The Tumor Coagulome as a Transcriptional Target and a Potential Effector of Glucocorticoids in Human Cancers.

BACKGROUND: The coagulome, defined as the repertoire of genes that locally regulate coagulation and fibrinolysis, is a key determinant of vascular thromboembolic complications of cancer. In addition to vascular complications, the coagulome may also regulate the tumor microenvironment (TME). Glucocorticoids are key hormones that mediate cellular responses to various stresses and exert anti-inflammatory effects. We addressed the effects of glucocorticoids on the coagulome of human tumors by investigating interactions with Oral Squamous Cell Carcinoma, Lung Adenocarcinoma, and Pancreatic Adenocarcinoma tumor types. METHODS: We analyzed the regulation of three essential coagulome components, i.e., the tissue factor (TF), urokinase-type plasminogen activator (uPA), and plasminogen activator inhibitor-1 (PAI-1) in cancer cell lines exposed to specific agonists of the glucocorticoid receptor (GR) (dexamethasone and hydrocortisone). We used QPCR, immunoblots, small-interfering RNA, Chromatin immunoprecipitation sequencing (ChIPseq) and genomic data from whole tumor and single-cell analyses. RESULTS: Glucocorticoids modulate the coagulome of cancer cells through a combination of indirect and direct transcriptional effects. Dexamethasone directly increased PAI-1 expression in a GR-dependent manner. We confirmed the relevance of these findings in human tumors, where high GR activity/high SERPINE1 expression corresponded to a TME enriched in active fibroblasts and with a high TGF-ß response. CONCLUSION: The transcriptional regulation of the coagulome by glucocorticoids that we report may have vascular consequences and account for some of the effects of glucocorticoids on the TME.

High-temperature oxidation and reduction of the inverse ceria/Cu(111) catalyst characterized by LEED, STM, nc-AFM and KPFM.

The inverse catalyst 'cerium oxide (ceria) on copper' has attracted much interest in recent time because of its promising catalytic activity in the water-gas-shift reaction and the hydrogenation of CO2. For such reactions it is important to study the redox behaviour of this system, in particular with respect to the reduction by H2. Here, we investigate the high-temperature O2oxidation and H2reduction of ceria nanoparticles (NPs) and a Cu(111) support by low energy electron diffraction (LEED), scanning tunnelling microscopy (STM), non-contact atomic force microscopy (nc-AFM) and Kelvin probe force microscopy (KPFM). After oxidation at 550 °C, the ceria NPs and the Cu(111) support are fully oxidized, with the copper oxide exhibiting a new oxide structure as verified by LEED and STM. We show that a high H2dosage in the kilo Langmuir range is needed to entirely reduce the copper support at 550 °C. A work function (WF) difference of △ϕrCeria/Cu-Cu≈ -0.6 eV between the ceria NPs and the metallic Cu(111) support is measured, with the Cu(111) surface showing no signatures of separated and confined surface regions composed by an alloy of Cu and Ce. After oxidation, the WF difference is close to zero (△ϕCeria/Cu-Cu≈ -0.1…0 eV), which probably is due to a WF change of both, ceria and copper.