Why stress is BAD for cancer patients

Behavioral stress is known to promote tumor progression in experimental models, but the role of behavioral stress in cancer initiation is less clear. In this issue, Hassan et al. focus on the signaling and biological effects induced by stress hormones that lead to tumor cell evasion from apoptosis, resulting in prostate cancer progression.

A stressor is often defined as a stimulus that is capable of activating the hypothalamic-pituitary-adrenal (HPA) axis and/or the sympathetic nervous system (SNS). HPA activation induces hypothalamic production of neurohormones, such as corticotropin-releasing hormone and vasopressin. This, in turn, results in secretion of the adrenocorticotropic hormone from the pituitary and subsequent release of glucocorticoids from the adrenal cortex. SNS activation results in the release of epinephrine and norepinephrine from sympathetic neurons and adrenal medulla. At a broad level, behavioral stress can be considered as acute or chronic. While acute stress may be adaptive for preservation of the organism and can have beneficial effects (e.g., enhanced immune response), chronic stress can lead to disease states such as cardiovascular and metabolic diseases. Moreover, a growing number of studies have uncovered major roles for chronic stress in cancer progression (1).

Catecholamine-dependent signaling is known to promote several protumoral processes that collectively result in increased tumor progression. For example, chronic stress results in increased epinephrine and norepinephrine, whereas dopamine levels are reduced. This catecholamine shift leads to a microenvironment that is conducive to increased tumor growth and progression in experimental models of disease (2). Specifically, elevated norepinephrine levels have been associated with increased angiogenesis, invasion, and protection from anoikis (2–5). Adrenergic activation has been implicated as the key mediator of these effects by modulating several growth factors (e.g., VEGF, IL-6, IL-8, matrix metalloproteinases, and FAK) in multiple cancers. Upon β-adrenergic receptor (ADRB) activation, increased cAMP-PKA activity is frequently noted as an intracellular mediator of the stress response.

Chronic stress plays a significant role in cancer progression, and decreased cancer incidence is observed among patients who take beta blockers for the treatment of other diseases (6). Cancer diagnosis and associated treatment can potentially elevate a patient’s stress levels, whereas social support has been associated with increased patient survival (7). Recent findings regarding the role of stress hormones in chemoresistance, metastasis, cancer relapse, and surgical recovery have moved the field forward, but the molecular mechanisms underlying these effects are not fully understood (6, 8). In this issue of the JCI, Hassan et al. have used a variety of experimental models of prostate cancer in an effort to demonstrate the underlying mechanisms by which behavioral stress promotes tumor growth and to provide the basis to support pharmacological and behavioral interventions for prostate cancer patients (9).

The acquired ability of tumor cells to evade apoptosis is a classic hallmark of cancer (10). In advanced prostate cancer, activating antiapoptotic signaling is believed to be an important factor in chemoresistance and androgen-independent tumor growth (11). In the study by Hassan et al., epinephrine was found to activate signaling pathways that led to the inhibition of apoptosis (9). The authors used two mouse models of prostate cancer: a prostate-specific, androgen-dependent Hi-Myc transgenic model, and an androgen-independent PTEN mutant xenograft model (Figure 1). To model behavioral stress, mice were immobilized with or without exposure to predator scent, resulting in markedly elevated epinephrine and norepinephrine levels in the tumor, spleen, and prostate. In both models, stress hormones had an antiapoptotic effect on tumor cells. Additionally, in the PTEN mutant model, epinephrine abrogated the apoptotic effect of a PI3K inhibitor, but this could be restored by delivery of an ADRB2 antagonist. Hassan et al. also provided evidence that PKA could potentially mediate this stress response (9).

Figure 1

Hassan et al. explored the role of stress in two models of prostate cancer (9). (A) In an androgen-independent Pten mutant model, signaling through the adrenergic receptor led to phosphorylation (and inactivation) of the proapoptotic molecule BAD, promoting survival of prostate cancer cells. (B) In an androgen-dependent model, stress signaling blocked apoptosis by the PKA/BAD pathway and contributed to androgen therapy resistance.

The authors found that chronic stress increased the incidence of premalignant lesions in the prostate-specific inducible Hi-Myc transgenic mouse model, but this effect was blocked by an ADRB2 inhibitor. Moreover, epinephrine induced activation of ADRB2, resulting in increased PKA-mediated BAD phosphorylation and apoptosis inhibition. Importantly, the authors showed that behavioral stress led to resistance to antiandrogen (bicalutamide) therapy, an effect abrogated by treatment with the ADRB2 inhibitor (9). These data support a role for behavioral stress as a promoter of androgen therapy resistance and provide a mechanism that could be potentially targeted to restore sensitivity.

