Biobehavioral Influences on Matrix Metalloproteinase Expression in Ovarian Carcinoma

Department of Psychology, University of Iowa, Iowa City, Iowa 52242, USA.
Clinical Cancer Research (Impact Factor: 8.72). 11/2008; 14(21):6839-46. DOI: 10.1158/1078-0432.CCR-08-0230
Source: PubMed


Stromal cells in the tumor microenvironment, such as macrophages, play an active role in tumor growth and angiogenesis. However, little is known about relationships of biobehavioral factors with angiogenic cytokines and matrix metalloproteinases (MMP) produced by stromal cells. This study examined distress, MMPs, and angiogenic cytokines in ovarian cancer patients and in vitro.
Patients suspected of ovarian cancer completed preoperative questionnaires. At surgery, 56 were confirmed to have epithelial ovarian cancer. Tumor samples were analyzed for macrophage (CD68(+)) and tumor cell levels of MMP-2, MMP-9, and vascular endothelial growth factor. In vitro stimulation of isolated macrophage cells by the stress hormones norepinephrine and cortisol was done to assess effects on MMP-9.
Depressed patients showed significant elevations of MMP-9 in CD68(+) cells, adjusting for stage (P<0.0001). Patients with higher levels of current stress (P=0.01), life stress over the last 6 months (P=0.004), and general negative affect (P=0.007) also showed significantly greater MMP-9 in CD68(+) cells. In contrast, higher social support was associated with lower levels of MMP-9 (P=0.023) and vascular endothelial growth factor (P=0.036) in tumor cells. In vitro analyses showed that macrophage MMP-9 production could be directly enhanced (up to a 2-fold increase) by the stress hormones norepinephrine and cortisol.
Ovarian cancer patients with elevated depressive symptoms, chronic stress, and low social support showed elevations in MMP-9 in tumor-associated macrophages. Direct in vitro enhancement of stromal MMP-9 production by stress hormones was also shown. These findings may have implications for patient outcomes in ovarian cancer.

