中枢神经系统环路在抑郁促进乳腺癌进程中的作用
作者简介:
吴迎朝，男，博士，住院医师，主要从事中医药治疗乳腺肿瘤的临床和基础研究，ORCID: 0000-0002-4810-0399
陈前军: 医学博士，主任中医师，博士生导师，博士后合作导师。广东省中医院副院长、广东省中医院珠海医院院长、广东省中医院乳腺病专科医院院长。广州中医药大学中医外科学学科带头人，广东省杰出青年医学人才、广州中医药大学千百十计划人才、广东省中医院拔尖人才、中华中医药学会乳腺病学会主任委员、中华中医药学会（乳腺病）科学传播专家团队首席科学传播专家、中华中医药学会名医名家科普工作室首席专家。主要从事中医药治疗乳腺肿瘤的临床和基础研究，依托中医证候全国重点实验室，紧扣林毅国医大师提出的乳腺癌“分期辩证”理论和“因郁致瘤”病机理论，创新性地提出情志相关乳腺癌的“脑-乳神经轴”理论，探讨中枢“脑-乳神经轴”与外周肿瘤免疫微环境调控机制。执笔制订多部国家指南与行业共识。近5年主持国家自然科学基金面上项目3项，获批广东省自然科学基金1项、广州市重点实验室项目1项以及校级课题4项。发表SCI收录论文17篇（单篇最高IF=9.756），获得广东省科技进步奖二等奖1项、中华中医药学会科学技术奖二等奖1项，获批专利3项
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通讯作者:
Role of Central Nervous System Circuits in Promotion of Breast Cancer Progression by Depression
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摘要:
随着神经科学与肿瘤学的发展，中枢神经系统环路对肿瘤的直接调控作用被逐渐揭示。越来越多的证据表明，靶向情绪相关脑区的治疗，可能在阻断抑郁促进乳腺癌进程中具有很大的潜力，其背后复杂的机制涉及抑郁产生及中枢神经系统环路对肿瘤的调控，然而，该研究领域尚缺乏系统性的总结。本文综述了中枢神经系统环路与抑郁产生、中枢神经系统与外周肿瘤神经联系、交感神经系统调控肿瘤免疫微环境的最新研究进展，系统梳理了中枢神经系统环路在抑郁促进乳腺癌进展中的潜在机理，以期为乳腺癌的综合治疗提出新的解决方法。
Abstract:With the development of neuroscience and oncology, the direct regulation effect of central nervous system circuits on tumors has been gradually revealed. Evidence indicates that the therapy targeting emotion-related encephalic regions may have great potential in blocking the promotion of breast cancer progression by depression. The underlying complex mechanisms involve the generation of depression and the regulation of tumors by central nervous system circuits. However, a systematic summary is lacking in this field. This article reviews the latest research progress of the central nervous system circuits and the generation of depression, the neural connection between the central nervous system and peripheral tumor, and the regulation of the tumor immune microenvironment by the sympathetic nervous system. It also systematically investigates the potential mechanism of the central nervous system circuit in the promotion of breast cancer progression by depression to establish new solutions for the comprehensive treatment of breast cancer.
