| Summary: | Cell adaptation to hypoxia requires activation of transcriptional programs that coordinate expression of genes involved in oxygen delivery (via- angiogenesis) and metabolic adaptation (via glycolisis). During migration and invasion of normal and pathological tissues, cells may encounter different oxygen levels, due to poor or altered vascularization, and recent evidence has suggested that chemotaxis is a cell function which may be affected by oxygen availability. This thesis describes how oxygen avaibility is a determinant parameter in the setting of chemotactic responsiveness to Stromal-Derived Factor 1 (SDF-1, CXCL12). Low oxygen concentration induces high expression of the CXCL12 receptor CXCR4, in different cell types (monocytes, monocyte-derived macrophages, tumor associated macrophages, endothelial cells, cancer cells and dendritic cells) as both mRNA and protein expression, which is paralleled by increased chemotactic responsiveness to its specific ligand. Furthermore, preliminary results on dendritic cells (DC) show that hypoxia may affect their maturation (CCR7'°'/CCR5h'gh) and functions. In particular, hypoxia-derived DC do not migrate in response to the CCR7 ligand CCL 19, while they do express higher levels of pro-inflammatory cytokines (IL-12, TNF-a), as compared to normoxia-derived DC. CXCR4 induction by hypoxia is dependent on both activation of hypoxia-inducible factor 1 (HIF-la) and transcript stabilization. Our data identify the hypoxia/HIF-1/CXCR4 pathway as a relevant molecular circuit in the functional tuning of the chemokine system and provide novel insights into the mechanisms controlling cell migration in hypoxic regions, with potential relevance in the pathogenesis of human diseases, including chronic inflammatory diseases and cancer
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