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[A Review of Chronic Stress and the Initiation and Evolution of Cancer]. Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition 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. 10.12182/20210160203
Neuroimmunology of cancer and associated symptomology. Immunology and cell biology Evolutionarily, the nervous system and immune cells have evolved to communicate with each other to control inflammation and host responses against injury. Recent findings in neuroimmune communication demonstrate that these mechanisms extend to cancer initiation and progression. Lymphoid structures and tumors, which are often associated with inflammatory infiltrate, are highly innervated by multiple nerve types (e.g. sympathetic, parasympathetic, sensory). Recent preclinical and clinical studies demonstrate that targeting the nervous system could be a therapeutic strategy to promote antitumor immunity while simultaneously reducing cancer-associated neurological symptoms, such as chronic pain, fatigue and cognitive impairment. Sympathetic nerve activity is associated with physiological or psychological stress, which can be induced by tumor development and cancer diagnosis. Targeting the stress response through suppression of sympathetic activity or activation of parasympathetic activity has been shown to drive activation of effector T cells and inhibition of myeloid-derived suppressor cells within the tumor. In addition, there is emerging evidence that sensory nerves may regulate tumor growth and metastasis by promoting or inhibiting immunosuppression in a tumor-type specific manner. Because neural effects are often tumor-type specific, further study is required to optimize clinical therapeutic strategies. This review examines the emerging evidence that neuroimmune communication can regulate antitumor immunity as well as contribute to development of cancer-related neurological symptoms. 10.1111/imcb.12496
Chronic stress-induced immune dysregulation in cancer: implications for initiation, progression, metastasis, and treatment. Zhang Leyi,Pan Jun,Chen Wuzhen,Jiang Jinxin,Huang Jian American journal of cancer research Psychological stress is a well-accepted risk factor in cancer initiation and progression. The explosive growth of psychoneuroimmunology research in the past decade has yielded an unprecedented wealth of information about the critical role of chronic stress in the immune dysfunction that influences tumor behaviors, which presents insights to mitigate distress and improve prognosis in cancer patients. Chronic stress exacerbates inflammation and causes a metabolism disorder, making it difficult for the organisms to maintain homeostasis and increasing its susceptibility to cancer. The shifted differentiation and redistribution of the immune system induced by chronic stress fail to combat cancer efficiently. Chronic stress increases the tumor-educated immune suppressive cells and impairs the cytotoxicity of cellular immunity, thereby promoting lymphatic metastasis and hematogenous metastasis. In addition, the efficacy of existing cancer therapies is undermined because chronic stress prevents the immune system from responding properly. Emerging stress-reduction measures have been administered to assist cancer patients to cope with the adverse effects of chronic stress. Here we systematically review the current molecular, cellular, physiological mechanisms about stress-mediated immune responses in the enhancement of tumor initiation and progression, remodeling of tumor microenvironment and impairment of anti-tumor treatment. We also summarize the potential clinically applicable stress-oriented strategies towards cancer and discuss briefly where important knowledge gaps remain.
