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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    • "Recent experimental evidence suggests that dysregulated stress hormones such as cortisol and catecholamines, which have been observed in depressed patients, may promote growth and progression of ovarian cancer via stress-mediated pathways[13,14]. Several observational studies in ovarian cancer patients also showed a poorer prognosis and shorter survival associated with higher levels of depression or stress15161718. However, whether depression is associated with an increased risk of ovarian cancer remains unknown. "
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    ABSTRACT: Objectives: While emerging evidence supports a possible link between depression and ovarian cancer progression, no prospective studies have explored the association with ovarian cancer risk. Methods: We prospectively followed 77 451 women from the Nurses' Health Study (1992-2010) and 106 452 women from the Nurses' Health Study II (1993-2011). Depression was defined as having one or more of the following: a 5-item Mental Health Index (MHI-5) score≤52, antidepressant use, or physician-diagnosed depression. Multivariate-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between depression and incident ovarian cancer. Results: We documented 698 incident cases of epithelial ovarian cancer during follow-up. In multivariable analyses, depression assessed 2-4years before cancer diagnosis was associated with a modestly higher incidence of ovarian cancer (HR=1.30, 95% CI1.05-1.60). Compared to women with persistent negative depression status, the adjusted HRs were 1.34 (95% CI 1.01-1.76) for women with persistent positive depression status and 1.28 (95% CI 0.88-1.85) for women with worsening depression status over follow-up. The association did not appear to vary by ovarian cancer risk factors or tumor characteristics. Conclusions: Our findings suggest that depression may be associated with a modestly increased risk of ovarian cancer. Given the relatively high prevalence of depression in women, future work in larger prospective human studies is needed to confirm our results.
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    • "However, the role of psychosocial factor implicated in CAD, in elevation of MMPs, has received little scientific attention. It has been reported that psychosocial factors like hostility and depression are positively associated with MMP-9 levels (Lutgendorf et al., 2008), and that sense of coherence (a resilience factor reflecting comprehensibility, manageability and meaningfulness), is associated with decreases in MMP-9, in a middle aged normal population (Garvin et al., 2009). In contrast, Jönsson et al. (2014) reported that there were no relationships between depressive mood and MMP-9 expression in patients after AMI. "
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    ABSTRACT: Objective: To evaluate the relationships between hostility, perceived stress and social support with MMPs activity in patients after an Acute Myocardial Infarction (AMI). Methods: Blood samples were obtained from 76 patients on admission, post-angioplasty, 24h, 7 days and 3 months after AMI. Hostility, perceived stress and social support were evaluated by validated questionnaires. Results: Social support was positively correlated with patientś ejection fraction (r=0.453, p=0.009). Patients with higher infarct size presented increased MMP-2 activity at admission (p=0.04). Patients with one diseased vessel had more social support than those with three diseased vessels (p=0.05). The highest values of MMP-2 and MMP-9 activity were observed at the acute event, decreasing, with the lowest activity at 3 months post-AMI (p<0.001). Only in patients with low social support, hostility correlated with MMP-2 activity, from AMI onset (r=0.645, p=0.013), to 7 days post AMI (r=0.557, p=0.038). Hostility explained up to 28% of the variance in MMP-2 activity (R(2)=0.28, p=0.005). Finally, in patients with high hostility, MMP-9 was positively correlated with IL-1β (r=0.468, p=0.02). Conclusions: This study adds weight to the idea that two psychosocial factors, namely hostility and social support, acting jointly, may affect MMP-2 activity. Moreover, in hostile patients, there is a link between IL-1β and MMP-9. These findings support the role of psychosocial factors in plaque destabilization and in the inflammatory process in AMI.
    No preview · Article · Oct 2015 · Psychoneuroendocrinology
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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.
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