Notch3 is activated by chronic hypoxia and contributes to the progression of human prostate cancer.

Prostate cancer (PC) is still the second cause of cancer-related death among men. Although patients with metastatic presentation have an ominous outcome, the vast majority of PCs are diagnosed at an early stage. Nonetheless, even among patients with clinically localized disease the outcome may vary considerably. Other than androgen sensitivity, little is known about which other signaling pathways are deranged in aggressive, localized cancers. The elucidation of such pathways may help to develop innovative therapies aimed at specific molecular targets. We report that in a hormone-sensitive PC cell line, LNCaP, Notch3 was activated by hypoxia and sustained cell proliferation and colony formation in soft agar. Hypoxia also modulated cellular cholesterol content and the number and size of lipid rafts, causing a coalescence of small rafts into bigger clusters; under this experimental condition, Notch3 migrated from the non-raft into the raft compartment where it colocalized with the γ-secretase complex. We also looked at human PC biopsies and found that expression of Notch3 positively correlated with Gleason score and with expression of carbonic anhydrase IX, a marker of hypoxia. In conclusion, hypoxia triggers the activation of Notch3, which, in turn, sustains proliferation of PC cells. Notch3 pathway represents a promising target for adjuvant therapy in patients with PC.

Adiponectin, diabetes and ischemic heart failure: a challenging relationship.

BACKGROUND: Several peptides, named adipokines, are produced by the adipose tissue. Among those, adiponectin (AD) is the most abundant. AD promotes peripheral insulin sensitivity, inhibits liver gluconeogenesis and displays anti-atherogenic and anti-inflammatory properties. Lower levels of AD are related to a higher risk of myocardial infarction and a worse prognosis in patients with coronary artery disease. However, despite a favorable clinical profile, AD increases in relation to worsening heart failure (HF); in this context, higher adiponectinemia is reliably related to poor prognosis. There is still little knowledge about how certain metabolic conditions, such as diabetes mellitus, modulate the relationship between AD and HF.We evaluated the level of adiponectin in patients with ischemic HF, with and without type 2 diabetes, to elucidate whether the metabolic syndrome was able to influence the relationship between AD and HF. RESULTS: We demonstrated that AD rises in patients with advanced HF, but to a lesser extent in diabetics than in non-diabetics. Diabetic patients with reduced systolic performance orchestrated a slower rise of AD which began only in face of overt HF. The different behavior of AD in the presence of diabetes was not entirely explained by differences in body mass index. In addition, NT-proBNP, the second strongest predictor of AD, did not differ significantly between diabetic and non-diabetic patients. These data indicate that some other mechanisms are involved in the regulation of AD in patients with type 2 diabetes and coronary artery disease. CONCLUSIONS: AD rises across chronic heart failure stages but this phenomenon is less evident in type 2 diabetic patients. In the presence of diabetes, the progressive increase of AD in relation to the severity of LV dysfunction is hampered and becomes evident only in overt HF.

Mutant p53-dependent mitochondrial metabolic alterations in a mesenchymal stem cell-based model of progressive malignancy.

It is well accepted that malignant transformation is associated with unique metabolism. Malignant transformation involves a variety of cellular pathways that are associated with initiation and progression of the malignant process that remain to be deciphered still. Here we used a mouse model of mutant p53 that presents a stepwise progressive transformation of adult Mesenchymal Stem Cells (MSCs). While the established parental p53Mut-MSCs induce tumors, the parental p53WT-MSCs that were established in parallel, did not. Furthermore, tumor lines derived from the parental p53Mut-MSCs (p53Mut-MSC-TLs), exhibited yet a more aggressive transformed phenotype, suggesting exacerbation in tumorigenesis. Metabolic tracing of these various cell types, indicated that while malignant transformation is echoed by a direct augmentation in glycolysis, the more aggressive p53Mut-MSC-TLs demonstrate increased mitochondrial oxidation that correlates with morphological changes in mitochondria mass and function. Finally, we show that these changes are p53Mut-dependent. Computational transcriptional analysis identified a mitochondrial gene signature specifically downregulated upon knock/out of p53Mut in MSC-TLs. Our results suggest that stem cells exhibiting different state of malignancy are also associated with a different quantitative and qualitative metabolic profile in a p53Mut-dependent manner. This may provide important insights for cancer prognosis and the use of specific metabolic inhibitors in a personalized designed cancer therapy.

A Mutant p53-Dependent Embryonic Stem Cell Gene Signature Is Associated with Augmented Tumorigenesis of Stem Cells.

