Chronic stress in solid tumor development: from mechanisms to interventions

Abstract

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.

The contribution of the nervous system in the cancer progression

“…Ablation or chemogenetic inhibition of these neurons prevented cancer-induced anxiety and 4T1 tumor progression ( 58 ). This report is noteworthy since the investigation showed the influence of CRH neurons in CeM but not in the hypothalamus, given the evidence that hypothalamic CRH neurons contribute to stress-induced cancer progression ( 60 ). Taken together, these studies reveal the strong association between tumor growth and signals from the CNS, indicating the necessity to further research on the interconnections with various neural circuitries for therapeutic approaches targeting this link.…”

The Function of the Immune System, Beyond Strategies Based on Cell‐Autonomous Mechanisms, Determines Cancer Development: Immune Response and Cancer Development

“…In addition to the direct effect of stress hormones on the growth, migration, and survival of tumor cells and angiogenesis, these hormones suppress the immune response both in TME and systemically. [ 52 ] Stress hormones also suppress the production of IL‐2, IL‐12, and IFN‐γ, and cytotoxicity of NK cells. [ 53 ] In addition, T‐cell antitumor function is suppressed by chronic stressors, which are characterized by the elevation of immune checkpoint molecule expression, such as PD‐1.…”

Role of stress in the pathogenesis of cancer (Review)

“…Preclinical data published over the years have highlighted the potential role of mediators of the neuroendocrine stress response (particularly norepinephrine, epinephrine and cortisol) in processes related to carcinogenesis which act directly on cancer cells and promote tumour growth ( 5 , 12 , 102 , 111 - 113 ). Inflammation, angiogenesis, genomic instability, metastasis and the expression of stem cell-like genes are all facilitated by the binding of stress hormones to their receptors ( 5 , 102 , 111 ). This occurs through the epigenetic alteration or the activation of a variety of mechanisms.…”