immune interactions. Hence, in this review, we mainly focus on local and systemic effects of sensory nerve activity as well as Schwann cells in carcinogenesis and metastasis. Specific denervation of vagal sensory nerve fibers, or vagotomy, in animal models, has been reported to markedly increase lung metastases of breast carcinoma as well as pancreatic and gastric tumor growth, with the formation of liver metastases demonstrating the protective role of vagal sensory fibers against cancer. Clinical studies have revealed that patients with gastric ulcers who have undergone a vagotomy have a greater risk of stomach, colorectal, biliary tract, and lung cancers. Protective effects of vagal activity have also been documented by epidemiological studies demonstrating that high vagal activity predicts longer survival rates in patients with colon, non-small cell lung, prostate, and breast cancers. However, several studies have reported that inhibition of sensory neuronal activity reduces the development of solid tumors, including prostate, gastric, pancreatic, head and neck, cervical, ovarian, and skin cancers. These contradictory findings are likely to be due to the post-nerve injury-induced activation of systemic sensory fibers, the level of aggressiveness of the tumor model used, and the local heterogeneity of sensory fibers. As the aggressiveness of the tumor model and the level of the inflammatory response increase, the protective role of sensory nerve fibers is apparent and might be mostly due to systemic alterations in the neuro-immune response. Hence, more insights into inductive and permissive mechanisms, such as systemic, cellular neuro-immunological mechanisms of carcinogenesis and metastasis formation, are needed to understand the role of sensory neurons in tumor growth and spread. View Full-Text
Keywords: tumor innervation; neuro-immunology; neuropeptides; metastasis tumor innervation; neuro-immunology; neuropeptides; metastasis
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MDPI and ACS Style

Erin, N.; Shurin, G.V.; Baraldi, J.H.; Shurin, M.R. Regulation of Carcinogenesis by Sensory Neurons and Neuromediators. Cancers 2022, 14, 2333. https://doi.org/10.3390/cancers14092333

AMA Style

Erin N, Shurin GV, Baraldi JH, Shurin MR. Regulation of Carcinogenesis by Sensory Neurons and Neuromediators. Cancers. 2022; 14(9):2333. https://doi.org/10.3390/cancers14092333

Chicago/Turabian Style

Erin, Nuray, Galina V. Shurin, James H. Baraldi, and Michael R. Shurin. 2022. "Regulation of Carcinogenesis by Sensory Neurons and Neuromediators" Cancers 14, no. 9: 2333. https://doi.org/10.3390/cancers14092333

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