Patients diagnosed with cancer often undergo considerable psychological distress, and the induction of the psychological stress response has been linked with a poor response to chemotherapy. The psychological stress response is mediated by fluctuations of the hormones glucocorticoids (GCs) and catecholamines. Binding to their respective receptors, GCs and the catecholamines adrenaline/noradrenaline are responsible for signalling a wide range of processes involved in cell survival, cell cycle and immune function. Synthetic GCs are also often prescribed as co-medication alongside chemotherapy, and increasing evidence suggests that GCs may induce chemoresistance in multiple cancer types. In this review, we bring together evidence linking psychological stress hormone signalling with resistance to chemo- and immune therapies, as well as mechanistic evidence regarding the effects of exogenous stress hormones on the efficacy of chemotherapies.
The psychological stress response is designed to facilitate a response to perceived threat in order to maintain homeostatic equilibria. In humans, the stress response is controlled by fluctuations in hormonal secretions, primarily glucocorticoids and catecholamines, under the control of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS)[
Glucocorticoids (GCs) are regulated though the HPA axis and function in many roles, including roles in the circadian rhythm as well as mediating adaptive responses under the stress system[
Stress hormone mechanism of action. The HPA signals the release of glucocorticoids. Activation of the GR mediates transactivation and transrepression of genes through binding to the GRE, which controls the expression of genes involved in inflammation, survival and apoptosis. Stimulation of the SNS promotes the release of catecholamines. Activation of the BADR by adrenaline/noradrenaline stimulates synthesis of cAMP which in turn activates PKA. Phosphorylation of a number of PKA-receptive proteins involved in cell survival, proliferation and gene transcription can then occur. HPA: hypothalamic-pituitary-axis; GR: glucocorticoid receptor; GRE: glucocorticoid response element; SNS: sympathetic nervous system; BADR: beta-adrenergic receptor; cAMP: cyclic adenosine monophosphate; PKA: protein kinase A
The catecholamines adrenaline (A) and noradrenaline (NA) are produced in the adrenal medulla by chromaffin cells and released into circulation when stressors activate the SNS. Neural fibres of the SNS are able to release these neurotransmitters into all the major organ systems within seconds, allowing for rapid physiological responses. Once released the effects of catecholamines are mediated by α- or β-adrenergic receptors (ARs), which exist in subtypes (α1-, α2-, β1-, β2- and β3-) and are distributed throughout tissues accordingly. α-adrenergic receptors primarily mediate vasoconstriction and contraction of smooth muscle and are present on vascular muscle. β-adrenergic receptors also regulate muscle contraction with β1-adrenergic receptors located on myocardial muscle acting to increase blood pressure and heart rate thus increasing blood flow to skeletal muscles. β2-adrenergic receptors present on bronchial smooth muscles facilitate muscle relaxation and vasodilation and also stimulate glucose metabolism[
Stress hormones mediate a wide range of biological processes in the cancer setting, and as such the effects of stress hormone signalling on chemotherapies is thought to be due to various mechanisms and dependent on the chemotherapeutic agent. The effects of stress hormone signalling on the efficacy of various anti-cancer treatments is reviewed below.
