Effects of tumour hypoxia on cell migration
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