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Key words:
- Depression /
- Breast cancer /
- Neural circuit /
- Sympathetic nerve /
- Tumor immune microenvironment
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0 引言
近日，中国国家癌症中心发布了2022年中国癌症疾病负担数据[1-2]，报告指出，女性中乳腺癌位居所有癌种发病率的第二位，死亡人数位居所有癌种的第五位，这提示我们仍然需要寻找更好的方法来预防和治疗乳腺癌。抑郁是乳腺癌患者常见的合并症[3-4]，我们中心一项对282 203名乳腺癌患者的系统回顾和荟萃分析显示，抑郁与癌症复发、全因死亡率和癌症特异性死亡率相关[5]。此外，国医大师林毅教授提出乳腺癌“因郁致瘤”理论，认为抑郁是乳腺癌发生发展的重要诱因[6]。因此，从抗抑郁的角度着手对乳腺癌患者开展全方位的综合治疗，可能是改善乳腺癌预后的重要手段。
近年来，肿瘤科学和神经科学的相关研究表明，抑郁通过多种方式影响肿瘤发生与发展，其中包括促进肿瘤生长和转移，诱导治疗抵抗和肿瘤复发等。在伴有抑郁的肿瘤患者中，除了经典的下丘脑-垂体-肾上腺轴，存在异常激活的交感神经系统同样会释放过量的应激激素（如去甲肾上腺素），作于肿瘤细胞本身或肿瘤微环境的受体，通过调节细胞增殖、生存、血管生成等作用[7-9]，促进肿瘤的进展。其中，与非抑郁肿瘤患者相比，抑郁肿瘤患者的肿瘤免疫微环境会发生显著的改变，这也进一步降低了免疫治疗的效果[10]。抑郁的发生通常是通过情感中枢脑区激活或抑制改变中枢神经环路活性实现的[11-12]。因此，通过调控中枢并缓解抑郁情绪可能有助于改变肿瘤免疫微环境组成，并提高免疫治疗效果，延缓肿瘤发展进程和改善患者生存状况。
基于上述理论，已有文献报道，抑郁小鼠中央内侧杏仁核中的促皮质素释放激素神经元被激活，通过交感神经建立了中枢神经系统与外周肿瘤的联系，最终介导了抑郁促进乳腺癌增长的过程[13]。遗憾的是，目前关于抑郁与肿瘤的研究大部分集中于外周包括肿瘤免疫微环境在内的肿瘤微环境，对于抑郁的诱发与感知中心——中枢神经系统的研究较少，同时关于中枢神经环路与外周肿瘤神经纤维的连接研究也较为缺乏。解析抑郁相关的中枢环路-外周肿瘤神经连接与肿瘤免疫微环境改变的关系，对理解中枢神经系统调控外周肿瘤的相关机制具有重要意义。
1 中枢神经系统环路与抑郁产生
抑郁症是一种患病率高、自杀率高的精神疾病。抑郁症的病因很复杂，至今尚未完全了解。目前的观点认为，神经炎性反应、神经可塑性、肠脑轴等因素参与了这一过程[14-16]。此外，目前的治疗方法对于重度抑郁症的效果仍然存在局限性。既往针对抑郁的研究，大多聚焦于分子功能和细胞内信号通路，但显然易见的聚焦于分子和信号通路的研究并不能很好地解决抑郁症的难题，而从神经系统整体出发，关注神经元之间的联系，可能是寻找更好的办法解决抑郁的途径之一。此前的研究表明，某些大脑区域的改变或功能障碍与抑郁症的发生有关[17]。神经系统由众多神经元组成，神经元与神经元又通过突触建立联系，而每个神经元又有大量的突触，于是便构成了极端复杂的信息传递和加工的神经回路。事实上，单个神经元极少单独地执行某种功能，神经回路才是脑内信息处理的基本单位。据此，深入了解神经环路在抑郁症中所起的作用可能会让我们更好地了解抑郁症的病因、症状和治疗。
快感缺失、食欲改变和社交回避是抑郁症的主要症状，研究表明上述症状产生的主要原因在于内侧前额叶皮质、腹侧被盖区和海马等相关中枢神经系统环路的功能失调[18-21]，厘清关键脑区与抑郁相关的神经环路的功能，对全面了解抑郁的产生并进一步改善和优化抑郁相关乳腺癌的临床治疗具有重要意义。
1.1 内侧前额叶皮质
最初在针对抑郁症患者进行的影像学研究发现，前额叶皮质功能对抑郁症的结局有强有力的影响[22]。随后实验研究进一步证实，多种范式或光遗传学均可通过干预内侧前额叶皮质活性影响小鼠的抑郁样行为[21, 23-24]。