Prostate cancer is associated with various common genetic modifications, including loss of the tumor suppressor genes p53 and PTEN and activation of oncogenes such as c-Jun and c-Myc (12). Additionally, it has been shown that increased Bcl2 levels can lead to the development of androgen-independent prostate cancer (13). This team had previously demonstrated that adrenergic stimulation of a prostate cancer cell line that is PTEN mutant with constitutively active Bcl2 can protect cells from apoptosis (14). Their present findings further suggest that behavioral stress promotes apoptosis resistance, potentially leading to tumor initiation and progression in androgen-dependent and -independent prostate cancer models (9). Coupled with the authors’ previous findings, the current study makes a convincing case for antiapoptotic effects of stress in prostate cancer.

The findings presented in this study have potential clinical implications, suggesting the possibility that beta blockers, generally prescribed to treat high blood pressure or arrhythmia, may increase bicalutamide efficacy. However, although adrenergic activation plays a role in the development of androgen independence, other factors will also confer a survival advantage for cancer cells. These include the activation of the MAPK and AKT signaling pathways, which have been linked to adrenergic signaling in other diseases (13); it will be important to consider these in the development of treatment strategies.

Hassan et al. also demonstrated that immobilization stress accelerated the occurrence of premalignant lesions in the Hi-Myc model (9). Although additional work is needed before there is conclusive proof that behavioral stress can induce cancer onset, these observations provide a fertile ground upon which further studies can be developed to investigate the effect of behavioral stress on cancer initiation.

Clinical studies have shown that in socially isolated ovarian cancer patients, intratumoral levels of norepinephrine were higher than levels in patients with greater social support, whereas the plasma levels were similar between the two groups (15). Here, the authors showed that systemic levels of epinephrine and norepinephrine were higher during stress in the animal models of prostate cancer (9). Furthermore, 12 of 62 prostate cancer patients had elevated epinephrine levels in blood. However, the authors did not show any correlation of blood and intratumor epinephrine levels, outcomes, or progression markers. Ideally, tumor tissue should be used to assess catecholamine levels at the level of the tumor microenvironment, as tissue levels are more likely to adequately reflect catecholamine activity relevant to tumor growth and are likely to be more stable than plasma levels due to the acidic tumor microenvironment. Among the important results from this study is the identification of ADRB downstream signaling as a potential predictive factor for patients likely to gain benefit from adjuvant beta blocker therapy while receiving androgen ablation therapy.

Although the current study provides a new mechanistic understanding of the effects of stress on cancer progression, there remain many unanswered questions with regard to such effects. Among these is the identification of specific patient subsets that are most likely to benefit from interventions targeted against stress-related pathways. Whether such subsets should be identified based on behavioral and/or molecular features is currently unknown. Moreover, identifying reliable downstream markers to test the efficacy of stress-based interventions may allow a more rational selection of therapies. Much like cancer, stress pathways are extremely complex, and it is unclear whether SNS-targeted interventions will be sufficient or whether blocking other pathways, such as HPA mediators or inflammation, will also be required. Addressing these and other questions will be an important component of realizing the full translational potential of the preclinical findings presented in this and other research. Nevertheless, the field continues to rapidly evolve, and novel signaling mechanisms are being discovered that provide a deeper understanding of the effects of behavioral stress on tumor biology. The present study moves the field forward by demonstrating that behavioral stress enables prostate cancer cells to evade apoptosis, an important characteristic in the process of tumor growth and metastasis. In addition, the authors provide a new understanding of mechanisms by which prostate cancer cells could acquire resistance to androgen therapy.

The authors are supported by NIH grants (CA140933, CA104825, CA109298, P50CA083639, P50CA098258, CA128797, U54CA151668), an Ovarian Cancer Research Fund Program Project Development Grant, the Department of Defense (OC073399, W81XWH-10-1-0158, OC100237), the Betty Ann Asche Murray Distinguished Professorship, the Marcus Foundation, and the Blanton-Davis Ovarian Cancer Research Program.

Address correspondence to: Anil K. Sood, Departments of Gynecologic Oncology and Cancer Biology, The University of Texas MD Anderson Cancer Center, Unit 1362, PO Box 301439, Houston, Texas 77230-1439, USA. Phone: 713.745.5266; Fax: 713.792.7586; E-mail: asood@mdanderson.org.

Conflict of interest: The authors have declared that no conflict of interest exists.

Reference information: J Clin Invest. 2013;123(2):558–560. doi:10.1172/JCI67887.

See the related article at Behavioral stress accelerates prostate cancer development in mice.

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