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¹ Istituto di Ricerche Farmacologiche Mario Negri, 20157 Milan, Italy
² Centro di Eccellenza per l'Innovazione Diangnostica e Terapeutica, Institute of Pathology, State University of Milan, 20133 Milan, Italy
³ Institute for Research in Biomedicine, Bellinzona, CH6500 Switzerland
⁴ Institute of Pathology, Department of Clinical Sciences L. Sacco, University of Milan, 20157 Milan, Italy
⁵ Development Therapeutic Program, Tumor Hypoxia Laboratory, Science Applications International Corporation-Frederick, Inc., National Cancer Institute, Frederick, MD 21702

Address correspondence to Antonio Sica, Istituto di Ricerche Farmacologiche Mario Negri, via Eritrea 62, 20157 Milan, Italy. Phone: 39-02-2390-14530; Fax: 39-02-2332-00231; email: sica{at}marionegri.it; or Giovanni Melillo, Development Therapeutic Program, Tumor Hypoxia Laboratory, Science Applications International Corporation-Frederick, Inc., National Cancer Institute, Frederick, MD 21701. Phone: (301) 846-5050; Fax: (301) 846-6081; email: melillo{at}dtpax2.ncifcrf.gov

Cell adaptation to hypoxia (Hyp) requires activation of transcriptional programs that coordinate expression of genes involved in oxygen delivery (via angiogenesis) and metabolic adaptation (via glycolysis). Here, we describe that oxygen availability is a determinant parameter in the setting of chemotactic responsiveness to stromal-derived factor 1 (CXCL12). Low oxygen concentration induces high expression of the CXCL12 receptor, CXC receptor 4 (CXCR4), in different cell types (monocytes, monocyte-derived macrophages, tumor-associated macrophages, endothelial cells, and cancer cells), which is paralleled by increased chemotactic responsiveness to its specific ligand. CXCR4 induction by Hyp is dependent on both activation of the Hyp-inducible factor 1 and transcript stabilization. In a relay multistep navigation process, the Hyp–Hyp-inducible factor 1 –CXCR4 pathway may regulate trafficking in and out of hypoxic tissue microenvironments.

Key Words: cell migration • SDF-1/CXCL12 receptor (CXCR4) • low oxygen concentration • hypoxia-inducible factor 1 (HIF-1)

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