Hypoxia Negatively Regulates Antimetastatic PEDF in Melanoma Cells by a Hypoxia Inducible Factor-Independent, Autophagy Dependent Mechanism

Pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor (SERPIN) superfamily, displays a potent antiangiogenic and antimetastatic activity in a broad range of tumor types. Melanocytes and low aggressive melanoma cells secrete high levels of PEDF, while its expression is lost in highly aggressive melanomas. PEDF efficiently abrogates a number of functional properties critical for the acquisition of metastatic ability by melanoma cells, such as neovascularization, proliferation, migration, invasiveness and extravasation. In this study, we identify hypoxia as a relevant negative regulator of PEDF in melanocytes and low aggressive melanoma cells. PEDF was regulated at the protein level. Importantly, although downregulation of PEDF was induced by inhibition of 2-oxoglutarate-dependent dioxygenases, it was independent of the hypoxia inducible factor (HIF), a key mediator of the adaptation to hypoxia. Decreased PEDF protein was not mediated by inhibition of translation through untranslated regions (UTRs) in melanoma cells. Degradation by metalloproteinases, implicated on PEDF degradation in retinal pigment epithelial cells, or by the proteasome, was also excluded as regulatory mechanism in melanoma cells. Instead, we found that degradation by autophagy was critical for PEDF downregulation under hypoxia in human melanoma cells. Our findings show that hypoxic conditions encountered during primary melanoma growth downregulate antiangiogenic and antimetastasic PEDF by a posttranslational mechanism involving degradation by autophagy and could therefore contribute to the acquisition of highly metastatic potential characteristic of aggressive melanoma cells

ICES PGCCDBS Report 2010, ICES Advisory Committee, ICES CM 2010/ACOM:39 - Report of the Planning Group on Commercial Catches, Discards and Biological Sampling (PGCCDBS)

The Planning Group on Commercial Catches, Discards and Biological Sampling [PGCCDBS] (Co-Chairs: Christoph Stransky, Germany, and Kjell Nedreaas, Norway) met 1¿5 March 2010 in Lisbon, Portugal. The Planning Group and workshops are proposed in response to the EC-ICES Memorandum of Understanding that requests ICES to provide support for the Data Collection Framework (DCF; EC Reg. 199/2008 and 665/2008, Decisions 2008/949/EC and 2010/93/EU). PGCCDBS is the ICES forum for planning and co-ordination of collection of data for stock assessment purposes; it coordinates and initiates the development of methods and adopts sampling stan-dards and guidelines. Many activities in this group are closely linked to the activities of the DCF, and DG MARE of the European Commission is a member of PGCCDBS to ensure coordination with the DCF activities. Stock assessment requires data cover-ing the total removal from the fish stocks and the PG serves as a forum for coordina-tion with non-EU member countries where appropriate. Since 2007, Mediterranean scientists have organised a Mediterranean Planning Group for Methodological De-velopment (PGMED) to deal with specific sampling issues of this area. Although or-ganised in an autonomous group, it was agreed among all scientists that the contact and cooperation between the Mediterranean area the ICES area should be promoted and maintained. The link between the two planning groups is maintained through: (i) the organisation of parallel meetings; (ii) the organisation of joint plenary sessions for generic issues, and (iii) the organisation of joint workshops.JRC.DG.G.4-Maritime affair

Loss of pigment epithelium-derived factor enables migration, invasion and metastatic spread of human melanoma

Pigment epithelium-derived factor (PEDF) is a multifunctional secreted glycoprotein that displays broad anti-tumor activity based on dual targeting of the tumor microenvironment (anti-angiogenic action) and the tumor cells (direct anti-tumor action). Here, we show that PEDF expression is high in melanocytes, but it is lost during malignant progression of human melanoma. Using a high-throughput analysis of the data from microarray studies of molecular profiling of human melanoma, we found that PEDF expression is lost in highly invasive melanomas. In paired cell lines established from the same lesion but representing the high and low extremes of malignant potential, abundant PEDF expression was restricted to the poorly aggressive counterparts. We used RNA interference to directly address the functional consequences of PEDF silencing. PEDF knockdown in poorly aggressive melanoma cell lines augmented migration, invasion and vasculogenic mimicry, which translated into an increased in vivo metastatic potential. PEDF interference also significantly enhanced the migratory and invasive capability of normal melanocytes and moderately increased their proliferative potential. Our results show that loss of PEDF enables melanoma cells to acquire an invasive phenotype and, therefore, modulation of this multifunctional factor could be critical for the malignant progression of human melanoma