Mutations in the tumor suppressor p53 are the most frequent alterations in human cancer. These mutations include p53-inactivating mutations as well as oncogenic gain-of-function (GOF) mutations that endow p53 with capabilities to promote tumor progression. A primary challenge in cancer therapy is targeting stemness features and cancer stem cells (CSC) that account for tumor initiation, metastasis, and cancer relapse. Here we show that in vitro cultivation of tumors derived from mutant p53 murine bone marrow mesenchymal stem cells (MSC) gives rise to aggressive tumor lines (TL). These MSC-TLs exhibited CSC features as displayed by their augmented oncogenicity and high expression of CSC markers. Comparative analyses between MSC-TL with their parental mutant p53 MSC allowed for identification of the molecular events underlying their tumorigenic properties, including an embryonic stem cell (ESC) gene signature specifically expressed in MSC-TLs. Knockout of mutant p53 led to a reduction in tumor development and tumorigenic cell frequency, which was accompanied by reduced expression of CSC markers and the ESC MSC-TL signature. In human cancer, MSC-TL ESC signature-derived genes correlated with poor patient survival and were highly expressed in human tumors harboring p53 hotspot mutations. These data indicate that the ESC gene signature-derived genes may serve as new stemness-based prognostic biomarkers as well as novel cancer therapeutic targets.Significance: Mesenchymal cancer stem cell-like cell lines express a mutant p53-dependent embryonic stem cell gene signature, which can serve as a potential prognostic biomarker and therapeutic target in cancer. Cancer Res; 78(20); 5833-47. ©2018 AACR.

External Cardioversion of Atrial Fibrillation Causes an Early Improvement of Cardiac Performance: A Longitudinal Strain Analysis Study.

INTRODUCTION: Atrial fibrillation (AF) is often associated with heart failure. Several studies have demonstrated that resumption of sinus rhythm (SR) improves cardiac output in the long-term. Aims of this study were to evaluate the acute variations of left ventricular (LV) performance, following successful external cardioversion (ECV) of persistent AF using longitudinal strain (LSt) analysis, and the influence of inflammation. MATERIALS AND METHODS: We enrolled 48 patients with AF (age: 73 ± 12 years, men: 83.3%). A standard transthoracic echocardiographic evaluation was performed before the procedure and 6 h later; this included the analysis of LV endocardial peak LSt, a measure of myocardial deformation. In the last 32 patients, plasma concentration of interleukin-6 (IL-6) was also determined. RESULTS: Restoration of SR led to the decrease of heart rate (HR) (74 ± 21 vs 64 ± 10 bpm, P < 0.001) and LV end-systolic volume (30 ± 16 vs 27 ± 17 mL/m2, P = 0.001), and to the increase of LV end-diastolic volume (LVEDV) (56 ± 20 vs 60 ± 21 mL/m2, P = 0.036) and ejection fraction (EF) (48 ± 10 vs 57 ± 11%, P < 0.001). Peak LSt improved in 43 (89.6%) patients (-12.9 ± 3.3 vs -18.0 ± 4.7%, P < 0.001). Multivariate analysis (R = 0.729, P < 0.001) showed that strain changes were directly correlated with basal HR and the appearance of atrial mechanical activity and inversely correlated with corrected thyroid dysfunction, LVEDV and the presence of a permanent pacemaker. Higher levels of IL-6 negatively affected LV performance improvement. CONCLUSIONS: Effective ECV of AF determines a significant and fast improvement of LV performance, which is readily captured by LSt analysis. Inflammatory status may impact the response to SR restoration.

Notch signaling modulates hypoxia-induced neuroendocrine differentiation of human prostate cancer cells.

UNLABELLED: Prostate carcinoma is among the most common causes of cancer-related death in men, representing 15% of all male malignancies in developed countries. Neuroendocrine differentiation (NED) has been associated with tumor progression, poor prognosis, and with the androgen-independent status. Currently, no successful therapy exists for advanced, castration-resistant disease. Because hypoxia has been linked to prostate cancer progression and unfavorable outcome, we sought to determine whether hypoxia would impact the degree of neuroendocrine differentiation of prostate cancer cells in vitro. RESULTS: Exposure of LNCaP cells to low oxygen tension induced a neuroendocrine phenotype, associated with an increased expression of the transcription factor neurogenin3 and neuroendocrine markers, such as neuron-specific enolase, chromogranin A, and ß3-tubulin. Moreover, hypoxia triggered a significant decrease of Notch 1 and Notch 2 mRNA and protein expression, with subsequent downregulation of Notch-mediated signaling, as shown by reduced levels of the Notch target genes, Hes1 and Hey1. NED was promoted by attenuation of Hes1 transcription, as cells expressing a dominant-negative form of Hes1 displayed increased levels of neuroendocrine markers under normoxic conditions. Although hypoxia downregulated Notch 1 and Notch 2 mRNA transcription and receptor activation also in the androgen-independent cell lines, PC-3 and Du145, it did not change the extent of NED in these cultures, suggesting that androgen sensitivity may be required for transdifferentiation to occur. CONCLUSIONS: Hypoxia induces NED of LNCaP cells in vitro, which seems to be driven by the inhibition of Notch signaling with subsequent downregulation of Hes1 transcription.

Glucagon-like peptide-1, diabetes, and cognitive decline: possible pathophysiological links and therapeutic opportunities.

Metabolic and neurodegenerative disorders have a growing prevalence in Western countries. Available epidemiologic and neurobiological evidences support the existence of a pathophysiological link between these conditions. Glucagon-like peptide 1 (GLP-1), whose activity is reduced in insulin resistance, has been implicated in central nervous system function, including cognition, synaptic plasticity, and neurogenesis. We review the experimental researches suggesting that GLP-1 dysfunction might be a mediating factor between Type 2 diabetes mellitus (T2DM) and neurodegeneration. Drug treatments enhancing GLP-1 activity hold out hope for treatment and prevention of Alzheimer's disease (AD) and cognitive decline.