Identification of MAGI1 as a tumor-suppressor protein induced by cyclooxygenase-2 inhibitors in colorectal cancer cells.

Cyclooxyganase-2 (COX-2), a rate-limiting enzyme in the prostaglandin synthesis pathway, is overexpressed in many cancers and contributes to cancer progression through tumor cell-autonomous and paracrine effects. Regular use of non-steroidal anti-inflammatory drugs or selective COX-2 inhibitors (COXIBs) reduces the risk of cancer development and progression, in particular of the colon. The COXIB celecoxib is approved for adjunct therapy in patients with Familial adenomatous polyposis at high risk for colorectal cancer (CRC) formation. Long-term use of COXIBs, however, is associated with potentially severe cardiovascular complications, which hampers their broader use as preventive anticancer agents. In an effort to better understand the tumor-suppressive mechanisms of COXIBs, we identified MAGUK with Inverted domain structure-1 (MAGI1), a scaffolding protein implicated in the stabilization of adherens junctions, as a gene upregulated by COXIB in CRC cells and acting as tumor suppressor. Overexpression of MAGI1 in CRC cell lines SW480 and HCT116 induced an epithelial-like morphology; stabilized E-cadherin and ß-catenin localization at cell-cell junctions; enhanced actin stress fiber and focal adhesion formation; increased cell adhesion to matrix proteins and suppressed Wnt signaling, anchorage-independent growth, migration and invasion in vitro. Conversely, MAGI1 silencing decreased E-cadherin and ß-catenin localization at cell-cell junctions; disrupted actin stress fiber and focal adhesion formation; and enhanced Wnt signaling, anchorage-independent growth, migration and invasion in vitro. MAGI1 overexpression suppressed SW480 and HCT116 subcutaneous primary tumor growth, attenuated primary tumor growth and spontaneous lung metastasis in an orthotopic model of CRC, and decreased the number and size of metastatic nodules in an experimental model of lung metastasis. Collectively, these results identify MAG1 as a COXIB-induced inhibitor of the Wnt/ß-catenin signaling pathway, with tumor-suppressive and anti-metastatic activity in experimental colon cancer.

Developing a European grid infrastructure for cancer research: vision, architecture and services.

Life sciences are currently at the centre of an information revolution. The nature and amount of information now available opens up areas of research that were once in the realm of science fiction. During this information revolution, the data-gathering capabilities have greatly surpassed the data-analysis techniques. Data integration across heterogeneous data sources and data aggregation across different aspects of the biomedical spectrum, therefore, is at the centre of current biomedical and pharmaceutical R&D.This paper reports on original results from the ACGT integrated project, focusing on the design and development of a European Biomedical Grid infrastructure in support of multi-centric, post-genomic clinical trials (CTs) on cancer. Post-genomic CTs use multi-level clinical and genomic data and advanced computational analysis and visualization tools to test hypotheses in trying to identify the molecular reasons for a disease and the stratification of patients in terms of treatment.The paper provides a presentation of the needs of users involved in post-genomic CTs and presents indicative scenarios, which drive the requirements of the engineering phase of the project. Subsequently, the initial architecture specified by the project is presented, and its services are classified and discussed. A range of such key services, including the Master Ontology on sCancer, which lie at the heart of the integration architecture of the project, is presented. Special efforts have been taken to describe the methodological and technological framework of the project, enabling the creation of a legally compliant and trustworthy infrastructure. Finally, a short discussion of the forthcoming work is included, and the potential involvement of the cancer research community in further development or utilization of the infrastructure is described.