A Review of Chronic Stress and the Initiation and Evolution of Cancer
摘要: 慢性应激是指激活经典的下丘脑-垂体-肾上腺轴神经内分泌系统和交感神经系统而引发的机体持续非特异性适应性反应。现已证实，慢性应激可诱发肿瘤发生并促进肿瘤演进，特别是对机体的免疫功能和肿瘤微环境的重塑具有重要影响。然而，由于慢性应激自身机制复杂，个体耐受差异较大，导致其在肿瘤发生与演进中的研究证据尚不确切。因此，本文就慢性应激与肿瘤发生、演进的相关性研究进行综述，重点解析慢性应激促进肿瘤发生发展的分子机制，抑制机体免疫反应、重塑肿瘤免疫微环境的作用及机制，探讨健康人群与肿瘤患者的应激管理方案，以期为靶向慢性应激逆转肿瘤的新策略研究提供新的线索与方向。我们认为，靶向环磷酸腺苷/蛋白激酶A/环磷腺苷效应元件结合蛋白（cAMP/PKA/CREB）信号通路逆转肿瘤发生的治疗策略，应激、炎症与免疫以及肿瘤之间的关系，β受体拮抗剂的“抑癌”活性及其机制以及与不同联合治疗方案的选择，仍需进一步探索。健康的生活方式、积极的生活态度与专业的应激管理指导对肿瘤的防治来说至关重要。Abstract: Chronic stress activates the typical neuroendocrine system, hypothalamus pituitary adrenal axis and sympathetic nervous system, and leads to a sustained non-specific adaptive response. It has been proved that chronic stress can promote tumor initiation and induce tumor evolution, especially in immune function and remodeling of tumor microenvironment. However, due to the complex mechanism of chronic stress and the great difference in individual tolerance, the research evidence of chronic stress in tumor genesis and progression is still unclear. Therefore, in this paper, we review the research on the relationship between chronic stress and tumor initiation and evolution, focusing on the molecular mechanism of chronic stress promoting tumor occurrence and development, inhibiting immune response and remodeling tumor immune microenvironment, and exploring the stress management program of healthy people and cancer patients, so as to provide clues for exploring new strategies of cancer prevention and treatment. In our opinion, targeting the cAMP/PKA/CREB signaling pathway to reverse tumor treatment strategy, the relationship between the tumor and stress, inflammation, immunity, the suppressor activity of β receptor antagonist and its mechanism as well as associated with different treatment options, still need to be further explored. A healthy lifestyle, positive life attitudes and professional stress management guidance are essential for the prevention and treatment of cancer.
图 1 慢性应激参与肿瘤发生和发展的机制
Figure 1. The mechanism of chronic stress involved in tumor initiation and evolution
A: Chronic stress promotes the occurrence and initiation of tumors by activating two classical stress pathways, hypothalamic-pituitary-adrenal axis (HPA axis) and sympathetic nervous system (SNS); B: Catecholamine promotes tumorigenesis through the cAMP/PKA/CREB signaling pathway. CRF: Corticotropin releasing factor; ACTH: Adrenocorticotropic hormone; βARs: β Adrenergic receptors; VEGF: Vascular endothelial growth factor; MMPs: Matrix metalloproteinases; PKA: Proteinkinase A.
图 2 慢性应激抑制免疫应答，重塑肿瘤免疫微环境
Figure 2. Chronic stress inhibits the immune response and reshapes the tumor tomor immune microenvironment
A: Immunotherapy can induce tumor cells releasing tumor-associated antigens, which subsequently activate dendritic cells (DCs) and cytotoxic T lymphocytes (CTLs) and ultimately kill tumor cells; B: Under chronic stress, glucocorticoids inhibit secretion of tumor-associated antigens and cytotoxic function of CTLs through multiple mechanisms, including down-regulation of interferon β and chemokine lignad 1/9/10 (CXCL1/9/10), etc.. HSP90: Heat shock proteins 90; IFN-γ: Interferon-γ.
表 1 全身适应综合征
Table 1. General adaptation syndrome (GAS)
Stage Time of occurrence Characteristics Significance Alarm Appear after stress immediately Activating the sympathetic- adrenal medulla system;Increasing adrenal corticosteroids Defense mechanism;Last for a short time Resistance Appear after the warning response High level secretion of adrenal corticosteroids Increase the metabolic rate; Weaken inflammation and immune response Exhaustion Appears after stimulation of continuous and intensive stressors Continuous increase in levels of adrenal corticosteroids; Decrease in the number and affinity of glucocorticoid receptors The negative effects of the stress response start to appear, such as the related diseases, declined of organ function, even shock or death may occur It is not necessarily to occur in the same order, most of stressors only induce the appearance of alarm stage or resistance stage.