Chronic Stress: Impacts on Tumor Microenvironment and Implications for Anti-Cancer Treatments. Tian Wentao,Liu Yi,Cao Chenghui,Zeng Yue,Pan Yue,Liu Xiaohan,Peng Yurong,Wu Fang Frontiers in cell and developmental biology Chronic stress is common among cancer patients due to the psychological, operative, or pharmaceutical stressors at the time of diagnosis or during the treatment of cancers. The continuous activations of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), as results of chronic stress, have been demonstrated to take part in several cancer-promoting processes, such as tumorigenesis, progression, metastasis, and multi-drug resistance, by altering the tumor microenvironment (TME). Stressed TME is generally characterized by the increased proportion of cancer-promoting cells and cytokines, the reduction and malfunction of immune-supportive cells and cytokines, augmented angiogenesis, enhanced epithelial-mesenchymal transition, and damaged extracellular matrix. For the negative effects that these alterations can cause in terms of the efficacies of anti-cancer treatments and prognosis of patients, supplementary pharmacological or psychotherapeutic strategies targeting HPA, SNS, or psychological stress may be effective in improving the prognosis of cancer patients. Here, we review the characteristics and mechanisms of TME alterations under chronic stress, their influences on anti-cancer therapies, and accessory interventions and therapies for stressed cancer patients. 10.3389/fcell.2021.777018
Inflammation and Inflammasomes: Pros and Cons in Tumorigenesis. Journal of immunology research Over the past decade, it has been well established that tumorigenesis is affected by chronic inflammation. During this event, proinflammatory cytokines are produced by numerous types of cells, such as fibroblasts, endothelial cells, macrophages, and tumor cells, and are able to promote the initiation, progression, and metastasis of different types of cancer. When persistent inflammation occurs, activation of inflammasome complexes is initiated, leading to its assembly and further activation of caspase, production of proinflammatory cytokines, and pyroptosis induction. The function of this multiprotein complex is not only to reassure inflammation and to promote cell death, through caspase activity, but also has been identified to have significant contributions during tumorigenesis and cancer development. So far, many efforts have been made in order to extend the knowledge of inflammasome implications and how its components could be targeted as therapeutic agents. Additionally, microRNAs (miRNAs), evolutionary conserved noncoding molecules, have emerged as pivotal players during numerous biological events by regulating gene and protein expression. Therefore, dysregulations of miRNA expressions have been correlated with inflammation during tumor development. In this review, we aim to highlight the dual role of inflammasomes and proinflammatory cytokines during carcinogenesis paired with the distinguished effects of miRNAs upon inflammation cascades during tumor growth and progression. 10.1155/2020/2549763
A nervous tumor microenvironment: the impact of adrenergic stress on cancer cells, immunosuppression, and immunotherapeutic response. Eng Jason W-L,Kokolus Kathleen M,Reed Chelsey B,Hylander Bonnie L,Ma Wen W,Repasky Elizabeth A Cancer immunology, immunotherapy : CII Long conserved mechanisms maintain homeostasis in living creatures in response to a variety of stresses. However, continuous exposure to stress can result in unabated production of stress hormones, especially catecholamines, which can have detrimental health effects. While the long-term effects of chronic stress have well-known physiological consequences, recent discoveries have revealed that stress may affect therapeutic efficacy in cancer. Growing epidemiological evidence reveals strong correlations between progression-free and long-term survival and β-blocker usage in cancer patients. In this review, we summarize the current understanding of how the catecholamines, epinephrine and norepinephrine, affect cancer cell survival and tumor progression. We also highlight new data exploring the potential contributions of stress to immunosuppression in the tumor microenvironment and the implications of these findings for the efficacy of immunotherapies. 10.1007/s00262-014-1617-9
