Chronic Stress Promotes Tumor Progression and Metastasis: From Mechanisms to Therapeutic Strategies
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摘要:
转移是导致肿瘤患者死亡的关键原因，大量肿瘤患者合并精神心理异常，即处于慢性应激状态。慢性应激通过下丘脑-垂体-肾上腺轴和交感神经系统影响多种激素和神经递质的释放，如肾上腺素、去甲肾上腺素、多巴胺、糖皮质激素、皮质醇、性激素等，这些物质可作用于肿瘤细胞、免疫细胞及肿瘤微环境中其他细胞上的β-肾上腺素能受体、糖皮质激素受体等，通过直接增强肿瘤细胞的侵袭转移能力，诱导免疫抑制微环境的形成，促进肿瘤血管生成等途径促进肿瘤的进展和转移。基于上述机制，抗精神病药物、β-受体阻滞剂、糖皮质激素受体拮抗剂对慢性应激介导的肿瘤转移具有抑制作用，并取得了一定的临床疗效。此外，中药复方和单体也开展了相关的研究，可通过调控免疫微环境和逆转慢性应激介导的激素改变抑制肿瘤转移。肿瘤患者的心理问题逐步受到重视，基于慢性应激促进肿瘤进展和转移的作用机制，开发抗转移新药为肿瘤整体防治效率的提高提供了新的思路。
Abstract:Metastasis is a key cause of death in tumor patients, and a number of tumor patients have comorbid psychosomatic abnormalities and are in a state of chronic stress. Chronic stress affects the release of many kinds of hormones and neurotransmitters, such as epinephrine, norepinephrine, dopamine, glucocorticoids, cortisol, sex hormones, etc., through the hypothalamus–pituitary–adrenal axis and sympathetic nervous system. These substances can act on the β-adrenergic receptor, glucocorticoid receptor, etc., on tumor cells, immune cells, and other cells in the tumor microenvironment and promote the tumor progression and metastasis by directly enhancing the invasive and metastatic ability of tumor cells, inducing the formation of the immunosuppressive microenvironment and promoting tumor angiogenesis and other pathways. Antipsychotic drugs, β-blockers, and glucocorticoid receptor antagonists have inhibitory effects on chronic stress-mediated tumor metastasis and have achieved certain clinical efficacy. Relevant studies have been carried out on traditional Chinese medicine decoctions and monomers, which can inhibit tumor metastasis by modulating the immune microenvironment and reversing chronic stress-mediated hormonal changes. The psychological problems of tumor patients have gradually received attention, and the development of new anti-metastatic drugs based on the mechanism of action of chronic stress in promoting tumor progression and metastasis provides new ideas for the improvement of the overall efficiency of tumor prevention and treatment.
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Key words:
- Tumor /
- Metastasis /
- Chronic stress /
- Immune /
- β-adrenergic receptor /
- Glucocorticoid receptor /
- Therapeutic status
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0 引言