 TAO W, LUO X, CUI B, et al. Practice of traditional Chinese medicine for psychobehavioral intervention improves quality of life in cancer patients: a systematic review and meta-analysis. Oncotarget,2015,6(37): 39725–39739. doi: 10.18632/oncotarget.5388  ANTONI M, DHABHAR F. The impact of psychosocial stress and stress management on immune responses in patients with cancer: stress, stress management, and immunity. Cancer,2019,125(9): 1417–1431. doi: 10.1002/cncr.31943  MRAVEC B, TIBENSKY M, HORVATHOVA L. Stress and cancer. Part I: Mechanisms mediating the effect of stressors on cancer. J Neuroimmunol, 2020, 3(346): 577311[2020-10-12]. https://doi.org/10.1016/j.jneuroim.2020.577311.  KRIZANOVA O, BABULA P, PACAK K. Stress, catecholaminergic system and cancer. Stress,2016,19(4): 419–428. doi: 10.1080/10253890.2016.1203415  HUANG T, POOLE E, OKEREKE O, et al. Depression and risk of epithelial ovarian cancer: results from two large prospective cohort studies. Gynecol Oncol,2015,139(3): 481–486. doi: 10.1016/j.ygyno.2015.10.004  HALBERT C H, JEFFERSON M S, DANIELSON C, et al. An observational study and randomized trial of stress reactivity in cancer disparities. Health Psychol,2020,39(9): 745–757. doi: 10.1037/hea0000882  COKER A L, BOND S, MADELEINE M M, et al. Psychosocial stress and cervical neoplasia risk. Psychosom Med,2003,65(4): 644–651. doi: 10.1097/01.PSY.0000041471.57895.08  KIRSI L, VERKASALO P, JAAKKO K, et al. Stressful life events and risk of breast cancer in 10 808 women: a cohort study. Am J Epidemiol,2003,157(5): 415–423. doi: 10.1093/aje/kwg002  BLANC L A, ROUSSEAU M C, PARENT M E. Perceived workplace stress is associated with an increased risk of prostate cancer before age 65. Front Oncol, 2017, 13(7): 269[2020-10-12]. https://doi.org/10.3389/fonc.2017.00269.  AFRISHAM R, PAKNEJAD M, SOLIEMANIFAR O, et al. The influence of psychological stress on the initiation and progression of diabetes and cancer. Int J Endocrinol Metab,2019,17(2): e67400[2020-10-12]. https://doi.org/10.5812/ijem.67400.  BRAADLAND P, RAMBERG H, GRYTLI H, et al. The β2-adrenergic receptor is a molecular switch for neuroendocrine transdifferentiation of prostate cancer cells. Mol Cancer Res,2019,17(11): 2154–2168. doi: 10.1158/1541-7786.MCR-18-0605  XIA Y, ZHAN C, FENG M, et al. Targeting CREB pathway suppresses small cell lung cancer. Mol Cancer Res,2018,16: 825–832. doi: 10.1158/1541-7786.MCR-17-0576  HASSAN S, KARPOVA Y, BAIZ D, et al. Behavioral stress accelerates prostate cancer development in mice. J Clin Invest,2013,123(2): 874–886.  HONG Q Z, QING B K, JIAO W, et al. Complex roles of cAMP-PKA-CREB signaling in cancer. Exp Hematol Oncol,2020,9: 32[2020-11-01].https://doi.org/10.1186/s40164-020-00191-1.  CHO E A, KIM E J, KWAK S J, et al. cAMP signaling inhibits radiation-induced ATM phosphorylation leading to the augmentation of apoptosis in human lung cancer cells. Molecular Cancer,2014,13(1): 36–36. doi: 10.1186/1476-4598-13-36  XU L, LI S, ZHOU W, et al. p62/SQSTM1 enhances breast cancer stem-like properties by stabilizing MYC mRNA. Oncogene,2017,36(3): 304–317. doi: 10.1038/onc.2016.202  TAM W, LU H, BUIKHUISEN J, et al. Protein kinase C α is a central signaling node and therapeutic target for breast cancer stem cells. Cancer Cell,2013,24(3): 347–364. doi: 10.1016/j.ccr.2013.08.005  BOWEN Z, CHENZHOU W, WEN C, et al. The stress hormone norepinephrine promotes tumor progression through β2-adrenoreceptors in oral cancer. Arch Oral Biol, 2020, 113: 104712[2020-11-01]. https://doi.org/10.1016/j.archoralbio.2020.104712.  CUI B, LUO Y, TIAN P, et al. Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells. J Clin Invest,2019,129(3): 1030–1046. doi: 10.1172/JCI121685  DAN L, XIANG C, MING S, et al. Chronic psychological stress promotes lung metastatic colonization of circulating breast cancer cells by decorating a pre‐metastatic niche through activating β‐adrenergic signaling. J Pathol,2018,244(1): 49–60. doi: 10.1002/path.4988  DAI S, MO Y, WANG Y, et al. Chronic stress promotes cancer development. Front Oncol,2020,10: 1492[2020-11-01]. https://doi.org/10.3389/fonc.2020.01492.  OBRADOVIC M, HAMELIN B, MANEVSKI N, et al. Glucocorticoids promote breast cancer metastasis. Nature,2019,567(7749): 540–544. doi: 10.1038/s41586-019-1019-4  ZHAO L, XU J, LIANG F, et al. Effect of chronic psychological stress on liver metastasis of colon cancer in mice. PLoS One, 2015, 10(10): e0139978[2020-11-01]. https://doi.org/10.1371/journal.pone.0139978.  ZHI X, LI B, LI Z, et al. Adrenergic modulation of AMPK-dependent autophagy by chronic stress enhances cell proliferation and survival in gastric cancer. Int J Oncol,2019,54(5): 1625–1638.  LE P, NOWELL C, KIM C, et al. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination. Nat Commun, 2016, 1: 10634[2020-11-01]. https://doi.org/10.1038/ncomms10634.  KIM F, LE C, PIMENTEL M, et al. Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for beta-adrenergic signaling in the pancreatic microenvironment. Brain Behav Immun,2014,40: 40–47. doi: 10.1016/j.bbi.2014.02.019  CLAIRE M. Autonomic nerve development contributes to prostate cancer progression. Science, 2013, 341(6142): 1236361[2020-11-01]. https://doi.org/10.1126/science.1236361.  WEI L, LI Y, TANG W, et al. Chronic unpredictable mild stress in rats induces colonic inflammation. Front Physiol, 2019, 10: 1228[2020-11-01]. https://doi.org/10.3389/fphys.2019.01228.  MURAKAMI T, KAMADA K, MIZUSHIMA K, et al. Changes in intestinal motility and gut microbiota composition in a rat stress model. Digestion,2017,95(1): 55–60. doi: 10.1159/000452364  ROOKS M, GARRETT W. Gut microbiota, metabolites and host immunity. Nat Rev Immunol,2016,16(6): 341–352. doi: 10.1038/nri.2016.42  ZHANG Y, ZANOS P, JACKSON I, et al. Psychological stress enhances tumor growth and diminishes radiation response in preclinical model of lung cancer. Radiother Oncol,2020,146: 126–135. doi: 10.1016/j.radonc.2020.02.004  KANG Y, NAGARAJA A, ARMAIZ P, et al. Adrenergic stimulation of DUSP1 impairs chemotherapy response in ovarian cancer. Clin Cancer Res,2016,22(7): 1713–1724. doi: 10.1158/1078-0432.CCR-15-1275  MUTHUSWAMY R, OKADA N J, JENKINS F J, et al. Epinephrine promotes COX-2-dependent immune suppression in myeloid cells and cancer tissues. Brain Behav Immun,2017,62: 78–86. doi: 10.1016/j.bbi.2017.02.008  YANG H, XIA L, CHEN J, et al. Stress-glucocorticoid-TSC22D3 axis compromises therapy-induced antitumor immunity. Nat Med,2019,25(9): 1428–1441. doi: 10.1038/s41591-019-0566-4  MATYSZAK M, CITTERIO S, RESCIGNO M, et al. Differential effects of corticosteroids during different stages of dendritic cell maturation. Eur J Immunol,2000,30(4): 1233–1242. doi: 10.1002/(SICI)1521-4141(200004)30:4<1233::AID-IMMU1233>3.0.CO;2-F  MA X, WANG M, YIN T, et al. Myeloid-derived suppressor cells promote metastasis in breast cancer after the stress of operative removal of the primary cancer. Front Oncol,2019,10(9): 855[2020-11-01].https://doi.org/10.3389/fonc.2019.00855.  SOMMERSHOF A, SCHEUERMANN L, KOERNER J, et al. Chronic stress suppresses anti-tumor TCD8+ responses and tumor regression following cancer immunotherapy in a mouse model of melanoma. Brain Behav Immun,2017,10(65): 140–149.  HYLANDER B, GORDON C, REPASKY E. Manipulation of ambient housing temperature to study the impact of chronic stress on immunity and cancer in mice. J Immunol,2019,202(3): 631–636. doi: 10.4049/jimmunol.1800621  BARITAKI S, BREE E, CHATZAKI E, et al. Chronic stress, inflammation, and colon cancer: a CRH system-driven molecular crosstalk. J Clin Med,2019,8(10): 1669[2020-11-01].https://doi.org/10.3390/jcm8101669.  