Sympathetic Neurotransmitters and Tumor Angiogenesis-Link between Stress and Cancer Progression. Journal of oncology Recent evidence supports a longstanding hypothesis that chronic stress can influence tumor growth and progression. It has been shown that sympathetic neurotransmitters, such as catecholamines and neuropeptides, can affect both cancer cell growth and tumor vascularization. Depending on neurotransmitter and type of tumor, these effects can be both stimulatory and inhibitory. Norepinephrine (NE) and epinephrine (E) are potent stimulators of vascularization, acting both by inducing the release of angiogenic factors from tumor cells and directly on endothelial cell (EC) functions. As a result, activation of the adrenergic system increases growth of various types of tumors and has been shown to mediate stress-induced augmentation of tumor progression. Dopamine (DA), on the other hand, interferes with VEGF signaling in endothelial cells, blocks its angiogenic functions and inhibits tumor growth. Another sympathetic neurotransmitter coreleased with NE, neuropeptide Y (NPY), directly stimulates angiogenesis. However, proangiogenic actions of NPY can be altered by its direct effect on tumor cell proliferation and survival. In consequence, NPY can either stimulate or inhibit tumor growth, depending on tumor type. Hence, sympathetic neurotransmitters are powerful modulators of tumor growth and can become new targets in cancer therapy. 10.1155/2010/539706
Interplay between stress and cancer-A focus on inflammation. Frontiers in physiology Stress is an integral part of life. While acute responses to stress are generally regarded as beneficial in dealing with immediate threats, chronic exposure to threatening stimuli exerts deleterious effects and can be either a contributing or an aggravating factor for many chronic diseases including cancer. Chronic psychological stress has been identified as a significant factor contributing to the development and progression of cancer, but the mechanisms that link chronic stress to cancer remain incompletely understood. Psychological stressors initiate multiple physiological responses that result in the activation of the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic nervous system, and the subsequent changes in immune function. Chronic stress exposure disrupts the homeostatic communication between the neuroendocrine and immune systems, shifting immune signaling toward a proinflammatory state. Stress-induced chronic low-grade inflammation and a decline in immune surveillance are both implicated in cancer development and progression. Conversely, tumor-induced inflammatory cytokines, apart from driving a tumor-supportive inflammatory microenvironment, can also exert their biological actions distantly circulation and therefore adversely affect the stress response. In this minireview, we summarize the current findings on the relationship between stress and cancer, focusing on the role of inflammation in stress-induced neuroendocrine-immune crosstalk. We also discuss the underlying mechanisms and their potential for cancer treatment and prevention. 10.3389/fphys.2023.1119095
Chronic Stress Exacerbates the Immunosuppressive Microenvironment and Progression of Gliomas by Reducing Secretion of CCL3. Cancer immunology research As understanding of cancer has deepened, increasing attention has been turned to the roles of psychological factors, especially chronic stress-induced depression, in the occurrence and development of tumors. However, whether and how depression affects the progression of gliomas are still unclear. In this study, we have revealed that chronic stress inhibited the recruitment of tumor-associated macrophages (TAM) and other immune cells, especially M1-type TAMs and CD8+ T cells, and decreased the level of proinflammatory cytokines in gliomas, leading to an immunosuppressive microenvironment and glioma progression. Mechanistically, by promoting the secretion of stress hormones, chronic stress inhibited the secretion of the chemokine CCL3 and the recruitment of M1-type TAMs in gliomas. Intratumoral administration of CCL3 reprogrammed the immune microenvironment of gliomas and abolished the progression of gliomas induced by chronic stress. Moreover, levels of CCL3 and M1-type TAMs were decreased in the tumor tissues of glioma patients with depression, and CCL3 administration enhanced the antitumor effect of anti-PD-1 therapy in orthotopic models of gliomas undergoing chronic stress. In conclusion, our study has revealed that chronic stress exacerbates the immunosuppressive microenvironment and progression of gliomas by reducing the secretion of CCL3. CCL3 alone or in combination with an anti-PD-1 may be an effective immunotherapy for the treatment of gliomas with depression. See related Spotlight by Cui and Kang, p. 514. 10.1158/2326-6066.CIR-23-0378
Chronic stress in solid tumor development: from mechanisms to interventions. Journal of biomedical science Chronic stress results in disturbances of body hormones through the neuroendocrine system. Cancer patients often experience recurrent anxiety and restlessness during disease progression and treatment, which aggravates disease progression and hinders treatment effects. Recent studies have shown that chronic stress-regulated neuroendocrine systems secret hormones to activate many signaling pathways related to tumor development in tumor cells. The activated neuroendocrine system acts not only on tumor cells but also modulates the survival and metabolic changes of surrounding non-cancerous cells. Current clinical evidences also suggest that chronic stress affects the outcome of cancer treatment. However, in clinic, there is lack of effective treatment for chronic stress in cancer patients. In this review, we discuss the main mechanisms by which chronic stress regulates the tumor microenvironment, including functional regulation of tumor cells by stress hormones (stem cell-like properties, metastasis, angiogenesis, DNA damage accumulation, and apoptotic resistance), metabolic reprogramming and immune escape, and peritumor neuromodulation. Based on the current clinical treatment framework for cancer and chronic stress, we also summarize pharmacological and non-pharmacological therapeutic approaches to provide some directions for cancer therapy. 10.1186/s12929-023-00903-9