肿瘤是危害全世界人类健康的重大疾病之一，转移是导致肿瘤患者死亡的关键事件，制约了临床疗效的提高。肿瘤是一个复杂的疾病，除肿瘤病灶导致的躯体症状外，患者往往合并焦虑、抑郁等负性心理情绪，以长期负性心理情绪为代表的慢性应激将促进肿瘤的进展和转移[1]。流行病学和临床研究显示，慢性应激与肿瘤的发病率和死亡风险增加呈正相关[2]。面对复发转移风险并长期处于慢性应激的状态将导致其临床疗效不理想[3]。近三十年来，肺癌、乳腺癌、结肠癌、胃癌、肝癌、黑色素瘤、卵巢癌、前列腺癌等多种实体瘤的临床和基础研究显示，慢性应激将促进肿瘤的进展和转移[4]。
长期和反复暴露于慢性应激将激活下丘脑-垂体-肾上腺轴（Hypothalamic-pituitary-adrenal axis, HPA）和交感神经系统（Sympathetic nervous system, SNS），导致机体神经递质和内分泌激素水平变化，通过作用于肿瘤细胞或肿瘤微环境（Tumor micro-environment, TME）中的免疫细胞或影响细胞外基质等其他因素直接及间接地促进肿瘤的进展和转移[4]。然而，目前的肿瘤防治体系中尚未纳入相关的治疗方式。因此，亟需针对大量肿瘤患者合并精神心理异常的迫切临床问题，进一步创新肿瘤转移的防治理论，指导开展下游的机制研究，从精神-神经-内分泌的角度开发肿瘤转移的防治新药，形成新的转移防治策略。本文归纳梳理慢性应激促进肿瘤进展和转移的作用机制及目前的对应治疗现状，期望为肿瘤转移的治疗和预防提供新的思路。
1 慢性应激促进肿瘤进展和转移的机制
慢性应激通过激活HPA轴和SNS调节肿瘤微环境。一方面，慢性应激激活HPA轴，促进下丘脑释放促肾上腺皮质激素释放激素，随后触发垂体前叶分泌促肾上腺皮质激素，然后刺激肾上腺皮质分泌皮质类固醇，如糖皮质激素（皮质醇、皮质酮）、盐皮质激素（醛固酮等）、性激素（雌激素等）[5]。另一方面，慢性应激激活SNS，通过神经突触释放乙酰胆碱、5-羟色胺等神经递质从而促进肾上腺皮质合成儿茶酚胺，包括肾上腺素和去甲肾上腺素等；SNS的神经突触还将释放去甲肾上腺素直接支配各个脏器[6]。有研究发现，皮质醇、儿茶酚胺等激素可作为诊断慢性应激的潜在生物标志物[7]。这些神经递质和激素水平的变化有以下作用：（1）作用于肿瘤细胞上的肾上腺素能受体（Adrenergic receptor, AR）和糖皮质激素受体（Glucocorticoid receptor, GR），增强其侵袭转移能力[8]；（2）作用于TME中的免疫细胞，如T淋巴细胞、巨噬细胞、自然杀伤细胞（Natural killer cell, NK）、中性粒细胞、树突状细胞（Dendritic cells, DCs）、肥大细胞等，破坏神经内分泌和免疫系统之间的通讯稳态，形成免疫抑制微环境，导致免疫监视能力下降[9]；（3）作用于其他细胞，如成纤维细胞、脂肪细胞、各脏器细胞等[10]，调节TME中的水液、蛋白质和脂肪代谢能力；最终形成有利于肿瘤进展和转移的内环境。
1.1 直接促进肿瘤细胞的侵袭转移
1.1.1 儿茶酚胺类
儿茶酚胺是慢性压力应激和肿瘤进展之间的主要介质[11]。临床研究发现，乳腺癌患者的血浆儿茶酚胺水平较正常人更高，且这种现象在远处转移的患者中更明显[12]。此外，血浆儿茶酚胺水平较高的肿瘤患者，其抑郁分级显著升高[13]。肾上腺素和去甲肾上腺素通过肾上腺素能信号通路作用于肿瘤细胞，促进其以ADRB/cAMP/Epac/JAK依赖的方式产生脑源性神经营养因子，增加TME中的神经支配，与总生存期降低显著相关[14]。肾上腺素通过增强USP22的稳定性激活FOXO1和ATGL的下游通路介导脂肪分解促进乳腺癌转移[15]；去甲肾上腺素水平的升高将过度激活β2-STAT3/ERK-YKL-40信号通路，促进胃腺癌细胞的增殖转移[16]；异丙肾上腺素通过上调乳腺癌细胞HIF-1α的表达，激活乙酰肝素酶的转录从而增强乳腺癌细胞的增殖转移能力[17]。多巴胺是肾上腺素和去甲肾上腺素的神经递质前体，也属于儿茶酚胺，多巴胺受体（Dopamine receptors, DR）在多种肿瘤细胞中均有表达，有多个亚型，敲除或拮抗D1DR将增强乳腺癌细胞的体外迁移和侵袭及体内肺转移能力，激活D1DR则对肿瘤生长和肺转移具有抑制作用[18]。
1.1.2 非儿茶酚胺类
由慢性应激介导的乙酰胆碱水平升高可通过调节α5-nAChR/DNMT1/FHIT轴增强A549和H1299细胞的侵袭转移能力[19]。卵巢癌患者高表达GR与预后不良有关，PFS显著缩短，由皮质醇介导的GR激活通过促进SGK1、MKP1、DUSP1等基因的转录抑制肿瘤细胞凋亡，从而诱导化疗耐药[20]。醛固酮通过激活G蛋白偶联雌激素受体促进小鼠肾皮质腺癌细胞的增殖和转移，切除肾上腺可抑制肾癌的肺转移[21]。雌激素可促进肿瘤细胞在转移过程中的内渗、外渗、存活、定殖及凋亡抵抗，尤其是乳腺癌、宫颈癌、子宫内膜癌等妇科肿瘤中较为显著[22]。
1.2 调控免疫细胞抑制抗肿瘤免疫效应
慢性应激介导的神经内分泌因子水平改变将加剧炎性反应并导致新陈代谢紊乱，增加肿瘤相关的免疫抑制性细胞，同时降低效应免疫细胞的细胞毒活性，诱导形成免疫抑制微环境，从而促进了肿瘤的血行和淋巴转移[23]。
1.2.1 T淋巴细胞
T淋巴细胞是抗肿瘤免疫细胞的主力军。慢性应激激活肾上腺素能信号转导将诱导肿瘤微环境中的T淋巴细胞的耗竭表型，并促进其代谢功能障碍从而减弱抗肿瘤作用[24]；β2-AR在CD8+T细胞中高表达，阻断β2-AR的信号转导可促进T淋巴细胞的活化、增殖和细胞因子的释放从而增强抗肿瘤免疫效应[25]；内源性皮质醇通过激活GR抑制T细胞的活化和促炎细胞因子分泌，影响慢性应激下PD-1的免疫治疗疗效[26]。
1.2.2 NK细胞
NK细胞具有显著的抗肿瘤免疫效应[27]。继发抑郁症状的肝癌患者的外周血NK细胞数量显著降低，影响远期生存[28]。糖皮质激素是肿瘤微环境中诱导NK细胞表达PD-1的关键分子，通过下调整合素LFA-1的表达降低NK细胞与靶细胞的黏附，从而减弱细胞毒活性并抑制其增殖，有利于肿瘤细胞发生免疫逃逸[29]。NK细胞也高表达β2-AR，肾上腺素和去甲肾上腺素将抑制NK细胞产生细胞毒性因子，然而目前其具体的作用机制尚未被揭示[30]。
