Glucocorticoids promote breast cancer metastasis

Diversity within or between tumours and metastases (known as intra-patient tumour heterogeneity) that develops during disease progression is a serious hurdle for therapy(1-3). Metastasis is the fatal hallmark of cancer and the mechanisms of colonization, the most complex step in the metastatic cascade(4), remain poorly defined. A clearer understanding of the cellular and molecular processes that underlie both intra-patient tumour heterogeneity and metastasis is crucial for the success of personalized cancer therapy. Here, using transcriptional profiling of tumours and matched metastases in patient-derived xenograft models in mice, we show cancer-site-specific phenotypes and increased glucocorticoid receptor activity in distant metastases. The glucocorticoid receptor mediates the effects of stress hormones, and of synthetic derivatives of these hormones that are used widely in the clinic as anti-inflammatory and immunosuppressive agents. We show that the increase in stress hormones during breast cancer progression results in the activation of the glucocorticoid receptor at distant metastatic sites, increased colonization and reduced survival. Our transcriptomics, proteomics and phospho-proteomics studies implicate the glucocorticoid receptor in the activation of multiple processes in metastasis and in the increased expression of kinase ROR1, both of which correlate with reduced survival. The ablation of ROR1 reduced metastatic outgrowth and prolonged survival in preclinical models. Our results indicate that the activation of the glucocorticoid receptor increases heterogeneity and metastasis, which suggests that caution is needed when using glucocorticoids to treat patients with breast cancer who have developed cancer-related complications.Peer reviewe

Nitric oxide, thyroglobulin, and calcitonin: unraveling the nature of thyroid nodules

BackgroundThyroid nodules (TN) are localized morphological changes in the thyroid gland and can be benign or malignant.ObjectiveThe present study investigates the relationships between biochemical markers in serum (s) and their homologs in washout (w) after fine-needle aspiration biopsy (FNAB) of the TN of interest and their correlation with cytology specimen findings.MethodsWe investigated the relationships between serum biochemical markers nitric oxide (NO), thyroglobulin (TG), and calcitonin (CT), their homologs in washout after FNAB of the TN of interest, and cytology findings of biopsy samples classified according to the Bethesda system for thyroid cytopathology in this study, which included 86 subjects.ResultsWashout TG (TGw) level positively correlates with the cytology finding of the biopsy. A higher level of TGw correlates with higher categories of the Bethesda classification and indicates a higher malignant potential. The levels of serum NO (NOs), serum TG (TGs), serum CT (CTs), and washout CT (CTw) do not correlate with the cytology finding of the biopsy, and the higher levels of washout NO (NOw) correspond to the more suspicious ultrasound findings.ConclusionThe findings of our study suggest that TGw and NOw could be used as potential predictors of malignancy in TN

Phytochemical profiles and antioxidant activities of Serbian table and wine grapes

International audienceThree table grapes and 4 wine grapes collected from a southern Serbian vineyard were evaluated and compared for their antioxidant properties and phenolic profile. Among the varieties tested, 'Cabernet Sauvignon' contained the highest total phenolic content with 173.6 mg/100 g of fresh weight. Also, the total flavonoid and antocyanin content of 'Cabernet Sauvignon' was significantly higher from the other. 'Cabernet Sauvignon' and 'Merlot' had the strongest DPPH center dot radicals scavenging activity (1,318.6 and 1,282.0 mu mol Trolox equivalent/100 g, respectively). 'Cabernet Sauvignon', 'Merlot', 'Prokupac', 'Vranac', 'Muscat Hamburg', and 'Ribier' grape varieties were found to be rich in malvidin-3-O-glucoside, while 'Cardinal' grape variety was found to be rich in peonidin-3-O-glucoside. The following compounds were also identified and quantified using HPLC-DAD: 2 flavan-3-ols and 4 hydroxycinnamic acids in all grape samples. The results suggested that phytochemicals in the selected table and wine grapes have potent antioxidant activities in correlation with phenolic content

A new role of AMP-activated protein kinase in regulating proliferation of mesenchymal stem cells

Purpose: Natriuretic peptides (NPs) administered during early reperfusion are protective in models of myocardial infarction. A previous study examining the endogenous components of B-type natriuretic peptide (BNP) protection of reperfused myocardium, implicated both sarcolemmal (s) KATP and mitochondrial (m) KATP channels. The indirect evidence characterising the relationship between BNP signalling and KATP was obtained using sulphonylurea receptor inhibitors in a rat isolated heart model of ischaemia-reperfusion injury. Here we seek to further examine the relationship between NPs and sKATP openings using single channel electrophysiology. Given our previous findings and the overarching consensus that cardioprotective autacoids open KATP channels, it was hypothesised that NPs elicit sKATP opening. Methods: Cardiomyocyte isolation. Left ventricular cardiomyocytes were isolated from male Sprague-Dawley rat hearts subjected to enzymatic digestion with Liberase Blendzyme DL. Cardiomyocytes were cultured overnight in Medium 199, prior to patch clamp. Single channel patch clamp. Single channel recordings at room temperature (22°C) were made from cell attached patches bathed in Na+ Locke, pH 7.2. The recording pipette contained high KCl (140 mM), pH 7.2. Recordings (45 sec) were made over a range of patch potentials (0, -30, -60, -90, -120 mV), in the absence (control) and in the presence of bath applied BNP (10, 100 nM and 1 µM), pinacidil (200 µM) or pinacidil vehicle (DMSO, 0.25%). Recordings were also made with BNP and pinacidil applied concomitantly. Data are mean ± S.E.M. Results: The current voltage relationship of sKATP under control conditions was linear at –ve patch potentials, the mean conductance being 52.9 ± 1.8 pS (n = 18 hearts, n = 35 cells). Pinacidil caused a four fold increase in sKATP open probability compared to control. Mean channel conductance in the presence of pinacidil was 59.9 ± 1.9 pS (n = 16 hearts, n = 44 cells). Interestingly BNP at all concentrations had negligible effects on sKATP open probability and unitary conductance. However, BNP at all concentrations and patch potentials inhibited pinacidil induced sKATP openings, restoring channel open probability to baseline. Conclusion: These data illustrate the inhibitory effect of NP signalling on sKATP function in the cardiomyocyte under normoxia. They are concordant with the inhibitory effect of atrial NP on KATP in the pancreatic beta cell, but are in apparent conflict with the current cardioprotection paradigm. However, differential effects on sKATP and mKATP and the effects of hypoxia-reoxygenation require further exploration