Endothéline-1, angiotensine II et cancer

L’endothéline-1 (ET-1) et l’angiotensine II (AngII) sont des peptides vasoactifs, mais aussi mitogènes et pro-angiogéniques. Tous deux exercent leurs actions par l’intermédiaire de récepteurs couplés aux protéines G : ETA-R et ETB-R pour ET-1 ; AT1R et AT2R pour AngII. L’expression des composants des systèmes ET-1 et AngII dans diverses tumeurs présente généralement une ou plusieurs des caractéristiques suivantes : surexpression du peptide et/ou du récepteur, modification du sous-type de récepteur exprimé et localisation nucléaire du récepteur. ET-1 et AngII agissent sur les différentes étapes de la progression tumorale, et l’utilisation d’antagonistes spécifiques de leurs récepteurs, ou d’inhibiteurs de leur synthèse, est efficace pour ralentir la croissance tumorale in vitro et in vivo dans différents modèles animaux. Des essais cliniques utilisant des antagonistes d’ETA-R donnent des résultats encourageants pour le traitement antitumoral, et une approche similaire ayant pour objectif de bloquer ETB-R ou AT1R est envisageable. De plus, une thérapie combinée ciblant les deux systèmes, ET-1 et AngII, pourrait se révéler bénéfique pour le traitement de tumeurs fortement angiogéniques.Endothelin-1 (ET-1) and angiotensin II (AngII), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (ETA-R and ETB-R for ET-1, AT1R and AT2R for AngII) that all belong to the superfamily of G-protein coupled receptors. There is increasing evidence that ETA-R, ETB-R and AT1R are expressed in a variety of cancer cells and tissues, and may play a role on tumor growth, angiogenesis and invasion in vivo. This review summarizes the similarities and differences between the ET-1 and AngII systems with regard to their reported effects on various aspects of cancer. In addition to being expressed on vascular endothelium, ET-1 and AngII receptors participate in tumor angiogenesis through the production of the angiogenic factor VEGF. Furthermore, recent clinical studies indicate that a selective ETA-R antagonist has beneficial effects in prostate cancer, suggesting that a similar approach using ETB-R and AT1R blockers might be envisioned. Experimental data presented here suggest that a combined therapy targeting both ET-1 and AngII systems may prove valuable for future treatments of highly angiogenic tumors

The blood-brain barrier in brain homeostasis and neurological diseases

AbstractBrain endothelial cells are unique among endothelial cells in that they express apical junctional complexes, including tight junctions, which quite resemble epithelial tight junctions both structurally and functionally. They form the blood-brain-barrier (BBB) which strictly controls the exchanges between the blood and the brain compartments by limiting passive diffusion of blood-borne solutes while actively transporting nutrients to the brain. Accumulating experimental and clinical evidence indicate that BBB dysfunctions are associated with a number of serious CNS diseases with important social impacts, such as multiple sclerosis, stroke, brain tumors, epilepsy or Alzheimer's disease. This review will focus on the implication of brain endothelial tight junctions in BBB architecture and physiology, will discuss the consequences of BBB dysfunction in these CNS diseases and will present some therapeutic strategies for drug delivery to the brain across the BBB

8p22 MTUS1 Gene Product ATIP3 Is a Novel Anti-Mitotic Protein Underexpressed in Invasive Breast Carcinoma of Poor Prognosis

BACKGROUND: Breast cancer is a heterogeneous disease that is not totally eradicated by current therapies. The classification of breast tumors into distinct molecular subtypes by gene profiling and immunodetection of surrogate markers has proven useful for tumor prognosis and prediction of effective targeted treatments. The challenge now is to identify molecular biomarkers that may be of functional relevance for personalized therapy of breast tumors with poor outcome that do not respond to available treatments. The Mitochondrial Tumor Suppressor (MTUS1) gene is an interesting candidate whose expression is reduced in colon, pancreas, ovary and oral cancers. The present study investigates the expression and functional effects of MTUS1 gene products in breast cancer. METHODS AND FINDINGS: By means of gene array analysis, real-time RT-PCR and immunohistochemistry, we show here that MTUS1/ATIP3 is significantly down-regulated in a series of 151 infiltrating breast cancer carcinomas as compared to normal breast tissue. Low levels of ATIP3 correlate with high grade of the tumor and the occurrence of distant metastasis. ATIP3 levels are also significantly reduced in triple negative (ER- PR- HER2-) breast carcinomas, a subgroup of highly proliferative tumors with poor outcome and no available targeted therapy. Functional studies indicate that silencing ATIP3 expression by siRNA increases breast cancer cell proliferation. Conversely, restoring endogenous levels of ATIP3 expression leads to reduced cancer cell proliferation, clonogenicity, anchorage-independent growth, and reduces the incidence and size of xenografts grown in vivo. We provide evidence that ATIP3 associates with the microtubule cytoskeleton and localizes at the centrosomes, mitotic spindle and intercellular bridge during cell division. Accordingly, live cell imaging indicates that ATIP3 expression alters the progression of cell division by promoting prolonged metaphase, thereby leading to a reduced number of cells ungergoing active mitosis. CONCLUSIONS: Our results identify for the first time ATIP3 as a novel microtubule-associated protein whose expression is significantly reduced in highly proliferative breast carcinomas of poor clinical outcome. ATIP3 re-expression limits tumor cell proliferation in vitro and in vivo, suggesting that this protein may represent a novel useful biomarker and an interesting candidate for future targeted therapies of aggressive breast cancer

