Erin Nuray, Shurin Galina V, Baraldi James H, Shurin Michael R
Department of Medical Pharmacology, Immunopharmacology, and Immuno-Oncology Unit, School of Medicine, Akdeniz University, 07070 Antalya, Turkey.
Department of Pathology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, 15213 PA, USA.
Cancers (Basel). 2022 May 9;14(9):2333. doi: 10.3390/cancers14092333.
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.
免疫系统与神经系统之间的相互作用对维持体内平衡至关重要，而这些神经免疫相互作用的紊乱可能参与癌症的发生和转移。在人类和实验动物的实体瘤中已发现神经末梢。尽管传出交感神经和副交感神经支配在癌症发生中的作用已得到广泛研究，但传入感觉神经元和神经肽在肿瘤发展、生长和进展中的作用最近才受到重视。同样，目前的研究结果表明施万细胞作为神经免疫相互作用的一部分具有重要作用。因此，在本综述中，我们主要关注感觉神经活动以及施万细胞在癌症发生和转移中的局部和全身效应。据报道，在动物模型中，迷走感觉神经纤维的特异性去神经支配或迷走神经切断术会显著增加乳腺癌的肺转移以及胰腺和胃肿瘤的生长，肝转移的形成表明迷走感觉纤维对癌症具有保护作用。临床研究表明，接受迷走神经切断术的胃溃疡患者患胃癌、结直肠癌、胆道癌和肺癌的风险更高。流行病学研究也记录了迷走神经活动的保护作用，表明高迷走神经活动预示着结肠癌、非小细胞肺癌、前列腺癌和乳腺癌患者的生存率更长。然而，一些研究报告称，抑制感觉神经元活动会减少实体瘤的发生，包括前列腺癌、胃癌、胰腺癌、头颈癌、宫颈癌、卵巢癌和皮肤癌。这些相互矛盾的发现可能是由于神经损伤后全身感觉纤维的激活、所用肿瘤模型的侵袭性水平以及感觉纤维的局部异质性。随着肿瘤模型的侵袭性和炎症反应水平的增加，感觉神经纤维的保护作用变得明显，这可能主要归因于神经免疫反应的全身改变。因此，需要更深入了解诱导和允许机制，如癌症发生和转移形成的全身、细胞神经免疫机制，以了解感觉神经元在肿瘤生长和扩散中的作用。