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Available from: Frank Penedo, Aug 28, 2014
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    • "Regarding the mechanisms connecting stress and cancer progression, most of the early studies concentrated on the indirect effects of stress through immunosuppression in cancer patients (1-3). Recently, it has been reported that the stress-related hormones norepinephrine (NE) and epinephrine, especially NE, can directly induce gene expression and are involved in angiogenesis and metastasis in cancer progression in a variety of cancer cell lines (4-8), stromal cells (9), and immortalized epithelial cell lines (10). Several epidemiological studies have demonstrated that chronic stress may accelerate the progression of gastric cancer (11-13). "
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    ABSTRACT: In the current literature, there is evidence that psychological factors can affect the incidence and progression of some cancers. Interleukin 6 (IL-6) is known to be elevated in individuals experiencing chronic stress and is also involved in oncogenesis and cancer progression. However, the precise mechanism of IL-6 induction by the stress-related hormone norepinephrine (NE) is not clear, and, furthermore, there are no reports about the effect of NE on IL-6 expression in gastric epithelial cells. In this study, we examined the effect of NE on IL-6 expression in immortalized human gastric epithelial cells (GES-1 cells). Using real-time PCR and enzyme-linked immunoassay, we demonstrated that NE can induce IL-6 mRNA and protein expression in GES-1 cells. The induction is through the β-adrenergic receptor-cAMP-protein kinase A pathway and mainly at the transcriptional level. Progressive 5'-deletions and site-directed mutagenesis of the parental construct show that, although activating-protein-1 (AP-1), cAMP-responsive element binding protein (CREB), CCAAT-enhancer binding protein-β (C/EBP-β), and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) binding sites are all required in the basal transcription of IL-6, only AP-1 and CREB binding sites in the IL-6 promoter are required in NE-induced IL-6 expression. The results suggest that chronic stress may increase IL-6 secretion of human gastric epithelial cells, at least in part, by the stress-associated hormone norepinephrine, and provides basic data on stress and gastric cancer progression.
    Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.] 02/2014; 47(2):101-9. DOI:10.1590/1414-431X20133346 · 1.01 Impact Factor
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    • "But administration of ␤-adrenoceptor antagonist, propranolol could completely abrogate the secretion of these factors and their mediated functions, implying that ␤-blockers have potential therapeutic value for the management of relevant cancers. Furthermore, Lutgendorf et al. [48] illuminated that noradrenaline not only induced the increase of MMP-9 and VEGF in ovarian cancer cells but also stimulated the secretion of MMP-9 in macrophages isolated from ovarian cancer specimens . It has been shown that tumour associated macrophages (TAM) and MMP9 released by TAM play an essential role in angiogenesis through presenting VEGF access to relevant receptors on endothelial cells and degrading extracellular matrix to release other pro-angiogenic factors [49] [50]. "
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    ABSTRACT: β-Adrenoceptors are broadly distributed in various tissues of the body. Stress hormones regulate a panel of important physiological functions and disease states including cancer. Nicotine and its derivatives could stimulate the release of stress hormones from cancer cells, leading to the promotion of cancer development. β-blockers have been widely used to control hypertension for decades. Recently, these agents could have significant implications in cancer therapy through blockade of adrenoceptors in tumor tissues. In this review, we summarize recent advancements about the influence of stress hormones, nicotine and β-adrenoceptors on cancer cell proliferation, apoptosis, invasion and metastasis, and also tumor vasculature normalization. Relevant signal pathways and potential value of β-blockers in the treatment of cancer are also discussed in this review.
    Seminars in Cancer Biology 09/2013; 23(6). DOI:10.1016/j.semcancer.2013.08.009 · 9.33 Impact Factor
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    • "Indeed, exploratory analyses suggested that women with higher levels of cancer-related hyperarousal experienced more psychological and physical symptoms at baseline and over time. Intrusive thoughts may also lead to increased activity in neuroendocrine and immunologic stress pathways (Lutgendorf et al., 2008; Andersen et al., 1998; Mundy-Bosse, Thornton, Yang, Andersen, & Carson, 2011), with potential effects on depressive symptoms, fatigue, and other sickness behaviors (Bower, 2008). Future research should explore psychological and biological mechanisms through which cognitive disruptions may increase the experience of physical symptoms. "
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    ABSTRACT: Objective: Behavioral symptoms are common in breast cancer survivors, including disturbances in energy, sleep, and mood, though few risk factors for these negative outcomes have been identified. Our study examined intrusive thoughts as a predictor of lingering symptoms in breast cancer survivors in the year following treatment. Method: Data come from the Moving Beyond Cancer psychoeducational intervention trial, aimed at easing the transition from patient to survivor. Women (n = 558) completed psychosocial questionnaires within 4 weeks posttreatment and again 2, 6, and 12 months later. We examined intrusive thoughts about cancer at the baseline assessment as a predictor of fatigue, sleep problems, pain, breast cancer-specific symptoms, depressive symptoms, negative affect, and quality of life using growth curve modeling, controlling for study condition and other covariates. Results: Intrusive thoughts were associated with higher levels of all symptoms at baseline and at the 12-month assessment. Intrusive thoughts also influenced the trajectory of pain, depressive symptoms, negative affect, and physical functioning over time; women with higher intrusions at baseline started worse and improved over time, whereas those with lower intrusions remained at a constant, lower level over time. Intrusions were not associated with the trajectory of fatigue, sleep, breast cancer-specific symptoms, or mental functioning; women with higher intrusions at baseline started worse and remained worse over time. Conclusion: Intrusive thoughts are associated with enduring elevations in behavioral symptoms and impaired quality of life in the year after breast cancer treatment and may be a risk factor for poor outcomes.
    Health Psychology 02/2013; 33(2). DOI:10.1037/a0031131 · 3.59 Impact Factor
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