Chronic Stress Effects on Tumor: Pathway and Mechanism. Hong Hanqing,Ji Min,Lai Dongmei Frontiers in oncology Chronic stress is an emotional experience that occurs when people encounter something they cannot adapt to. Repeated chronic stress increases the risk of a variety of diseases, such as cardiovascular disease, depression, endocrine disease, inflammation and cancer. A growing body of research has shown that there is a link between chronic stress and tumor occurrence in both animal studies and clinical studies. Chronic stress activates the neuroendocrine system (hypothalamic-pituitary-adrenal axis) and sympathetic nervous system. Stress hormones promote the occurrence and development of tumors through various mechanisms. In addition, chronic stress also affects the immune function of the body, leading to the decline of immune monitoring ability and promote the occurrence of tumors. The mechanisms of chronic stress leading to tumor include inflammation, autophagy and epigenetics. These factors increase the proliferation and invasion capacity of tumor cells and alter the tumor microenvironment. Antagonists targeting adrenergic receptors have played a beneficial role in improving antitumor activity, as well as chemotherapy resistance and radiation resistance. Here, we review how these mechanisms contribute to tumor initiation and progression, and discuss whether these molecular mechanisms might be an ideal target to treat tumor. 10.3389/fonc.2021.738252
Stress, depression, the immune system, and cancer. Reiche Edna Maria Vissoci,Nunes Sandra Odebrecht Vargas,Morimoto Helena Kaminami The Lancet. Oncology The links between the psychological and physiological features of cancer risk and progression have been studied through psychoneuroimmunology. The persistent activation of the hypothalamic-pituitary-adrenal (HPA) axis in the chronic stress response and in depression probably impairs the immune response and contributes to the development and progression of some types of cancer. Here, we overview the evidence that various cellular and molecular immunological factors are compromised in chronic stress and depression and discuss the clinical implications of these factors in the initiation and progression of cancer. The consecutive stages of the multistep immune reactions are either inhibited or enhanced as a result of previous or parallel stress experiences, depending on the type and intensity of the stressor and on the animal species, strain, sex, or age. In general, both stressors and depression are associated with the decreased cytotoxic T-cell and natural-killer-cell activities that affect processes such as immune surveillance of tumours, and with the events that modulate development and accumulation of somatic mutations and genomic instability. A better understanding of the bidirectional communication between the neuroendocrine and immune systems could contribute to new clinical and treatment strategies. 10.1016/S1470-2045(04)01597-9
Chronic inflammation and cytokines in the tumor microenvironment. Journal of immunology research Acute inflammation is a response to an alteration induced by a pathogen or a physical or chemical insult, which functions to eliminate the source of the damage and restore homeostasis to the affected tissue. However, chronic inflammation triggers cellular events that can promote malignant transformation of cells and carcinogenesis. Several inflammatory mediators, such as TNF-α, IL-6, TGF-β, and IL-10, have been shown to participate in both the initiation and progression of cancer. In this review, we explore the role of these cytokines in important events of carcinogenesis, such as their capacity to generate reactive oxygen and nitrogen species, their potential mutagenic effect, and their involvement in mechanisms for epithelial mesenchymal transition, angiogenesis, and metastasis. Finally, we will provide an in-depth analysis of the participation of these cytokines in two types of cancer attributable to chronic inflammatory disease: colitis-associated colorectal cancer and cholangiocarcinoma. 10.1155/2014/149185
