Tissue Factor Regulation by Epidermal Growth Factor Receptor and Epithelial-to-Mesenchymal Transitions: Effect on Tumor Initiation and Angiogenesis

ErbB oncogenes drive the progression of several human cancers. Our study shows that in human carcinoma (A431) and glioma (U373) cells, the oncogenic forms of epidermal growth factor receptor (EGFR; including EGFRvIII) trigger the up-regulation of tissue factor (TF), the transmembrane protein responsible for initiating blood coagulation and signaling through interaction with coagulation factor VIIa. We show that A431 cancer cells in culture exhibit a uniform TF expression profile; however, these same cells in vivo exhibit a heterogeneous TF expression and show signs of E-cadherin inactivation, which is coupled with multilineage (epithelial and mesenchymal) differentiation. Blockade of E-cadherin in vitro, leads to the acquisition of spindle morphology and de novo expression of vimentin, features consistent with epithelial-to-mesenchymal transition. These changes were associated with an increase in EGFR-dependent TF expression, and with enhanced stimulation of vascular endothelial growth factor production, particularly following cancer cell treatment with coagulation factor VIIa. In vivo, cells undergoing epithelial-to-mesenchymal transition exhibited an increased metastatic potential. Furthermore, injections of the TF-blocking antibody (CNTO 859) delayed the initiation of A431 tumors in immunodeficient mice, and reduced tumor growth, vascularization, and vascular endothelial growth factor expression. Collectively, our data suggest that TF is regulated by both oncogenic and differentiation pathways, and that it functions in tumor initiation, tumor growth, angiogenesis, and metastasis. Thus, TF could serve as a therapeutic target in EGFR-dependent malignancies

Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme

In glioblastoma multiforme, the most common adult primary brain tumor, the glycolytic enzyme hexokinase 2 facilitates growth and therapeutic resistance

Applying mass spectrometry based proteomic technology to advance the understanding of multiple myeloma

Abstract Multiple myeloma (MM) is the second most common hematological malignancy in adults. It is characterized by clonal proliferation of terminally differentiated B lymphocytes and over-production of monoclonal immunoglobulins. Recurrent genomic aberrations have been identified to contribute to the aggressiveness of this cancer. Despite a wealth of knowledge describing the molecular biology of MM as well as significant advances in therapeutics, this disease remains fatal. The identification of biomarkers, especially through the use of mass spectrometry, however, holds great promise to increasing our understanding of this disease. In particular, novel biomarkers will help in the diagnosis, prognosis and therapeutic stratification of MM. To date, results from mass spectrometry studies of MM have provided valuable information with regards to MM diagnosis and response to therapy. In addition, mass spectrometry was employed to study relevant signaling pathways activated in MM. This review will focus on how mass spectrometry has been applied to increase our understanding of MM

RNAseq analysis for the diagnosis of muscular dystrophy

Abstract The precise genetic cause remains elusive in nearly 50% of patients with presumed neurogenetic disease, representing a significant barrier for clinical care. This is despite significant advances in clinical genetic diagnostics, including the application of whole‐exome sequencing and next‐generation sequencing‐based gene panels. In this study, we identify a deep intronic mutation in the DMD gene in a patient with muscular dystrophy using both conventional and RNAseq‐based transcriptome analyses. The implications of our data are that noncoding mutations likely comprise an important source of unresolved genetic disease and that RNAseq is a powerful platform for detecting such mutations

La violence

Qu’elle soit verbale. gestuelle ou intellectuelle, la violence interpelle. Hier comme aujourd'hui, elle reste un enjeu majeur et une préoccupation quotidienne de l'ensemble des acteurs sociaux et politiques tout comme des professionnels du droit. Pourtant, ce paradigme de violence, polysémique. d'une définition souvent floue, s'avère d'une analyse difficile et nécessite une approche plurielle, capable d'interroger à la fois la société, la religion, le droit et la politique, en Europe et dans le reste du monde, du Moyen Âge au xxe siècle. En adoptant cette méthode, qui autorise une lecture à variable multiple des formes de la violence, les vingt-neuf chercheurs ici réunis proposent des interprétations, des hypothèses et des résultats stimulants et fructueux, dans des champs aussi divers que ceux de l'histoire, de l'histoire de l'art, de la gender history, de la littérature, de l'histoire des idées et de l'anthropologie. Les études rassemblées dans ce volume prêtent une attention toute particulière aux cas singuliers et collectifs, ainsi qu'à l'acteur face au « système » existant (social, politique, religieux, économique), en mesure de saisir réellement ce phénomène pluriel sur un plan à la fois diachronique et synchronique. Aussi la violence, dans ses configurations multiples, dévoile-t-elle les réponses données par les autorités - religieuses et laïques -. la famille, la parenté, le voisinage, la communauté, les intellectuels, les artistes, les compositeurs entre le Moyen Age et l’époque contemporaine