摘要
精神、情绪等心理因素直接影响人类身体健康，慢性应激产生神经递质抑制机体免疫系统，机体内平衡被破坏，使细胞失去正常状态和功能，产生肿瘤细胞；肿瘤患者会经历慢性情绪压力，产生的神经递质会促进肿瘤的发生和发展。本文从神经递质正常生理功能和在肿瘤发生发展中的作用机制两方面系统总结了主要神经递质的研究进展。为进一步探索神经递质的作用新机制和开发阻断神经递质作用的药物提供理论思考。
心理因素影响人类健康，古希腊著名内科医生Galen就提出，心理和生理是一个整体，通过心理治疗可以医治机体的器质性病变。神经主要通过将信息从中枢神经系统(CNS)传递到器官和组织，反之亦然。感觉神经、运动神经和自主神经 (交感神经和副交感神经) 构成一个直接或间接与中枢神经系统相连的神经网络，使身体各部分之间能够进行功能交
多巴胺(dopamine, DA)是大脑中重要的神经递质。共有两种类型的多巴胺受体：D1和D2。D1类受体可以通过Gs蛋白与腺苷酸环化酶正性偶联，激活腺苷酸环化酶。而D2类受体则抑制腺苷酸环化酶，并抑制C
DA与其受体同肿瘤的发生密切相关。调节性T细胞 (Treg) 是肿瘤逃逸宿主免疫系统的关键因子，DA通过D1型受体抑制人CD
肾上腺素(adrenaline)和去甲肾上腺素 (noradrenaline, NA)分别主要由肾上腺髓质和交感神经分泌。可以直接调节多种肿瘤的进展，如细胞增殖、存活和迁移。此外，还可以刺激内皮细胞、免疫细胞和成纤维细胞，因此对肿瘤的进展有广泛的影响。
神经系统参与对肿瘤的发生和发展的调控。一些实验表明交感神经系统的肾上腺素能纤维参与肿瘤进展的初始阶段。在卵巢癌细胞中，肾上腺素和NA可以调节细胞增殖、生存和肿瘤血管生成。β肾上腺素受体(β-AR)的激活能促进胸部、肺部、结肠和胰腺的肿瘤细胞迁移和侵袭，在多种肿瘤细胞中促进血管生成，促进血管内皮生长因子(VEGF)、白细胞介素-6(IL-6)的分泌。长期慢性的压力会导致肾上腺素和去甲肾上腺素水平增加，促进肿瘤血管生成和肿瘤发生转
血清素也称为5-羟色胺(5-hydroxy tryptamine，5-HT) ，不到1%的血清素游离存在于血液中，其余储存在血小板，突触前神经元和肠嗜铬细胞
在胰腺导管腺癌(PDAC)中，5-HT合成和降解酶的失控导致5-HT水平升高，通过HTR2B受体进一步激活PI3K/AKT/mTOR信号，而不是经典的第二信使系统，从而增强Warburg效
γ-氨基丁酸 (γ-aminobutyric acid，GABA)是中枢神经系统中主要的抑制性神经递质，还可以在神经发育过程中作为营养因子来调节神经细胞的增殖、迁移、分化和死
γ-氨基丁酸氨基转移酶 (ABAT) 是GABA分解代谢的关键酶。GABA介导的C
谷氨酸(glutamic acid, mGluR)是哺乳动物中枢神经系统中主要的兴奋性神经递质。它的功能通过两类受体介导：离子型和代谢型。以前一直认为mGluRs特异性地定位于中枢神经组织，即大脑和脊髓。然而，近年来的更多研究表明，这些受体还存在于皮肤、乳腺、前列腺、胃肠和肝脏等外围组
恶性黑色素瘤中mGluR1的过度激活是致癌的驱动因素，其作用独立于典型的黑色素瘤原癌基因BRAF或NRAS。mGluR1的表达促进了谷氨酸的产生和自分泌谷氨酸能信号，提示可以通过降低谷氨酸的生物利用度和依赖于GLS的谷氨酰胺到谷氨酸的转化来抑制肿
乙酰胆碱(acetylcholine, ACh)是副交感神经系统的神经递质，其生物活性受中枢和外周神经系统中烟碱(N-AChR)和毒蕈碱(M-AChR)乙酰胆碱受体的介导。AChRs除了在中枢神经系统和外周神经系统、自主神经系统和神经肌肉接头中发挥重要的生理作用外，还在人体不同器官中的广泛表
越来越多的证据表明，在不同的肿瘤中，AChRs的过表达介导了肿瘤细胞的增殖、凋亡、血管生成和上皮-间充质转化(EMT)等过程。α7烟碱型乙酰胆碱受体(α7-nAChR)是N-AChR家族的一员，广泛表达于胃上皮细
神经肽Y (neuropeptide Y, NPY) 是胰多肽家族中一个由36个氨基酸残基组成的多肽，广泛表达于中枢和外周神经系统，参与了多种生理过程，包括调节皮质兴奋性、昼夜节律、应激反应、痛觉、食物摄取和心血管功能。还与癫痫、焦虑抑郁、疼痛和镇痛、神经保护和神经形成有
NPY还能刺激细胞增殖，在多种恶性肿瘤中被认为是一种促生长因子。在这些肿瘤中，NPY主要通过两种受体Y2R和Y5R来介导肿瘤细胞的增殖、存活、迁移以及血管生成。实体肿瘤缺氧激活了NPY/Y2R/Y5R轴，这种激活是由缺氧诱导的Y2R/Y5R表达上调和二肽基肽酶IV(DPPIV)的刺激触发的，DPPIV将NPY转化为选择性的Y2R/Y5R激动剂NPY3-3
神经递质在肿瘤中的作用是复杂和多样的，神经递质可以作用于肿瘤细胞和周围的环境，影响到药物的治疗，开展肿瘤化疗和靶向治疗时，要考虑神经递质的作用。同时提示用于治疗精神疾病的药物可能在治疗肿瘤方面发挥重要的作用，可以拓展神经药物的新用途，尽管神经递质/受体系统在肿瘤生物学中有重要的作用，但也调节人体的正常生理功能，这些药物的使用可能会产生不良反应，可以通过结合肿瘤特异性靶向策略来解决，但还需要更多的技术来支持。神经递质对肿瘤发生发展的作用还有许多问题需要解决： (1) 不同类型的肿瘤中神经递质作用机制是否相同？(2) 神经递质如何通过肿瘤微环境中的其他细胞(如：成纤维细胞，内皮细胞和免疫细胞等)来参与对肿瘤细胞的调控？(3) 肿瘤中炎症反应同神经递质之间是否存在联系？(4) 神经肿瘤信号中能否找到生物标志物分子，可以作为肿瘤发生前的预测，肿瘤进展的分期和患者预后分析的标志物？神经系统对肿瘤的作用在研究肿瘤发生发展机制和肿瘤治疗中是一个不可忽略的因素，不同的神经递质在不同类型肿瘤中作用的机制各不相同，未来还需要更多的研究来阐明。
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