1.2.3 巨噬细胞
巨噬细胞是TME中数量最多的免疫细胞，以促肿瘤的M2型为主，通常被称为肿瘤相关巨噬细胞（Tumor associated macrophage, TAM），抗肿瘤的M1型巨噬细胞相对较少[31]。慢性应激介导的血清去甲肾上腺素增加通过促进CCL2的分泌破坏M1-M2极化平衡，增加荷瘤小鼠外周血中CD11b+Ly6C+CCR2+单核细胞和IL-1β的水平，从而促进肝癌的进展和转移[32]。皮质醇可抑制由IFN-γ诱导的人单核细胞THP-1和U937细胞向M1型极化，并增强脂肪酸和谷氨酰胺代谢促进其向M2型极化，从而有利于肿瘤的转移[33]。
1.2.4 中性粒细胞
中性粒细胞具有促肿瘤和抗肿瘤的双重作用。慢性应激介导的糖皮质激素释放增加将募集中性粒细胞在肺部积累，改变其昼夜节律，并诱导中性粒细胞外陷阱的形成增加，从而促进乳腺癌肺转移[34]。乙酰胆碱通过促进肺上皮细胞分泌CXCL2招募中性粒细胞并形成中性粒细胞外陷阱，重塑转移前生态位进而促进乳腺癌的肺转移[35]。
1.2.5 髓源性抑制细胞
髓源性抑制细胞（Myeloid-derived suppressor cells, MDSCs）被认为是负向调控的免疫细胞，促进肿瘤的进展和转移。慢性束缚应激介导的肾上腺素和去甲肾上腺素水平升高将上调MDSCs中CXCR2和pERK1/2的表达，促进H22肝癌细胞分泌CXCL5，将骨髓中的MDSCs动员至脾脏和肿瘤部位，形成免疫抑制微环境从而促进肝癌的进展[36]。去甲肾上腺素还通过β2-AR上调乳腺癌4T1细胞分泌IL-6，激活JAK/STAT3信号通路，从而促进MDSCs的增殖、分化和积累，有利于乳腺癌的肺转移[37]。
1.2.6 其他免疫细胞
慢性应激干预后的小鼠淋巴驻留DCs的成熟度和迁移率均降低，抗原提呈能力下降，直接损害CD8+T细胞的免疫效应，进而降低抗肿瘤免疫疫苗的有效性[38]。在慢性应激干预之前预激活固有免疫系统可以降低小鼠海马和内侧前额叶皮层的TNF-α、IL-1β和IL-6的mRNA表达水平，抑制神经炎性反应从而消除其抑郁和焦虑样行为[39]，有助于抑制肿瘤的进展和转移。
1.3 其他非直接的促肿瘤转移作用
各器官的相应基质细胞上同样存在β-AR、GR等激素受体。儿茶酚胺处理后的SKOV3卵巢癌细胞的CXCL1、2、3、8趋化因子的分泌及相关mRNA的表达显著增加，有利于卵巢癌的生长转移和血管生成。去甲肾上腺素可激活肝星状细胞分泌sFRP1从而激活Wnt16B/β-catenin正反馈回路，促进肝癌细胞的增殖、侵袭、转移、上皮间质转化能力和干细胞标志物的表达[40]。异丙肾上腺素可促进HUVEC细胞自分泌VEGF，激活plexinA1/VEGFR2-JAK2-STAT3信号转导促进肿瘤血管生成[41]。
2 慢性应激治疗现状
针对肿瘤患者合并的精神心理问题，临床中应用较多的包括奥氮平、舍曲林、氟西汀等抗精神病药物。最新研究发现，β2-AR受体阻滞剂普萘洛尔、GR受体拮抗剂米非司酮可显著抑制肿瘤的进展，可显著降低慢性应激介导的肿瘤转移风险。中医经方逍遥散、四逆散、栀子豉汤、酸枣仁汤等具有疏肝、解郁、除烦、安寐等功效，广泛应用于中医肿瘤临床诊疗，方中有效组分被现代研究证实具有抗抑郁和抗肿瘤的双重作用。除药物治疗之外，认知-行为、运动、音乐、功法导引等多种非药物治疗均用于肿瘤合并抑郁的临床治疗，其具体机制尚未明确。
2.1 药物治疗
2.1.1 抗精神病药物
合并抑郁焦虑症状的肿瘤患者常服用精神类药物缓解情绪，其作用机制主要是减少神经递质的释放和抑制神经元的过度兴奋，同时具有一定的抗肿瘤作用。奥氮平通过抑制mPFC中的神经活动并减少去甲肾上腺素的释放缓解小鼠的抑郁焦虑行为，同时下调ADRB2-cAMP-PKA-CREB通路抑制肿瘤细胞的干性和化疗耐药逆转由慢性应激介导的肺癌进展[42]。5-羟色胺再摄取抑制剂舍曲林可减少CD8+T细胞在TME中的浸润，同时逆转慢性应激介导的T细胞缺陷，上调IFN-γ和颗粒酶B而下调PD-1的表达，从而增强免疫治疗的疗效[43]。氟西汀可显著逆转慢性不可预知温和应激介导的T细胞免疫紊乱，诱导Th细胞向Th1分化，抑制其向Th2和Th17分化，抑制A549细胞的侵袭转移能力，并诱导其发生凋亡[44]。
2.1.2 β-AR阻滞剂
由慢性应激介导的β-AR信号通路激活有利于肿瘤细胞的增殖、运动、凋亡抵抗、上皮间质转化、转移以及获得血管生成和免疫抑制表型等，并抑制免疫细胞的抗肿瘤作用[45]。因此，β-AR信号转导在慢性应激介导的肿瘤进展和转移中具有关键作用。普萘洛尔是一种非选择性β受体阻滞剂，具有显著的抗肿瘤转移作用。临床研究发现，结肠癌患者围手术期联合应用普萘洛尔可显著降低肿瘤组织中上皮间质转化细胞、单核细胞、B细胞和NK细胞的浸润数量，降低复发转移的风险[46]。联合应用普萘洛尔与黑色素瘤的复发呈显著负相关，复发风险降低了约80%[47]；还可降低肝癌的死亡风险，延长不可切除或转移性肝癌患者的总生存期[48]。乳腺癌患者术前一周口服递增剂量的普萘洛尔可减少原发瘤内的间充质转化，并促进M1型巨噬细胞及T细胞的浸润，降低乳腺癌的转移风险[49]。
2.1.3 GR拮抗剂
GR是一种配体依赖的转录因子，在机体应激、能量代谢稳态和免疫调节中具有重要作用。慢性应激介导肾上腺皮质分泌更多的糖皮质激素，激活GR从而促进肿瘤的进展和转移。因此，开发选择性和非选择性的GR拮抗剂是一种新的治疗思路。米非司酮是一种合成的皮质类固醇，可拮抗GR，通过促进p21和p27的核定位、抑制CDK2的活性诱导细胞周期阻滞，并降低卵巢癌细胞的黏附能力抑制其增殖和侵袭转移[20]。
2.1.4 中医经典名方及中药单体
