Invited Minireview
The influence of glucocorticoid signaling on tumor progression

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Abstract

The diagnosis of cancer elicits a broad range of well-characterized stress-related biobehavioral responses. Recent studies also suggest that an individual’s neuroendocrine stress response can influence tumor biology. One of the major physiological pathways altered by the response to unrelenting social stressors is the hypothalamic–pituitary–adrenal or HPA axis. Initially following acute stress exposure, an increased glucocorticoid response is observed; eventually, chronic stress exposure can lead to a blunting of the normal diurnal cortisol pattern. Interestingly, recent evidence also links high primary tumor glucocorticoid receptor expression (and associated increased glucocorticoid-mediated gene expression) to more rapid estrogen-independent breast cancer progression. Furthermore, animal models of human breast cancer suggest that glucocorticoids inhibit tumor cell apoptosis. These findings provide a conceptual basis for understanding the molecular mechanisms underlying the influence of the individual’s stress response, and specifically glucocorticoid action, on breast cancer and other solid tumor biology. How this increased glucocorticoid signaling might contribute to cancer progression is the subject of this review.

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► The influence of glucocorticoid signaling on tumor progression: A mini-review on the current literature.

Introduction

The human biobehavioral response to stressors includes physiological changes that are initiated through an individual’s interaction with the social environment. In response to these environmental stressors, including social stressors, well-defined physiological changes occur at the organismal level. These changes can be buffered by social support networks, thereby mitigating the deleterious effects of the stress response. However, when life’s stressors are unrelenting and social support or other resources (e.g. financial resources) are insufficient, neuroendocrine pathways can become deregulated. It is this deregulation of physiological pathways that underlies the mechanisms whereby psychosocial stressors are hypothesized to influence the biology of chronic disease.

Cardiovascular and immune-related diseases have long served as examples of the stress response-disease relationship (Black and Garbutt, 2002, Stojanovich and Marisavljevich, 2008). More recent studies have begun to explore connections between psychosocial factors and cancer biology. Indeed, recent clinical, epidemiological, and animal-based studies suggest there is a biobehavioral influence on tumor progression (Armaiz-Pena et al., 2009, Costanzo et al., 2011). However, evidence for the impact of psychosocial factors on cancer initiation (rather than progression) has been less consistent (Costanzo et al., 2011). Nevertheless, it is well-established that neuroendocrine hormones (e.g. glucocorticoids and noradrenaline) can and do influence cancer biology (Armaiz-Pena et al., 2009). Thus, the fact that significant stress exposure can lead to deregulation of the neuroendocrine axis has led to further investigation into the effects of psychosocial factors on cancer biology as outlined below.

There are several neuroendocrine cell signaling mechanisms, executed downstream of both the adrenal and sympathetic systems, which could contribute to cancer growth. Recent reviews have outlined some neuroendocrine–cancer relationships and have extensively outlined neuroendocrine influences on the immune system (Armaiz-Pena et al., 2009, Costanzo et al., 2011). The immune system has well-established and important roles in the progression of some cancer types (e.g. melanoma and renal cell carcinoma); however, its role in other cancers is less well understood. The overall impact of the immune system on cancer biology [reviewed in (Grivennikov et al., 2010)] and specifically, the social stress-induced modulation of immunity are reviewed extensively elsewhere (Armaiz-Pena et al., 2009, Costanzo et al., 2011).

This review instead focuses specifically on glucocorticoids (GCs), steroid hormones that are either secreted from the adrenal gland during exposure to acute and chronic stressors or administered pharmacologically to reduce inflammation, and the role of GC signaling in epithelial cancer biology. We discuss potential mechanisms through which endogenous GCs (cortisol in humans and corticosterone in rodents) may influence cancer progression. These data suggest that the routine pharmacological use of synthetic GCs in some cancer treatment may not be optimal. Furthermore, we explore how psychosocial mechanisms might intersect with both systemic and tumor microenvironmental GC action to increase tumor progression.

Section snippets

Cortisol

The active GC in humans, cortisol, is produced and secreted by the adrenal cortex. Cortisol release into the circulation has important systemic roles in modulating metabolic and immune processes; cortisol also elicits cell-type-specific effects, some of which are discussed in detail below. Release of cortisol from the adrenal gland is regulated by the hypothalamic–pituitary–adrenal (HPA) axis, a biological circuit capable of integrating human experience with physiological signaling. In the

Pharmacological glucocorticoids and the role of GR activation in cancer

The potential for divergent GR activity in different cell types is striking when comparing GC effects on lymphocytic malignancies versus epithelial cell-derived cancers. In the former case, synthetic GCs, such as dexamethasone (DEX), are routinely used to induce apoptotic cell death in malignant lymphoid cells (e.g. lymphoma). Conversely, in epithelial (i.e. “solid”) tumors, several reports suggest that GCs have the opposite effect: GCs stimulate anti-apoptotic gene expression and antagonize

Endogenous glucocorticoids, stress response, and cancer progression

“Transdisciplinary” approaches apply expertise in two or more disciplines to a complex problem (Gehlert et al., 2010). For example, both psychology and cancer biology disciplines were recently applied to develop animal models that allow for in-depth analyses of stress responsiveness and tumor biology (Williams et al., 2009). This approach is beginning to uncover the molecular underpinnings linking the psychosocial stress response to cancer. For example, female Sprague–Dawley rats have an

Cancer-promoting effects of GCs in the tumor microenvironment

GC-mediated mechanisms influencing solid tumor progression are not limited to the effects of GCs directly on tumor cells. Tumor progression involves simultaneous interactions between the cancer cell, the microenvironment that supports the cancer cell’s proliferation, the host and the individual’s environment (Fig. 1). Neuroendocrine pathways have diverse targets. Indeed, nearly every mammalian tissue is believed to express the GR. Thus, attempting to integrate stress physiology with aspects of

Conflict of Interest

Dr. Conzen has a patent application pending proposing the use of glucocorticoid receptor antagonism in breast cancer. There is no financial conflict of interest.

Acknowledgments

We thank members of the SD Conzen, MJ Brady and MK McClintock laboratories for valuable discussions. This work is supported by RO1 CA148814 (SDC), the Avon Foundation (SDC) and W81XWH-07-1-0296 (PAV).

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