Etude structurale et fonctionnelle de la proteine kinase C-gamma: approche immunochimique

SIGLEINIST T 77561 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Fonctions de la protéine prion PrP

Les maladies à prion (scrapie du mouton, maladie de la vache folle, maladie de Creutzfeldt- Jakob chez l’homme) impliquent les deux isoformes, normale PrPc et pathologique ou scrapie PrPsc, de la protéine prion. La protéine PrPc est fortement exprimée dans le système nerveux central (neurones, cellules gliales) mais est aussi présente dans les cellules du système immunitaire, et les cellules épithéliales et endothéliales. Des études récentes permettent de classer les fonctions de la PrPc en deux grands domaines : (1) la survie cellulaire et (2) l’adhérence cellulaire, celle-ci étant liée à différentes fonctions selon le type cellulaire (neuritogenèse, intégrité des barrières épithéliale et endothéliale, migration transendothéliale de monocytes, activation de lymphocytes T). Ces observations suggèrent des fonctions de la PrPc importantes notamment en situations de stress cellulaire inflammatoire et d’infection

Overexpression of CD44 in neural precursor cells improves trans-endothelial migration and facilitates their invasion of perivascular tissues in vivo.

Neural precursor (NPC) based therapies are used to restore neurons or oligodendrocytes and/or provide neuroprotection in a large variety of neurological diseases. In multiple sclerosis models, intravenously (i.v) -delivered NPCs reduced clinical signs via immunomodulation. We demonstrated recently that NPCs were able to cross cerebral endothelial cells in vitro and that the multifunctional signalling molecule, CD44 involved in trans-endothelial migration of lymphocytes to sites of inflammation, plays a crucial role in extravasation of syngeneic NPCs. In view of the role of CD44 in NPCs trans-endothelial migration in vitro, we questioned presently the benefit of CD44 overexpression by NPCs in vitro and in vivo, in EAE mice. We show that overexpression of CD44 by NPCs enhanced over 2 folds their trans-endothelial migration in vitro, without impinging on the proliferation or differentiation potential of the transduced cells. Moreover, CD44 overexpression by NPCs improved significantly their elongation, spreading and number of filopodia over the extracellular matrix protein laminin in vitro. We then tested the effect of CD44 overexpression after i.v. delivery in the tail vein of EAE mice. CD44 overexpression was functional invivo as it accelerated trans-endothelial migration and facilitated invasion of HA expressing perivascular sites. These in vitro and in vivo data suggest that CD44 may be crucial not only for NPC crossing the endothelial layer but also for facilitating invasion of extravascular tissues

Effect of NPC delivery on EAE clincial features.

<p>Intravenous delivery of control (light grey) and CD44-NPCs (dark grey) in the tail vein after disease onset significantly improves clinical features over sham (black) in EAE mice. While clinical signs reach a plateau more rapidly after the first peak in CD44-NPC treated animals differences in severity between control and CD44-NPCs are not observed.</p

Effects of CD44 overexpression on trans-endothelial migration and spreading <i>in vitro</i>.

<p>(A, B) Trans-endothelial migration of actin eGFP CD44-NPCs (+) and control NPCs (-); quantification was performed using immunofluorescence for (A) eGFP or (B) c-myc. In response to SDF1α cells overexpressing CD44 migrate 2 fold more compared to control cells (experiments made in triplicate). (C, D) Spreading of NPCs <i>in vitro</i> on laminin: the number and length of filopodia are increased. (E, F) CD44 overexpressing cells are more elongated and spread than control NPCs. (* = p<0.5; ** = p<0.01, *** = p<0.01). (G) Immunocytochemistry for actin illustrating filopodia (arrowheads) in control-NPCs (Gi, Gii) and CD44-NPCs (Giii, Giv).</p