经方具有多重治疗作用，在合并精神心理异常的肿瘤患者中具有显著的治疗作用，临床应用广泛。基础研究发现，逍遥散可减少慢性应激诱导的结肠癌肝转移小鼠肿瘤组织中M2型巨噬细胞和MDSC的浸润，下调TGF-β、IL-6、MMP-9和VEGF的表达水平[50]；四逆散通过抑制GRP78和LRP5在乳腺癌细胞表面的相互作用下调Wnt/β-catenin信号转导，逆转皮质醇诱导的干细胞样细胞群的形成，从而抑制乳腺癌肺转移[51]；栀子豉汤通过调控微生物群-肠-脑轴调控MAPK和TNF信号通路改善慢性应激介导的小鼠的抑郁焦虑行为[52]；痛泻要方通过抑制慢性应激小鼠HPA轴激素的分泌，增强DCs细胞的抗原呈递能力，增强T细胞的抗肿瘤免疫效应[53]。中药单体具有更明确的抗肿瘤作用靶点，人参皂苷Rg1通过下调由去甲肾上腺素升高的ARG2、MMP-1和S100A4的mRNA表达，上调LAMC2、DSC2、KRT6A和FOSB的mRNA表达，增强粒细胞的抗肿瘤免疫效应[54]；酸枣仁皂苷B通过下调PI3K/Akt和MAPK/ERK/CREB的磷酸化水平抑制由慢性应激介导的5-羟色胺和色氨酸的分泌，对肺癌的生长和抑郁样表型具有双重抑制作用[55]。
2.2 非药物治疗
包括认知-行为疗法在内的身心干预是目前临床中对抗抑郁焦虑症状的主要手段。对围手术期乳腺癌患者进行一对一的个体化心理干预，可抑制肿瘤组织中肾上腺素能、糖皮质激素、促炎信号、促恶性信号转导，增加M1型巨噬细胞浸润，同时减轻抑郁痛苦和躯体化症状[56]。此外，饮食干预、音乐疗法、运动疗法、针灸推拿治疗、中医导引功法也具有相应的缓解焦虑抑郁从而减少转移的作用[8]。
3 总结和展望
肿瘤患者经历确诊和手术、放疗、化疗、免疫治疗、靶向治疗等综合治疗过程，长期面对包括家庭、经济、复发转移风险等多重压力，无形中处于慢性应激状态，临床可表现为抑郁、焦虑、乏力、失眠等症状，影响综合治疗疗效和远期生存。由慢性应激介导的下丘脑-垂体-肾上腺轴和交感神经系统的异常激活将释放大量的激素、神经递质、神经肽及神经生长因子等物质，诱导免疫稳态失衡和免疫逃逸，促进免疫抑制微环境的形成，介导转移的发生和进展[57]。肿瘤细胞和包括T淋巴细胞、自然杀伤细胞、巨噬细胞、中性粒细胞、MDSCs、DCs在内的免疫细胞以及人脐静脉内皮细胞等多种细胞表面均表达β-AR和GR[45,58]，这些受体受到儿茶酚胺和糖皮质激素等物质的调控，影响肿瘤的进展和转移。揭示慢性应激促进肿瘤进展和转移的作用机制有助于开发更高效的转移防治药物，提高肿瘤的整体防治效率。研究发现，抗精神病药物可通过减弱由慢性应激带来的激素水平变化，同时改善躯体症状，从而发挥抗肿瘤转移效应；β-AR和GR拮抗剂分别通过抑制肾上腺素、去甲肾上腺素和糖皮质激素触发的信号转导重塑免疫微环境抑制肿瘤转移；中医经方通过多途径多靶点调控肿瘤微环境并改善抑郁焦虑情绪；进一步研究发现，中药单体也具有逆转慢性应激介导的肿瘤转移的作用，其具体机制有待深入研究；身心治疗、运动疗法、中医功法导引等也具有一定的临床疗效。目前针对肿瘤合并精神心理异常的临床问题重视不足，尚未形成系统的防治方案，亟需开展大规模的临床研究收集循证医学证据，制定专家共识或指南，从精神-神经-内分泌的角度完善转移防治策略。
中医药在先秦时期便重视精神心理在养生和疗疾中的重要地位，《素问·上古天真论》：“上古之人，其知道者……故能形与神俱，而尽终其天年，度百岁乃去”，强调形神并存是长寿的关键要素。《灵枢·小针解》：“神者，正气也”，“粗守形，上守神”。在国医大师刘嘉湘教授“扶正治癌”思想指导下，田建辉教授融合《道德经》“有生于无”思想，传承《黄帝内经》“形与神俱”思想，提出“调神治癌”的学术观点[59]，并系统梳理“调神治癌”八法[60]，创制调神治癌方，授权国家发明专利（专利号：ZL 2022 1 0718678.8），广泛应用于中医肿瘤的临床诊疗。
课题组前期联合上海交通大学医学院附属精神卫生中心搭建了“调神治癌”研究平台[61]，开展了系列临床与基础研究。调神治癌方联合心理治疗可有效提高患者的免疫功能，改善临床症状，并提高生活质量[62]；抑郁是影响卵巢癌术后患者综合疗效最主要的临床因素，以调神治癌方联合心理干预治疗可有效改善患者的抑郁焦虑等精神心理异常，降低炎性反应水平，提高免疫功能从而提高卵巢癌患者的生活质量和综合疗效[63]；采用调神治癌方联合传统功法易筋经治疗肺癌术后患者可显著改善其心肺耐力指标如最大摄氧量、肺通气效率等，从而提高肺癌患者的生活质量[64]。在基础研究方面，构建了富集环境抗肺癌转移动物模型、慢性不可预知温和应激抑郁肿瘤模型和社交失败应激抑郁肿瘤模型，分别从正向和负向情绪对肿瘤进展影响的角度探索情志与肺癌转移的关系。发现以富集环境（快乐小鼠）为代表的“调神治疗”可有效抑制肺癌荷瘤小鼠的肿瘤生长和转移，并显著延长生存期，而抑郁模型可促进肺癌的进展和转移[61,65]。进一步研究发现，调神治癌方有效组分可显著改善慢性束缚应激介导的小鼠抑郁样行为；下调小鼠血浆中去甲肾上腺素、肾上腺素水平；上调脾脏中CD4−CD8+ T细胞比例，下调M2型巨噬细胞和中性粒细胞比例；下调肺脏中M2型巨噬细胞的比例，从而抑制肺癌转移（数据待发表）。
综上，慢性应激可促进肿瘤的进展和转移，同时临床中已运用抗精神病药物、身心治疗、运动治疗等多种药物和非药物的治疗方式以减轻肿瘤患者的抑郁焦虑症状。然而目前仍然缺乏大样本的临床研究，且尚未开发出针对慢性应激介导的肿瘤转移的特异性药物。本文通过综述慢性应激促进肿瘤进展和转移的作用机制，及梳理当前的治疗现状，期望为肿瘤转移的新药开发提供新的思路，提高肿瘤的整体防控疗效。
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：于 盼：文献搜集与分析、论文撰写与修改姚嘉良：论文修改田建辉：论文撰写指导与修改 -