Taxanes such as Paclitaxel and Docetaxel are widely used chemotherapeutic agents capable of disrupting microtubule formation and arresting the cell cycle, in turn inducing apoptosis[
It is also proposed that the induction of DNA damage can induce resistance to chemotherapies in breast cancer. Following DNA damage, activation of the serine/threonine kinases, ATM (ataxia-telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3-related), termed DNA sensors, may occur[
DNA damage response. DNA damage induced by stress hormones activates the DNA damage sensors ATM and ATR, which initiate downstream signal cascades controlling DNA repair, cell cycle arrest and apoptosis. ATM: ataxia-telangiectasia mutated; ATR: ataxia telangiectasia and Rad3-related
Several mechanisms have been proposed to explain the development of resistance to paclitaxel, including overexpression of multi-drug resistance (MDR) genes such as
Administration of GCs
However, little was understood about the mechanism by which GCs may exert anti-apoptotic effects in cancer cells challenged by chemotherapy. Activation of the GR has previously been shown promote cell survival signalling pathways and inhibit pro-apoptotic signalling in mammary epithelial cells[
Further investigation into molecular signalling downstream of the GR revealed GCs may also contribute to cell survival through interference with mitogen-activated protein kinase (MAPK) signalling[
Drawing together these two anti-apoptotic mechanisms, and to confirm the effect of GCs on the regulation of anti-apoptotic genes, the expression of SGK-1 and MKP-1 was evaluated in a clinical setting in ovarian cancer patients[
In another study of Triple Negative Breast Cancer (TNBC) resistance to paclitaxel was also induced by activation of the GR, and this was shown to occur as a result of activation of the transcription co-activator YAP. The GC mediated activation of YAP also promotes the expansion of cancer stem cells (CSCs), which are both highly metastatic and often resistant to chemotherapy[
Glucocorticoids and chemoresistance. Glucocorticoids can reduce the efficacy of chemotherapeutics (taxanes and platinum-based drugs) through upregulation of cell survival signalling, downregulation of apoptosis and interference with DNA repair mechanisms
Other treatments for cancer include platinum-based chemotherapies, a class of agents used in the treatment of nearly half of all cancers. The most commonly used drugs include cisplatin, carboplatin and oxaliplatin and are used against ovarian, testicular, bladder and colon cancers amongst others[
Stimulation of the adrenergic response has been shown to have adverse effects on the progression of ovarian cancer[
Activation of the GR has also been shown to promote cell survival signalling in high grade serous ovarian carcinoma cells and inhibit carboplatin-induced cell death. Subsequent antagonism of the GR using an inhibitor was able to enhance the effect of platinum-based chemotherapy on tumour growth in a xenograft model of ovarian carcinoma[
Similar results with GCs have been observed in cell lines representing TNBCs. Dexamethasone was able to decrease sensitivity to cisplatin, as well induce expression of Krüppel-like factor 5 (KLF5), a transcription factor that has been shown to promotes survival and proliferation in basal breast cancers[
In the treatment of cervical cancer, GCs may also play a role in response to therapy. Infection with certain strains of human papillomavirus (HPV) is strongly linked to an increased risk of cervical cancer. It is though that this occurs as a result of viral oncoproteins interfering with the normal functioning of the tumour suppressor p53. In HPV-positive cervical cancer cells glucocorticoids not only downregulated p53, but also a microRNA (miR-145) associated with tumour suppression and shown to be downregulated in cervical cancer tissues. The downregulation of miR-145 by cortisol correlated with an increase in resistance to the antitumor drug mitomycin C, and this was shown be a direct result of glucocorticoid-mediated expression of a viral oncoprotein[
However, dexamethasone has also been shown to enhance the cytotoxicity of cisplatin in cervical cancer cells, through the inhibition of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)[
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In a lung carcinoma cell line cell treated with cisplatin and dexamethasone, not only were the cells protected from apoptosis, they were able to recover and continue to proliferate after 3 weeks[
Doxorubicin is a non-selective anthracycline widely used in the treatment of breast, bladder and ovarian cancer as well as types of leukaemia and lymphoma, often in combination with other therapies[
Resistance to doxorubicin poses a significant problem in the treatment of aggressive breast cancers, and since there is currently no marker to predict the efficacy of Doxorubicin, it is often prescribed without a full understanding of the therapeutic gain[
Expression of
GCs have been shown promote cell survival signalling pathways in mammary epithelial cells[
GCs are also known to play a role in oxidative stress in cancer. Through genomic and non-genomic pathways the GR is involved in the transactivation and transrepression of multiple anti-inflammatory responses that suppress oxidative stress[
Alterations to DNA repair mechanisms are known to strongly influence the acquisition of resistance to many therapies including platinum-based therapies, due to the need for recognition and removal of platinum-DNA adducts. Activation of the DNA repair machinery slows down or halts the transition of cells through the cell cycle, and as such the ability of cells to repair the damaged DNA dictates sensitivity or resistance to platinum-based drugs[
