Regulation of Carcinogenesis by Sensory Neurons and Neuromediators

Abstract

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.

Keywords: metastasis; neuro-immunology; neuropeptides; tumor innervation.

Figure 1

Anatomical and functional classification of sensory nerve fibers.

Figure 2

Hypothetical role of sensory nerve fibers in the cancer immune response based on published data. Cancer cells go through immune editing and become more aggressive, while nerve fibers and Schwann cells go through cancer cell editing and become tumorigenic. Free sensory nerve endings of visceral and peripheral tissues are the first to sense the danger signals from pathogens and abnormal cells, inducing an acute inflammatory response as well as the compensatory anti-inflammatory pathway through the hypothalamic–pituitary–adrenal axis in the early stage. In the intermediate stage, partly functioning nerve fibers provide local anti-inflammatory-response cytokines/chemokines released by activated Schwann cells, enhancing cytotoxic immunity. In the advanced stage, complete degeneration of nerve fibers followed by formation of abnormal nerve fibers and tumorigenic Schwann cell activation markedly enhances chronic inflammation, and MDSCs impair cytotoxic immunity and induce metastasis.