[1] Wang YH, Li JQ, Shi JF, et al. Depression and anxiety in relation to cancer incidence and mortality: a systematic review and meta-analysis of cohort studies[J]. Mol Psychiatry, 2020, 25(7): 1487-1499. doi: 10.1038/s41380-019-0595-x
[2] Moore JX, Andrzejak SE, Bevel MS, et al. Exploring racial disparities on the association between allostatic load and cancer mortality: A retrospective cohort analysis of NHANES, 1988 through 2019[J]. SSM Popul Health, 2022, 19: 101185. doi: 10.1016/j.ssmph.2022.101185
[3] Fraterman I, Reijers ILM, Dimitriadis P, et al. Association between pretreatment emotional distress and neoadjuvant immune checkpoint blockade response in melanoma[J]. Nat Med, 2023, 29(12): 3090-3099. doi: 10.1038/s41591-023-02631-x
[4] Yan J, Chen Y, Luo M, et al. Chronic stress in solid tumor development: from mechanisms to interventions[J]. J Biomed Sci, 2023, 30(1): 8. doi: 10.1186/s12929-023-00903-9
[5] de Kloet ER, Joëls M. The cortisol switch between vulnerability and resilience[J]. Mol Psychiatry, 2024, 29(1): 20-34. doi: 10.1038/s41380-022-01934-8
[6] Wang C, Shen Y, Ni J, et al. Effect of chronic stress on tumorigenesis and development[J]. Cell Mol Life Sci, 2022, 79(9): 485. doi: 10.1007/s00018-022-04455-3
[7] Noushad S, Ahmed S, Ansari B, et al. Physiological biomarkers of chronic stress: A systematic review[J]. Int J Health Sci(Qassim), 2021, 15(5): 46-59.
[8] Cui B, Peng F, Lu J, et al. Cancer and stress: NextGen strategies[J]. Brain Behav Immun, 2021, 93: 368-383. doi: 10.1016/j.bbi.2020.11.005
[9] Liu Y, Tian S, Ning B, et al. Stress and cancer: The mechanisms of immune dysregulation and management[J]. Front Immunol, 2022, 13: 1032294. doi: 10.3389/fimmu.2022.1032294
[10] Zhang M, Yue X, Xu S, et al. Dipeptidyl peptidase-4 disturbs adipocyte differentiation via the negative regulation of the glucagon-like peptide-1/adiponectin-cathepsin K axis in mice under chronic stress conditions[J]. FASEB J, 2024, 38(10): e23684. doi: 10.1096/fj.202400158R
[11] Bernabé DG. Catecholamines Mediate Psychologic Stress-Induced Cancer Progression[J]. Cancer Res, 2021, 81(20): 5144-5146. doi: 10.1158/0008-5472.CAN-21-3077
[12] Sousa DM, Fernandes V, Lourenço C, et al. Profiling the Adrenergic System in Breast Cancer and the Development of Metastasis[J]. Cancers(Basel), 2022, 14(22): 5518.
[13] Pan C, Wu J, Zheng S, et al. Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine/β(2) -AR/MACC1 axis[J]. Cancer Commun(Lond), 2021, 41(10): 1049-1070.
