Using a matrix degradation assay, we found that furin colocalize at invadopodia sites with its substrate MT1-MMP under hypoxic conditions. This is associated with an increase in both formation and functions of invadopodia. To better characterize the impact of hypoxia on the invadopodia formation, we next demonstrate that overexpression of furin increases the number of invadopodia and their capacity to degrade ECM. Furthermore, the inhibition of furin

with PDX or the MT1-MMP Epigenetics inhibitor inhibitor click here GM6001 decreases invadopodia numbers and functions. This is correlated with a decrease in cell invasion in a 3D assay. Our results suggest that hypoxia promotes the formation of a peripheral processing

compartment in which furin is concentrated for enhanced processing of substrate involved in the formation of invadopodia leading to cell invasion. Poster No. 55 Insulin-like Growth Factor II (IGF-II) Enhances Tumor Progression and Stroma Activation in a Model of Skin Squamous Cell Carcinoma (SCC) Renate Becker 1 , Martina Oehme1, Carolin Bürck1, Margareta M. Mueller1 1 Tumor and Microenvironment, German Cancer Research Center, Heidelberg, Germany The loss of growth control is one important characteristic of tumor progression. This can be a consequence of a reduced dependence of the tumor cells on growth-stimulatory factors and/or of a decreased sensitivity to growth-inhibitory factors and can be caused by an aberrant expression of growth factors and their receptors. A progression NVP-BSK805 concentration model for human skin squamous cell carcinoma (SCC) based on the keratinocyte cell line HaCaT was used to elucidate the molecular basis of this increasing environment-independent tumor growth. This model system includes ras-transfected and in vivo passaged cells forming tumors of all stages of tumor progression, ranging from benign to late stage malignant and metastasizing tumors. Using a cDNA array comparing the transcriptome of the benign

HaCaT-ras A-5 and the high-grade malignant HaCaT-ras A-5RT3 cells, 67 differentially regulated cytokines, growth factors and receptors were identified. Among these differentially expressed genes, Insulin-like Acyl CoA dehydrogenase Growth Factor II (IGF-II) was shown to be up-regulated associated with increasing tumor malignancy. Stimulation of the benign HaCaT-ras A-5 cells with recombinant IGF-II resulted in increased proliferation and migration/invasion in cell monolayer and in 3-D skin organotypic culture (OTC). The stable IGF-II over-expressing HaCaT-ras A-5 transfectant E2 (A-5E2) demonstrated a proliferation stimulating phenotype leading to a highly increased epithelial growth and differentiation in comparison to the control transfected HaCaT-ras A-5 clone SV3 (A-5SV3) in skin OTCs in vitro as well as in transplantation assays in vivo.