Impact of stress on cancer metastasis

Department of Gynecologic Oncology, UTMD Anderson Cancer Center, 1155 Herman Pressler, Houston, TX 77030, USA.
Future Oncology (Impact Factor: 2.48). 12/2010; 6(12):1863-81. DOI: 10.2217/fon.10.142
Source: PubMed


The influence of psychosocial factors on the development and progression of cancer has been a longstanding hypothesis since ancient times. In fact, epidemiological and clinical studies over the past 30 years have provided strong evidence for links between chronic stress, depression and social isolation and cancer progression. By contrast, there is only limited evidence for the role of these behavioral factors in cancer initiation. Recent cellular and molecular studies have identified specific signaling pathways that impact cancer growth and metastasis. This article provides an overview of the relationship between psychosocial factors, specifically chronic stress, and cancer progression.

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    • "Stressor exposure, for example, can exacerbate the symptoms of many diseases including anxiety (Vinkers et al., 2008), depression (Charney and Manji, 2004), multiple sclerosis (Mei-Tal et al., 1970), irritable bowl syndrome (Mayer et al., 2001), diabetes (Black, 2006), obesity (Bose et al., 2009) and cardiovascular disease (Hartel, 1987; Pickering, 2001). In addition, intense or exhaustive stress can increase vulnerability to illness after exposure to infectious pathogens (Kiecolt-Glaser et al., 1996; Pedersen et al., 2010) and increase cancer metastasis (Dhabhar et al., 2012; Moreno-Smith et al., 2010). "

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    • "This finding in our study provided the basis for following research on the β-AR/cAMP/PKA pathway in B16F1 cells. Considering ARs play a key role mediating the effect on tumors induced by chronic stress and endow tumor cells the potential to respond to neurotransmitters, few scholars suggest the receptor-based interference of intracellular ARs signaling pathway as a new approach to resist this effect [9,42,67,68]. Powe et al. [69] found, in breast cancer, β2-AR strongly immunoreactive in cases with a luminal phenotype and good clinic outcome while α1b-AR and α2c-AR over-expressed in basal-like phenotypes of poor prognosis. So ARs might be supposed to be potential predictors for survival and probable indicators for targeted therapy with AR blockers. "
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    ABSTRACT: Sunitinib alone exhibits satisfactory efficacy in several mouse homografts and xenografts but unsatisfactory efficacy in many kinds of solid tumors in clinic. Different from animals, receiving a diagnosis of cancer impacts chronic stress on patients. Here, we examine whether norepinephrine (NE), one of the most potent stress related hormones, leads to the difference in the efficacy of sunitinib between clinical and preclinical trials. The influence of NE on mouse melanoma B16F1 cells under sunitinib was evaluated in vitro and in vivo. The beta-AR/cAMP/PKA (beta-adrenoceptor/cyclic adenosine monophosphate/protein kinase A) signaling pathway was also evaluated in human lung adenocarcinoma cells. We found that NE upregulated the expression of VEGF, IL-8 and IL-6 in vitro and stimulated tumor growth in vivo, which was mediated by beta-AR/cAMP/PKA signaling pathway and could be inhibited by propranolol, a beta-blocker for hypertension for decades. This research indicates exogenous norepinephrine attenuates the efficacy of sunitinib, and a combination of sunitinib and propranolol might be suggested as a new strategy in solid tumor in clinic.
    Journal of Experimental & Clinical Cancer Research 02/2014; 33(1):21. DOI:10.1186/1756-9966-33-21 · 4.43 Impact Factor
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    • "Glucocorticoids (such as dexamethasone) are widely used in cancer therapy and may have cell type-specific pro- or antiapoptotic effects, although when applied at high therapeutic doses their anti-tumor effects prevail [34]. Nevertheless there are very limited data regarding possible direct effects of stress hormones, at in vivo pathophysiological levels, on cancer cell proliferation [49]. Some early findings in leukemia research suggested a possible link between GSH and glucocorticoids effects in cancer cells [50]. "
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    ABSTRACT: Background Interleukin (IL)-6 (mainly of tumor origin) activates glutathione (GSH) release from hepatocytes and its interorgan transport to B16-F10 melanoma metastatic foci. We studied if this capacity to overproduce IL-6 is regulated by cancer cell-independent mechanisms. Methods Murine B16-F10 melanoma cells were cultured, transfected with red fluorescent protein, injected i.v. into syngenic C57BL/6J mice to generate lung and liver metastases, and isolated from metastatic foci using high-performance cell sorting. Stress hormones and IL-6 levels were measured by ELISA, and CRH expression in the brain by in situ hybridization. DNA binding activity of NF-κB, CREB, AP-1, and NF-IL-6 was measured using specific transcription factor assay kits. IL-6 expression was measured by RT-PCR, and silencing was achieved by transfection of anti-IL-6 small interfering RNA. GSH was determined by HPLC. Cell death analysis was distinguished using fluorescence microscopy, TUNEL labeling, and flow cytometry techniques. Statistical analyses were performed using Student’s t test. Results Plasma levels of stress-related hormones (adrenocorticotropin hormone, corticosterone, and noradrenaline) increased, following a circadian pattern and as compared to non-tumor controls, in mice bearing B16-F10 lung or liver metastases. Corticosterone and noradrenaline, at pathophysiological levels, increased expression and secretion of IL-6 in B16-F10 cells in vitro. Corticosterone- and noradrenaline-induced transcriptional up-regulation of IL-6 gene involves changes in the DNA binding activity of nuclear factor-κB, cAMP response element-binding protein, activator protein-1, and nuclear factor for IL-6. In vivo inoculation of B16-F10 cells transfected with anti-IL-6-siRNA, treatment with a glucocorticoid receptor blocker (RU-486) or with a β-adrenoceptor blocker (propranolol), increased hepatic GSH whereas decreased plasma IL-6 levels and metastatic growth. Corticosterone, but not NORA, also induced apoptotic cell death in metastatic cells with low GSH content. Conclusions Our results describe an interorgan system where stress-related hormones, IL-6, and GSH coordinately regulate metastases growth.
    Journal of Translational Medicine 03/2013; 11(1):72. DOI:10.1186/1479-5876-11-72 · 3.93 Impact Factor
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