[14] Allen JK, Armaiz-Pena GN, Nagaraja AS, et al. Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction[J]. Cancer Res, 2018, 78(12): 3233-3242. doi: 10.1158/0008-5472.CAN-16-1701
[15] Zhou Y, Chu P, Wang Y, et al. Epinephrine promotes breast cancer metastasis through a ubiquitin-specific peptidase 22-mediated lipolysis circuit[J]. Sci Adv, 2024, 10(33): eado1533. doi: 10.1126/sciadv.ado1533
[16] Qi YH, Yang LZ, Zhou L, et al. Sympathetic nerve infiltration promotes stomach adenocarcinoma progression via norepinephrine/β2-adrenoceptor/YKL-40 signaling pathway[J]. Heliyon, 2022, 8(12): e12468. doi: 10.1016/j.heliyon.2022.e12468
[17] Qiu J, Shen Z, Jiang G, et al. Isoproterenol-induced Upregulation of HPSE Accelerates Triple-negative Breast Cancer Cell Proliferation and Migration through Enhancing the Transcriptional Activity of HIF-1α[J]. Anticancer Agents Med Chem, 2023, 23(4): 470-477. doi: 10.2174/1871520622666220817125817
[18] Yong L, Yao Y, Chen GS, et al. QAP14 suppresses breast cancer stemness and metastasis via activation of dopamine D1 receptor[J]. Acta Pharmacol Sin, 2022, 43(4): 1001-1012. doi: 10.1038/s41401-021-00701-9
[19] Jiao Y, Kang G, Pan P, et al. Acetylcholine promotes chronic stress-induced lung adenocarcinoma progression via α5-nAChR/FHIT pathway[J]. Cell Mol Life Sci, 2023, 80(5): 119. doi: 10.1007/s00018-023-04742-7
[20] Buonaiuto R, Neola G, Cecere SC, et al. Glucocorticoid Receptor and Ovarian Cancer: From Biology to Therapeutic Intervention[J]. Biomolecules, 2023, 13(4): 653. doi: 10.3390/biom13040653
[21] Feldman RD, Ding Q, Hussain Y, et al. Aldosterone mediates metastatic spread of renal cancer via the G protein-coupled estrogen receptor (GPER)[J]. FASEB J, 2016, 30(6): 2086-2096. doi: 10.1096/fj.15-275552
[22] Nair S, Sachdeva G. Estrogen matters in metastasis[J]. Steroids, 2018, 138: 108-116. doi: 10.1016/j.steroids.2018.07.006
[23] Zhang L, Pan J, Chen W, et al. Chronic stress-induced immune dysregulation in cancer: implications for initiation, progression, metastasis, and treatment[J]. Am J Cancer Res, 2020, 10(5): 1294-1307.
[24] Qiao G, Chen M, Mohammadpour H, et al. Chronic Adrenergic Stress Contributes to Metabolic Dysfunction and an Exhausted Phenotype in T Cells in the Tumor Microenvironment[J]. Cancer Immunol Res, 2021, 9(6): 651-664. doi: 10.1158/2326-6066.CIR-20-0445
[25] Zhao X, Li F, Cheng C, et al. Social isolation promotes tumor immune evasion via β2-adrenergic receptor[J]. Brain Behav Immun, 2025, 123: 607-618. doi: 10.1016/j.bbi.2024.10.012
[26] Greenstein AE, Hunt HJ. The glucocorticoid receptor modulator relacorilant reverses the immunosuppressive effects of cortisol[J]. Int Immunopharmacol, 2023, 120: 110312. doi: 10.1016/j.intimp.2023.110312
[27] 于盼, 姜怡, 阙祖俊, 等. 调控固有免疫防治肺癌转移的研究进展[J]. 中国肿瘤临床, 2021, 48(7): 356-360. [Yu P, Jiang Y, Que ZJ, et al. Research progress of regulating innate immunity in prevention and treatment of lung cancer metastasis[J]. Zhongguo Zhong Liu Lin Chuang, 2021, 48(7): 356-360.] doi: 10.3969/j.issn.1000-8179.2021.07.602 Yu P, Jiang Y, Que ZJ, et al. Research progress of regulating innate immunity in prevention and treatment of lung cancer metastasis[J]. Zhongguo Zhong Liu Lin Chuang, 2021, 48(7): 356-360. doi: 10.3969/j.issn.1000-8179.2021.07.602
[28] Steel JL, Geller DA, Gamblin TC, et al. Depression, immunity, and survival in patients with hepatobiliary carcinoma[J]. J Clin Oncol, 2007, 25(17): 2397-2405. doi: 10.1200/JCO.2006.06.4592
[29] Sivori S, Della Chiesa M, Carlomagno S, et al. Inhibitory Receptors and Checkpoints in Human NK Cells, Implications for the Immunotherapy of Cancer[J]. Front Immunol, 2020, 11: 2156. doi: 10.3389/fimmu.2020.02156
[30] Capellino S, Claus M, Watzl C. Regulation of natural killer cell activity by glucocorticoids, serotonin, dopamine, and epinephrine[J]. Cell Mol Immun, 2020, 17(7): 705-711. doi: 10.1038/s41423-020-0477-9
[31] 于盼, 周奕阳, 罗斌, 等. 巨噬细胞在肺癌转移中的作用[J]. 中国肿瘤临床, 2022, 49(6): 299-303. [Yu P, Zhou YY, Luo B, et al. The role of macrophages in metastasis of lung cancer[J]. Zhongguo Zhong Liu Lin Chuang, 2022, 49(6): 299-303.] Yu P, Zhou YY, Luo B, et al. The role of macrophages in metastasis of lung cancer[J]. Zhongguo Zhong Liu Lin Chuang, 2022, 49(6): 299-303.
[32] Yang J, Wei W, Zhang S, et al. Chronic stress influences the macrophage M1-M2 polarization balance through β-adrenergic signaling in hepatoma mice[J]. Int Immunopharmacol, 2024, 138: 112568. doi: 10.1016/j.intimp.2024.112568
[33] Sharma A, Vikramdeo KS, Sudan SK, et al. Cortisol affects macrophage polarization by inducing miR-143/145 cluster to reprogram glucose metabolism and by promoting TCA cycle anaplerosis[J]. J Biol Chem, 2024, 300(10): 107753. doi: 10.1016/j.jbc.2024.107753
[34] He XY, Gao Y, Ng D, et al. Chronic stress increases metastasis via neutrophil-mediated changes to the microenvironment[J]. Cancer cell, 2024, 42(3): 474-486. e12.
