Effect of Inhibition of the Lysophosphatidic Acid Receptor 1 on Metastasis and Metastatic Dormancy in Breast Cancer

Background Previous studies identified the human nonmetastatic gene 23 (NME1, hereafter Nm23-H1) as the first metastasis suppressor gene. An inverse relationship between Nm23-H1 and expression of lysophosphatidic acid receptor 1 gene (LPAR1, also known as EDG2 or hereafter LPA1) has also been reported. However, the effects of LPA1 inhibition on primary tumor size, metastasis, and metastatic dormancy have not been investigated. Methods The LPA1 inhibitor Debio-0719 or LPA1 short hairpinned RNA (shRNA) was used. Primary tumor size and metastasis were investigated using the 4T1 spontaneous metastasis mouse model and the MDA-MB-231T experimental metastasis mouse model (n = 13 mice per group). Proliferation and p38 intracellular signaling in tumors and cell lines were determined by immunohistochemistry and western blot to investigate the effects of LPA1 inhibition on metastatic dormancy. An analysis of variance-based two-tailed t test was used to determine a statistically significant difference between treatment groups. Results In the 4T1 spontaneous metastasis mouse model, Debio-0719 inhibited the metastasis of 4T1 cells to the liver (mean = 25.2 liver metastases per histologic section for vehicle-treated mice vs 6.8 for Debio-0719-treated mice, 73.0% reduction, P < .001) and lungs (mean = 6.37 lesions per histologic section for vehicle-treated mice vs 0.73 for Debio-0719-treated mice, 88.5% reduction, P < .001), with no effect on primary tumor size. Similar results were observed using the MDA-MB-231T experimental pulmonary metastasis mouse model. LPA1 shRNA also inhibited metastasis but did not affect primary tumor size. In 4T1 metastases, but not primary tumors, expression of the proliferative markers Ki67 and pErk was reduced by Debio-0719, and phosphorylation of the p38 stress kinase was increased, indicative of metastatic dormancy. Conclusion The data identify Debio-0719 as a drug candidate with metastasis suppressor activity, inducing dormancy at secondary tumor site

Les solidarités à l'épreuve des crises

Notre système de protection sociale n'a pas échappé aux réformes engagées en Europe dans le contexte de crise. Il est perçu à la fois comme un rempart à la crise et comme un obstacle à une reprise économique. Les auteurs tentent donc de comprendre comment ces différentes idées pénètrent les réalités des solidarités publiques et privées

Weakening link to colorectal cancer ?

The catalytic α-subunit of the enzyme phosphatidylinositol-3-OH kinase (PI(3)Kα) relays signals from G- protein-coupled receptors at the cell membrane and mediates leukocyte responses to chemokines and chemoattractants1, 2, ³. Sasaki et al.⁴ report that mice that cannot produce PI(3)Kα have a high incidence of colorectal carcinomas, causing weight loss and premature death. However, PI(3)Kα-null mouse strains have been independently generated in three other laboratories; none of these mice developed tumours and their weight and lifespan were normal. This casts coubt on the idea that loss of functional PI(3)Kα leads directly to transformation of colon epithelial cells and tumour progression

Critères pharmacologiques d'un médicament pour la substitution de la pharmacodépendance aux opiacés

Nous proposons une définition actualisée des caractéristiques pharmacologiques minimales d'un médicament pouvant être prescrit dans le traitement de la pharmacodépendance aux opiacés. Ces nouveaux critères sont au nombre de six : (i) avoir les mêmes propriétés pharmacodynamiques que le produit à substituer; (ii) avoir une durée d'action longue (minimum 24 dvimheures, ne nécessitant pas plusieurs prises par jour) de façon à éviter les fluctuations d'effet et en particulier les signes et les symptômes de manque ; (iii) générer peu d'euphorie et avoir peu d'effet renforçateur pour le produit lui-même et les autres drogues; (iv) s'administrer par voie orale ou sublinguale et ne pas comporter d'attrait particulier pour les autres voies, en particulier intraveineuse; (v) avoir une autorisation de mise sur le marché (AMM) dans cette indication, établie à partir d'un dossier d'enregistrement comportant à la fois des données d'activité thérapeutique (essais comparatifs avec tirage au sort) et de sécurité clinique ; et (vi) être compatible avec une qualité de vie sociale satisfaisante. Nous discutons ensuite l'application de ces critères à la méthadone, la buprénorphine et à d'autres médicaments proposés dans le traitement de la pharmacodépendance aux opiacés

Chloroplast envelope membranes: a dynamic interface between plastids and the cytosol.

Chloroplasts are bounded by a pair of outer membranes, the envelope, that is the only permanent membrane structure of the different types of plastids. Chloroplasts have had a long and complex evolutionary past and integration of the envelope membranes in cellular functions is the result of this evolution. Plastid envelope membranes contain a wide diversity of lipids and terpenoid compounds serving numerous biochemical functions and the flexibility of their biosynthetic pathways allow plants to adapt to fluctuating environmental conditions (for instance phosphate deprivation). A large body of knowledge has been generated by proteomic studies targeted to envelope membranes, thus revealing an unexpected complexity of this membrane system. For instance, new transport systems for metabolites and ions have been identified in envelope membranes and new routes for the import of chloroplast-specific proteins have been identified. The picture emerging from our present understanding of plastid envelope membranes is that of a key player in plastid biogenesis and the co-ordinated gene expression of plastid-specific protein (owing to chlorophyll precursors), of a major hub for integration of metabolic and ionic networks in cell metabolism, of a flexible system that can divide, produce dynamic extensions and interact with other cell constituents. Envelope membranes are indeed one of the most complex and dynamic system within a plant cell. In this review, we present an overview of envelope constituents together with recent insights into the major functions fulfilled by envelope membranes and their dynamics within plant cells