基于内侧前额叶皮质在抑郁产生中的重要作用，内侧前额叶皮质与大脑其他区域之间的联系也引起了人们的极大兴趣[25]。中缝背核是与情绪调节有关的广泛网络的关键节点，激活投射到中缝背核的内侧前额皮质神经元会诱发抗抑郁行为[26]。研究表明，内侧前额叶皮质刺激后中缝背核中的5-HT活性发生了动态改变[27-28]，最终影响神经环路的活性并以环路为基础介导了抑郁的产生，这种改变的神经递质动力学和基于网络的功能框架可能有助于我们理解抑郁症状并寻找新的治疗靶点。
1.2 腹侧被盖区
腹侧被盖区的多巴胺能神经元在奖赏环路中的作用已被广泛研究，且强调其与抑郁症可能存在的联系[29]。蓝斑-腹侧被盖区环路介导中边缘多巴胺能神经元的稳态机制，刺激蓝斑-腹侧被盖区神经元可促进慢性社交挫败应激弹性样表型，并逆转腹侧被盖区-伏隔核环路的多巴胺能神经元的过度活跃[30]。此外，腹侧被盖区到网状黑质的多巴胺能投射参与了抑郁的过程[31]，这为重度抑郁症提供了一个潜在的治疗靶点。腹侧苍白球是一个中继核，接收来自伏隔核的传入信号并将信息传输到下游目标，例如腹侧被盖区和外侧僵核[32]。有趣的是，沉默腹侧苍白球小清蛋白神经元到腹侧被盖区和外侧僵核的投射会分别影响不同的抑郁样行为，这可能是抗抑郁药物疗效差异的神经解剖学基础。毫无疑问，腹侧被盖区与许多其他大脑区域之间存在着有待探索的环路联系。
1.3 海马
研究报告称，重度抑郁症患者的海马体积减小[33]。根据行为学和解剖学研究，海马可分为三个功能分区，包括背侧、中间和腹侧，其中腹侧海马调节对压力、情绪和情感的反应[34]。海马的上游环路，例如内嗅皮层，显示出重度抑郁症治疗的潜力[35]。
此外，抑郁动物模型中还涉及大量的其他脑区和神经环路[36]。这些证据均表明，中枢神经系统特定脑区的改变通过神经环路介导了抑郁的产生。然而，中枢的改变，往往需要周围神经与肿瘤产生联系，因此，我们需要厘清周围神经在中枢神经系统与外周肿瘤之间的角色。
2 中枢神经系统与外周肿瘤的神经联系
神经系统广泛分布于全身各处，可以通过受大脑控制的周围神经来调节器官的发育并维持体内平衡。越来越多的证据表明周围神经和肿瘤之间也存在直接联系[37-39]，例如，手术或药物去除胃神经可以显著减缓肿瘤进展[39]。交感神经系统是应激促进肿瘤生长的重要途径[40]。肿瘤特异性去除交感神经支配能在小鼠模型中抑制前列腺癌和乳腺癌的进展[41-42]。神经-癌组织之间串扰可以直接发生，也可以通过神经系统控制肿瘤微环境中的其他细胞类型发生，如免疫细胞和基质细胞[37-39]。交感神经系统神经递质去甲肾上腺素可能会激活肿瘤细胞或肿瘤微环境中其他细胞的α-和β-肾上腺素能受体[40]。上述研究虽然可以确定中枢神经系统与外周肿瘤之间存在神经连接，但具体的连接路径相关研究仍然非常缺乏。众所周知，抑郁焦虑会影响交感神经系统的活动，但目前尚不清楚抑郁焦虑背后的大脑神经活动如何控制肿瘤进展。
杏仁核和相连的大脑区域的神经环路被认为对于抑郁焦虑处理至关重要[43]。癌症患者表现出较高的抑郁焦虑症发病率，其特点是杏仁核过度活跃[44-45]。中央内侧杏仁核是杏仁核的主要输出核，它整合皮质和杏仁核内的传入神经，并通过投射到包括外侧巨细胞旁核在内的脑干核来调节焦虑。此外，中央内侧杏仁核促肾上腺皮质激素释放激素神经元已被证实能协调对焦虑的生理和行为反应[46-47]。以往的研究表明，外侧巨细胞旁核儿茶酚胺能神经元能通过支配交感肾上腺神经节前神经元，参与调节对各种应激源的自主神经反应[48-49]。鉴于肿瘤中有丰富的神经，并且它们最终可能与大脑相连[41-42]，因此探索脑神经元和相关环路是否通过直接神经连接控制抑郁焦虑情绪促进肿瘤进展具有重要意义。