[35] Pan J, Zhang L, Wang X, et al. Chronic stress induces pulmonary epithelial cells to produce acetylcholine that remodels lung pre-metastatic niche of breast cancer by enhancing NETosis[J]. J Exp Clin Cancer Res, 2023, 42(1): 255. doi: 10.1186/s13046-023-02836-5
[36] Cao M, Huang W, Chen Y, et al. Chronic restraint stress promotes the mobilization and recruitment of myeloid-derived suppressor cells through β-adrenergic-activated CXCL5-CXCR2-Erk signaling cascades[J]. Int J Cancer, 2021, 149(2): 460-472. doi: 10.1002/ijc.33552
[37] An J, Feng L, Ren J, et al. Chronic stress promotes breast carcinoma metastasis by accumulating myeloid-derived suppressor cells through activating β-adrenergic signaling[J]. Oncoimmunology, 2021, 10(1): 2004659. doi: 10.1080/2162402X.2021.2004659
[38] Sommershof A, Scheuermann L, Koerner J, et al. Chronic stress suppresses anti-tumor T(CD8+) responses and tumor regression following cancer immunotherapy in a mouse model of melanoma[J]. Brain Behav Immun, 2017, 65: 140-149. doi: 10.1016/j.bbi.2017.04.021
[39] Hu Z, Gu Y, Ye M, et al. Innate immune stimulation prevents chronic stress-induced depressive and anxiogenic-like behaviors in female mice[J]. Int Immunopharmacol, 2022, 111: 109126. doi: 10.1016/j.intimp.2022.109126
[40] Lin XH, Liu HH, Hsu SJ, et al. Norepinephrine-stimulated HSCs secrete sFRP1 to promote HCC progression following chronic stress via augmentation of a Wnt16B/β-catenin positive feedback loop[J]. J Exp Clin Cancer Res, 2020, 39(1): 64. doi: 10.1186/s13046-020-01568-0
[41] Lu Y, Zhao H, Liu Y, et al. Chronic Stress Activates PlexinA1/VEGFR2-JAK2-STAT3 in Vascular Endothelial Cells to Promote Angiogenesis[J]. Front Oncol, 2021, 11: 709057. doi: 10.3389/fonc.2021.709057
[42] Lu J, Zhang X, Su K, et al. Olanzapine suppresses mPFC activity-norepinephrine releasing to alleviate CLOCK-enhanced cancer stemness under chronic stress[J]. Cell Commun Signal, 2024, 22(1): 375. doi: 10.1186/s12964-024-01747-y
[43] Zhou S, Ye D, Xia H, et al. Sertraline inhibits stress-induced tumor growth through regulating CD8 + T cell-mediated anti-tumor immunity[J]. Anticancer Drugs, 2022, 33(9): 935-942. doi: 10.1097/CAD.0000000000001383
[44] Yang Z, Li Z, Guo Z, et al. Antitumor Effect of Fluoxetine on Chronic Stress-Promoted Lung Cancer Growth via Suppressing Kynurenine Pathway and Enhancing Cellular Immunity[J]. Front Pharmacol, 2021, 12: 685898. doi: 10.3389/fphar.2021.685898
[45] Nilsson MB, Le X, Heymach JV. β-Adrenergic Signaling in Lung Cancer: A Potential Role for Beta-Blockers[J]. J Neuroimmune Pharmacol, 2020, 15(1): 27-36. doi: 10.1007/s11481-019-09891-w
[46] Haldar R, Ricon-Becker I, Radin A, et al. Perioperative COX2 and β-adrenergic blockade improves biomarkers of tumor metastasis, immunity, and inflammation in colorectal cancer: A randomized controlled trial[J]. Cancer, 2020, 126(17): 3991-4001. doi: 10.1002/cncr.32950
[47] De Giorgi V, Grazzini M, Benemei S, et al. Propranolol for Off-label Treatment of Patients With Melanoma: Results From a Cohort Study[J]. JAMA Oncol, 2018, 4(2): e172908. doi: 10.1001/jamaoncol.2017.2908
[48] Chang PY, Chung CH, Chang WC, et al. The effect of propranolol on the prognosis of hepatocellular carcinoma: A nationwide population-based study[J]. PLoS One, 2019, 14(5): e0216828. doi: 10.1371/journal.pone.0216828
[49] Hiller JG, Cole SW, Crone EM, et al. Preoperative β-Blockade with Propranolol Reduces Biomarkers of Metastasis in Breast Cancer: A Phase Ⅱ Randomized Trial[J]. Clin Cancer Res, 2020, 26(8): 1803-1811. doi: 10.1158/1078-0432.CCR-19-2641
[50] Zhao L, Zhu X, Ni Y, et al. Xiaoyaosan, a traditional Chinese medicine, inhibits the chronic restraint stress-induced liver metastasis of colon cancer in vivo[J]. Pharma Biol, 2020, 58(1): 1085-1091.
[51] Zheng Y, Zhang J, Huang W, et al. Sini San Inhibits Chronic Psychological Stress-Induced Breast Cancer Stemness by Suppressing Cortisol-Mediated GRP78 Activation[J]. Front Pharmacol, 2021, 12: 714163. doi: 10.3389/fphar.2021.714163
[52] Tian X, Wang G, Teng F, et al. Zhi Zi Chi decoction (Gardeniae fructus and semen Sojae Praeparatum) attenuates anxious depression via modulating microbiota-gut-brain axis in corticosterone combined with chronic restraint stress-induced mice[J]. CNS Neurosci Ther, 2024, 30(4): e14519. doi: 10.1111/cns.14519
[53] Jiang Y, Hu Y, Yang Y, et al. Tong-Xie-Yao-Fang promotes dendritic cells maturation and retards tumor growth in colorectal cancer mice with chronic restraint stress[J]. J Ethnopharmacol, 2024, 319(Pt 1): 117069.
[54] Zhu Y, Chen J, Li J, et al. Ginsenoside Rg1 as a promising adjuvant agent for enhancing the anti-cancer functions of granulocytes inhibited by noradrenaline[J]. Front Immunol, 2023, 14: 1070679. doi: 10.3389/fimmu.2023.1070679
[55] Yang Z, Cai W, Chen Y, et al. Jujuboside B Reverse CUMS-Promoted Tumor Progression via Blocking PI3K/Akt and MAPK/ERK and Dephosphorylating CREB Signaling[J]. J Immunol Res, 2022, 2022: 5211368.