Recent animal studies have focused the attention on adrenergic stress effects on the efficiency of immune therapies. In particular, the role of stress on immune checkpoint therapy and on the immune tumour microenvironment has been shown using syngeneic models of breast cancer and melanoma. In this study, mice were exposed to mild, chronic cold stress and housed at 22 °C instead of 30 °C, causing the activation of the adrenergic signaling pathway. To block the adrenergic signaling, mice were treated with propranolol, a non-selective β-blocker. The stress effect on the immune response against cancer was assessed by evaluating the adaptive cell-mediated immune response. In particular, the presence of active CD8+ T cells was assessed in the tumour of stressed mice as well as the ratio between IFN-γ+ CD8+ and CD4+ cells. The tumour microenvironment was also studied considering the cancer-mediated immunosuppression via PD-1/PD-L1 interaction and mice were treated with a PD-1/PD-L1 inhibitor. Cold-stressed mice undergoing a treatment with propranolol showed a reduced tumour growth and an enhanced CD8+ T cell-mediated tumour immune response compared to control group housed at standard temperature. Moreover, PD-1 expression was increased in CD8+ tumour infiltrating lymphocytes (TILs) of cold-stressed mice with a decrease in the frequency in the propranolol treated group. This finding suggests that PD-1 signalling is one of the routes used by the adrenergic stress to cause immunosuppression in the tumour microenvironment and PD-1 blockade is significantly improved when cold-stressed mice are treated with propranolol[
The influence of β-adrenergic signalling on T-cell targeting immune therapies was also shown in a mouse model of lymphoma. In this study, mice treated with isoprenaline, a non-selective β-adrenergic agonist, showed an acceleration in the growth of lymphoma which was reversed when the treatment was administered in mice not expressing β-adrenergic receptors (β1β2AR-KO). The effect on immune therapies was evaluated by treating mice with monoclonal antibodies against 4-1BB and PD-1 showing a significant inhibition of lymphoma growth in the 4-1BB treated group. However, when mice were also treated with isoprenaline both α4-1BB and αPD-1 immune therapies were less effective. To further investigate the effect on the cell-mediated response, mice received tumour specific CD8+ T cells with adoptive transfer prior tumour inoculation and the functional status of these cells was assessed after the isoprenaline and immune treatments. Isoprenaline significantly decreased the IFN-γ production and the cytotoxicity that T cells acquired with the α4-1BB treatment[
Although these first studies confirm the idea that adrenergic stress weakens the efficacy of immune therapies by inhibiting the pro-inflammatory and anti-tumour response more work is necessary for a better understanding of the molecular mechanisms modulating the immune response against cancer. It is known that stress affects the cell-mediated immunity by regulating T cell subtypes and activation status. However, the literature is deficient in addressing some important aspects of the stress effect in cancer immunity that can undermine the immunotherapy potential. For instance, the efficacy of immunotherapies such as PD-1 and PD-L1 inhibitors is correlated with the immune infiltration (TILs) status of the tumour. In a study on metastatic melanoma, tumours from patients with high TILs, also known as “hot tumours”, showed a higher PD-L1 expression and a better outcome[
Stress hormone-mediated immune regulation. Glucocorticoids immune regulation is associated with the blockade of the pro-inflammatory gene expression. GCs bind the cytoplasmic glucocorticoid receptors (GRs) and translocate to the nucleus where they inhibit transcriptional factors such as NF-κB or AP-1 that regulate the expression of pro-inflammatory genes. Catecholamines can bind G-protein coupled adrenergic receptors on the membrane of immune T cells. The adrenergic signalling pathway blocks the production of the pro-inflammatory cytokine IFN-γ and consequently B cell production of IgG2a. On the contrary, β-adrenergic signalling is not thought to affect Th2 cells producing of IL-4 or B cells producing IgG1. Both GCs and the adrenergic hormones affect the T cell migration by regulating the T cell cytoskeleton and actin-binding proteins such as moesin. This leads to the hypothesis that stress hormones can have a role in the T cell trafficking into the tumour. Furthermore, stress hormones exposure correlates with the loss of the activation immune marker CD43.GCs: glucocorticoids; GRs: glucocorticoid receptors
Identification of the role of stress hormone signalling in cancer drug resistance highlights the need for greater understanding of biobehavioural factors in the treatment of cancers. Furthermore, the use of interventions including stress hormone receptor antagonism by both well-characterised and novel inhibitors may provide useful tools to complement current therapeutic strategies. Research into better anti-emetic therapies to reduce the use of synthetic glucocorticoids as co-treatments may also prove beneficial.
Contributed to the review of the material and writing of the review: Flaherty RL
Contributed to conception, the review and writing of the immunotherapy section: Falcinelli M
Made substantial contributions to conception and design and writing of the review: Flint MS
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All authors declared that there are no conflicts of interest.
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© The Author(s) 2019.