The systemic-level repercussions of cancer-associated inflammation mediators produced in the tumor microenvironment. Frontiers in endocrinology The tumor microenvironment is a dynamic, complex, and redundant network of interactions between tumor, immune, and stromal cells. In this intricate environment, cells communicate through membrane-membrane, ligand-receptor, exosome, soluble factors, and transporter interactions that govern cell fate. These interactions activate the diverse and superfluous signaling pathways involved in tumor promotion and progression and induce subtle changes in the functional activity of infiltrating immune cells. The immune response participates as a selective pressure in tumor development. In the early stages of tumor development, the immune response exerts anti-tumor activity, whereas during the advanced stages, the tumor establishes mechanisms to evade the immune response, eliciting a chronic inflammation process that shows a pro-tumor effect. The deregulated inflammatory state, in addition to acting locally, also triggers systemic inflammation that has repercussions in various organs and tissues that are distant from the tumor site, causing the emergence of various symptoms designated as paraneoplastic syndromes, which compromise the response to treatment, quality of life, and survival of cancer patients. Considering the tumor-host relationship as an integral and dynamic biological system, the chronic inflammation generated by the tumor is a communication mechanism among tissues and organs that is primarily orchestrated through different signals, such as cytokines, chemokines, growth factors, and exosomes, to provide the tumor with energetic components that allow it to continue proliferating. In this review, we aim to provide a succinct overview of the involvement of cancer-related inflammation at the local and systemic level throughout tumor development and the emergence of some paraneoplastic syndromes and their main clinical manifestations. In addition, the involvement of these signals throughout tumor development will be discussed based on the physiological/biological activities of innate and adaptive immune cells. These cellular interactions require a metabolic reprogramming program for the full activation of the various cells; thus, these requirements and the by-products released into the microenvironment will be considered. In addition, the systemic impact of cancer-related proinflammatory cytokines on the liver-as a critical organ that produces the leading inflammatory markers described to date-will be summarized. Finally, the contribution of cancer-related inflammation to the development of two paraneoplastic syndromes, myelopoiesis and cachexia, will be discussed. 10.3389/fendo.2022.929572
Inflammation and immune surveillance in cancer. Chow Melvyn T,Möller Andreas,Smyth Mark J Seminars in cancer biology Chronic inflammation is a risk factor for tumor development. However, understanding the effect of the immune system on tumor development has only been significantly advanced over the past two decades. We now appreciate that the immune system, in addition to tumor-suppressive function by eliminating nascent transformed tumor cells, can also exert selection pressure on tumor cells and facilitate tumor growth by providing a favorable tumor microenvironment. Yet, the distinctions between tumor-promoting inflammation and tumor-suppressive immunity are still not clear due to the dual role of some cytokines and other molecules in the immune system. The danger signal hypothesis has shaped our view of the role of immunity in cancer development, but still little is known about the exact role of danger signal receptors in cancer progression. In this review, we introduce the processes of cancer immunoediting and inflammation-induced cancer and discuss what is currently known about the role of danger signal receptors in cancer development and progression. 10.1016/j.semcancer.2011.12.004
Tumor Microenvironment - Selective Pressures Boosting Cancer Progression. Advances in experimental medicine and biology In 2018, 9.6 million deaths from cancer were estimated, being this disease the second leading cause of death worldwide. Notwithstanding all the efforts developed in prevention, diagnosis and new treatment approaches, chemoresistance seems to be inevitable, leading to cancer progression, recurrence and affecting the outcome of the disease. As more and more evidence support that cancer is an evolutionary and ecological process, this concept is rarely applied in the clinical context. In fact, cancer cells emerge and progress within an ecological niche - the tumor microenvironment - that is shared with several other cell types and that is continuously changing. Therefore, the tumor microenvironment imposes several selective pressures on cancer cells such as acidosis, hypoxia, competition for space and resources, immune predation and anti-cancer therapies, that cancer cells must be able to adapt to or will face extinction.In here, the role of the tumor microenvironment selective pressures on cancer progression will be discussed, as well as the targeting of its features/components as strategies to fight cancer. 10.1007/978-3-030-34025-4_2