[56] Hanalis-Miller T, Ricon-Becker I, Sakis N, et al. Peri-operative individually tailored psychological intervention in breast cancer patients improves psychological indices and molecular biomarkers of metastasis in excised tumors[J]. Brain Behav Immun, 2024, 117: 529-540. doi: 10.1016/j.bbi.2024.02.009
[57] Zhang S, Yu F, Che A, et al. Neuroendocrine Regulation of Stress-Induced T Cell Dysfunction during Lung Cancer Immunosurveillance via the Kisspeptin/GPR54 Signaling Pathway[J]. Adv Sci (Weinh), 2022, 9(13): e2104132.
[58] Qiao G, Chen M, Bucsek MJ, et al. Adrenergic Signaling: A Targetable Checkpoint Limiting Development of the Antitumor Immune Response[J]. Front Immunol, 2018, 9: 164. doi: 10.3389/fimmu.2018.00164
[59] 田建辉, 刘海涛, 董昌盛, 等. 御神在肿瘤防治中的作用探析[J]. 中医杂志, 2018, 59(24): 2093-2098. [Tian JH, Liu HT, Dong CS, et al. Discussion on Defending Spirit in Cancer Prevention and Treatment[J]. Zhong Yi Za Zhi, 2018, 59(24): 2093-2098.] Tian JH, Liu HT, Dong CS, et al. Discussion on Defending Spirit in Cancer Prevention and Treatment[J]. Zhong Yi Za Zhi, 2018, 59(24): 2093-2098.
[60] 刘海涛, 田建辉. 调神防治癌症八法[J]. 中华中医药杂志, 2019, 34(5): 2270-2273. [Liu HT, Tian JH. Eight therapies for cancer prevention and treatment by adjusting spirit[J]. Zhonghua Zhong Yi Yao Za Zhi, 2019, 34(5): 2270-2273.] Liu HT, Tian JH. Eight therapies for cancer prevention and treatment by adjusting spirit[J]. Zhonghua Zhong Yi Yao Za Zhi, 2019, 34(5): 2270-2273.
[61] 姚嘉良, 刘海涛, 赵外荣, 等. “调神治癌”研究平台的构建[J]. 世界科学技术-中医药现代化, 2023, 25(5): 1525-1532. [Yao JL, Liu HT, Zhao WR, et al. The Construction of a research platform for regulate the mind and treating cancer[J]. Shi Jie Ke Xue Ji Shu-Zhong Yi Yao Xian Dai Hua, 2023, 25(5): 1525-1532.] doi: 10.11842/wst.20210819020 Yao JL, Liu HT, Zhao WR, et al. The Construction of a research platform for regulate the mind and treating cancer[J]. Shi Jie Ke Xue Ji Shu-Zhong Yi Yao Xian Dai Hua, 2023, 25(5): 1525-1532. doi: 10.11842/wst.20210819020
[62] 刘海涛. 调“神”治疗肺癌的理论、临床与实验研究[D]. 上海中医药大学, 2023. [Liu HT. Clinical and Experimental Research on regulating spirit Treatment of Lung Cancer[D]. Shanghai University of Traditional Chinese Medicine, 2023.] Liu HT. Clinical and Experimental Research on regulating spirit Treatment of Lung Cancer[D]. Shanghai University of Traditional Chinese Medicine, 2023.
[63] 姚嘉良, 从恩朝, 李鹤, 等. 形神并调防治妇科恶性肿瘤概述[J]. 世界中医药, 2022, 17(3): 431-436. [Yao JL, Cong EC, Li H, et al. Overview of Prevention and Treatment of Gynecological Cancer by Adjusting Phusiological and Psychological Function[J]. Shi Jie Zhong Yi Yao, 2022, 17(3): 431-436.] doi: 10.3969/j.issn.1673-7202.2022.03.025 Yao JL, Cong EC, Li H, et al. Overview of Prevention and Treatment of Gynecological Cancer by Adjusting Phusiological and Psychological Function[J]. Shi Jie Zhong Yi Yao, 2022, 17(3): 431-436. doi: 10.3969/j.issn.1673-7202.2022.03.025
[64] 赵外荣, 马子霖, 程天翊, 等. 心肺运动试验在肺癌患者中的应用进展[J]. 中华肿瘤防治杂志, 2023, 30(15): 941-947. [Zhao WR, Ma ZL, Cheng TY, et al. The application of cardiopulmonary exercise test in patients with lung cancer: a review[J]. Zhonghua Zhong Liu Fang Zhi Za Zhi, 2023, 30(15): 941-947.] Zhao WR, Ma ZL, Cheng TY, et al. The application of cardiopulmonary exercise test in patients with lung cancer: a review[J]. Zhonghua Zhong Liu Fang Zhi Za Zhi, 2023, 30(15): 941-947.
[65] 田建辉. 传承《黄帝内经》重“神”思想, 倡导“调神治癌”——上海中医药大学附属市中医医院田建辉研究团队“调神治癌”概述[J]. 世界科学技术-中医药现代化, 2023, 25(5): 1517-1524. [Tian JH. Inheriting the idea of "spirit" from the Yellow Emperor's Classic of Internal Medicine, advocating "regulating the spirit to cure cancer"-Tian Jianhui's research team from Shanghai Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Overview of "Regulating the spirit to cure cancer"[J]. Shi Jie Ke Xue Ji Shu-Zhong Yi Yao Xian Dai Hua, 2023, 25(5): 1517-1524.] Tian JH. Inheriting the idea of "spirit" from the Yellow Emperor's Classic of Internal Medicine, advocating "regulating the spirit to cure cancer"-Tian Jianhui's research team from Shanghai Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Overview of "Regulating the spirit to cure cancer"[J]. Shi Jie Ke Xue Ji Shu-Zhong Yi Yao Xian Dai Hua, 2023, 25(5): 1517-1524.
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