NIRAULA A, WITCHER K, SHERIDAN J, et al. Interleukin-6 induced by social stress promotes a unique transcriptional signature in the monocytes that facilitate anxiety. Biol Psychiatry,2019,85(8): 679–689. doi: 10.1016/j.biopsych.2018.09.030  POWELL N, TARR A, SHERIDAN J, et al. Psychosocial stress and inflammation in cancer. Brain Behav Immun,2013(Suppl): S41–S47[2020-11-01].https://doi.org/10.1016/j.bbi.2012.06.015.  AYYADURAI S, GIBSON A, DCOSTA S, et al. Frontline science: corticotropin-releasing factor receptor subtype 1 is a critical modulator of mast cell degranulation and stress-induced pathophysiology. J Leukoc Biol,2017,102(6): 1299–1312. doi: 10.1189/jlb.2HI0317-088RR  MRAVEC B, TIBENSKY M, HORVATHOVA L. Stress and cancer. Part II: Therapeutic implications for oncology. J Neuroimmunol, 2020, 3(346): 577312[2020-11-01]. https://doi.org/10.1016/j.jneuroim.2020.577312.  FITZGERALD J. Beta blockers, norepinephrine, and cancer: an epidemiological viewpoint. Clin Epidemiol,2012,4: 151–156.  JANSEN L, HOFFMEISTER M, ARNDT V, et al. Stage-specific associations between beta blocker use and prognosis after colorectal cancer. Cancer,2014,120(8): 1178–1186. doi: 10.1002/cncr.28546  ZHANG X, ZHANG Y, HE Z, et al. Chronic stress promotes gastric cancer progression and metastasis: an essential role for ADRB2. Cell Death Dis, 2019, 10(11): 788[2020-11-01]. https://www.nature.com/articles/s41419-019-2030-2. doi: 10.1038/s41419-019-2030-2.  NILSSON M, SUN H, DIAO L, et al. Stress hormones promote EGFR inhibitor resistance in NSCLC: implications for combinations with β-blockers. Sci Transl Med,2017,9(415): 4307[2020-11-01].https://doi.org/10.1126/scitranslmed.aao4307.  LIAO X, CHE X, ZHAO W, et al. Effects of propranolol in combination with radiation on apoptosis and survival of gastric cancer cells. Radiat Oncol,2010,5: 98[2020-11-01].https://doi.org/10.1186/1748-717X-5-98.  WOLTER N, WOLTER J, ENEPEKIDES D, et al. Propranolol as a novel adjunctive treatment for head and neck squamous cell carcinoma. J Otolaryngol Head Neck Surg,2012,41(5): 334–344.  BARRE P V, PADMAJA G, RANA S, et al. Stress and quality of life in cancer patients: medical and psychological intervention. Indian J Psychol Med,2018,40(3): 232–238. doi: 10.4103/IJPSYM.IJPSYM_512_17  WANG A W, BOUCHARD L C, GUDENKAUF L M, et al. Differential psychological effects of cognitive-behavioral stress management among breast cancer patients with high and low initial cancer-specific distress. J Psychosom Res,2018,113: 52–57. doi: 10.1016/j.jpsychores.2018.07.011  PEDERSEN L, IDORN M, OLOFSSON G H, et al. Voluntary running suppresses tumor growth through epinephrine- and il-6-dependent NK cell mobilization and redistribution. Cell Metab,2016,23(3): 554–562. doi: 10.1016/j.cmet.2016.01.011  IDORN M, HOJMAN P. Exercise-dependent regulation of nk cells in cancer protection. Trends Mol Med,2016,22(7): 565–577. doi: 10.1016/j.molmed.2016.05.007  YANF, GAN Y, QANG Q, et al. Enriching the housing environment for mice enhances their NK cell antitumor immunity via sympathetic nerve-dependent regulation of NKG2D and CCR5. Cancer Res,2017,77(7): 1611–1622. doi: 10.1158/0008-5472.CAN-16-2143  ARAUJO R, FERNANDES A, NERY I, et al. Meditation effect on psychological stress level in women with breast cancer: a systematic review. Rev Esc Enferm USP,2019,53: e03529[2020-11-01].https://doi.org/10.1590/S1980-220X2018031303529.  RUSH S E, SHARMA M. Mindfulness-based stress reduction as a stress management intervention for cancer care: a systematic review. J Evid Based Complementary Altern Med,2017,22(2): 348–360. doi: 10.1177/2156587216661467  SCHELLEKENS M P J, PRINS J B, DONDERS A R T, et al. Mindfulness-based stress reduction added to care as usual for lung cancer patients and/or their partners: a multicentre randomized controlled trial. Psychooncology,2017,26(12): 2118–2126. doi: 10.1002/pon.4430