上面提到的促肾上腺皮质激素释放激素神经元，主要在下丘脑室旁核富集[50-51]，在抑郁与癌症的关系中被广泛研究的下丘脑-垂体-肾上腺轴的起始脑区正是下丘脑室旁核[52-55]。最近研究表明，下丘脑室旁核促肾上腺皮质激素释放激素神经元与外周的交感神经系统存在直接的神经连接[56-58]，通过该神经连接，下丘脑室旁核可直接调控外周组织的交感活动和生物学行为[56]。鉴于较多的证据证实下丘脑室旁核在肿瘤发生发展中的作用[59-60]，且下丘脑-垂体-肾上腺轴的功能无法完全解析下丘脑室旁核对肿瘤的调控作用[61]，即除下丘脑-垂体-肾上腺轴外，下丘脑室旁核极有可能通过神经连接对肿瘤进行直接调控。因此，未来对下丘脑-垂体-肾上腺轴的起点下丘脑室旁核进行更全面的剖析可能更利于诠释中枢神经系统与外周肿瘤发展之间的关系。值得注意的是，相关研究仍然处于起步阶段，我们需要在围绕周围神经进行更多的研究，以期为开发新型的抗抑郁型乳腺癌药物准备更优的候选靶点。
3 交感神经系统调控肿瘤微环境
最新研究表明，外周交感神经直接参与了抑郁诱导的肿瘤微环境免疫抑制[62-63]，抑郁状态时下丘脑室旁核的激活能诱导肿瘤免疫抑制[64]。2020年一项突破性研究发现，下丘脑室旁核通过与外周交感神经的直接连接，对免疫微环境产生影响[65]，提示下丘脑室旁核诱导肿瘤免疫抑制可能存在“下丘脑室旁核-交感神经轴”这一新型调控机制，因此，研究交感神经系统如何调控肿瘤微环境具有重要意义。
既往研究表明，交感神经能直接支配所有的初级和次级免疫器官来调节免疫[66]。在乳腺癌的发展过程中，交感神经系统通过抑制抗肿瘤免疫发挥促肿瘤作用。细胞毒性T细胞和自然杀伤细胞的抑制被认为在肿瘤术后转移中起重要作用，并与肿瘤细胞的转移增加有关[67]。首先，交感神经活动通过促进肿瘤相关巨噬细胞M2极化和抑制自然杀伤细胞活性来抑制内在免疫[68-70]。另一方面，交感神经活动通过阻断树突状细胞成熟和限制T细胞的细胞毒性作用来抑制适应性免疫[71-72]。此外，交感神经活动上调免疫抑制的调节性T细胞和髓源性抑制细胞的活性和数量，并进一步抑制抗肿瘤免疫[73]，此过程可能与β2-肾上腺素能受体受刺激后进而引起STAT3磷酸化有关[74]。进一步研究表明，与使用α-或β-受体阻滞剂相比，去除肿瘤特异性交感神经能在更大程度上下调免疫检查点分子的表达，其中包括PD-1、PD-L1和FOXP3。免疫检查点分子促进免疫抑制性肿瘤微环境的形成，进一步促进乳腺癌的生长[42]。此外，β-肾上腺素能信号通过增加巨噬细胞和MCP1的产生，增强了肿瘤微环境中免疫抑制性CD14+、CD68+细胞和巨噬细胞的浸润[75]。上述研究说明了交感神经能通过神经的直接作用调控肿瘤微环境。
在乳腺癌研究中，Kamiya等使用基于逆行腺相关病毒载体的遗传模型发现，交感神经分泌的神经递质和β2-肾上腺素能受体信号可加速癌症进展[42]。虽然交感神经去神经并没有改变CD4+或CD8+T细胞的数量，但它减少了这些细胞中PD-L1和FOXP3的表达，并增加了IFN-γ的表达[76-77]。这些免疫检查点分子和细胞因子除了在肿瘤微环境的免疫抑制中发挥重要作用，也能在开发新的免疫疗法以减缓癌症进展方面发挥重要作用。除了开发旨在减缓肿瘤生长的新治疗方法外，预防乳腺癌相关转移在阻止癌症进展中同样起着重要作用。使用β受体阻滞剂的研究表明，交感神经通过增加肿瘤相关巨噬细胞的浸润和NF-κB受体活化因子配体的表达来增加癌细胞向正常组织的迁移[68,78]，促进肿瘤转移。
4 总结与展望
中枢神经系统环路发生器质性改变是抑郁产生的基础，神经环路的改变可通过神经连接直接与外周肿瘤组织产生联系，异常激活的交感神经系统能通过多种途径调控肿瘤免疫微环境的组成，进而影响肿瘤的进展。基于这一新理论，可以帮助我们从中枢神经这一上游来解释抑郁是如何影响乳腺肿瘤进展，并以此来挖掘更为有效的肿瘤防治靶点。值得注意的是，中枢神经与肿瘤的神经联系可能存在双向作用，但目前仍然缺乏外周肿瘤通过直接神经联系影响中枢功能的研究，这是我们今后关注的方向，该方向未来可能为肿瘤相关的神经症状治疗提供指导。
Competing interests: The authors declare that they have no competing interests.利益冲突声明：所有作者均声明不存在利益冲突。作者贡献：吴迎朝：文章撰写梁裕琪：文章修改与编辑左 谦：文章选题、撰写指导陈前军：文章审校及修改 -
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