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      Regulation of the Chemokine Receptor CXCR4 by Hypoxia

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          Abstract

          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 α and transcript stabilization. In a relay multistep navigation process, the Hyp–Hyp-inducible factor 1 α–CXCR4 pathway may regulate trafficking in and out of hypoxic tissue microenvironments.

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          Most cited references45

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          Angiogenesis in cancer, vascular, rheumatoid and other disease.

          J Folkman (1995)
          Recent discoveries of endogenous negative regulators of angiogenesis, thrombospondin, angiostatin and glioma-derived angiogenesis inhibitory factor, all associated with neovascularized tumours, suggest a new paradigm of tumorigenesis. It is now helpful to think of the switch to the angiogenic phenotype as a net balance of positive and negative regulators of blood vessel growth. The extent to which the negative regulators are decreased during this switch may dictate whether a primary tumour grows rapidly or slowly and whether metastases grow at all.
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            HIF-1alpha is essential for myeloid cell-mediated inflammation.

            Granulocytes and monocytes/macrophages of the myeloid lineage are the chief cellular agents of innate immunity. Here, we have examined the inflammatory response in mice with conditional knockouts of the hypoxia responsive transcription factor HIF-1alpha, its negative regulator VHL, and a known downstream target, VEGF. We find that activation of HIF-1alpha is essential for myeloid cell infiltration and activation in vivo through a mechanism independent of VEGF. Loss of VHL leads to a large increase in acute inflammatory responses. Our results show that HIF-1alpha is essential for the regulation of glycolytic capacity in myeloid cells: when HIF-1alpha is absent, the cellular ATP pool is drastically reduced. The metabolic defect results in profound impairment of myeloid cell aggregation, motility, invasiveness, and bacterial killing. This role for HIF-1alpha demonstrates its direct regulation of survival and function in the inflammatory microenvironment.
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              Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma.

              Angiogenesis is a key process in tumor growth and metastasis and is a major independent prognostic factor in breast cancer. A range of cytokines stimulate the tumor neovasculature, and tumor-associated macrophages have been shown recently to produce several important angiogenic factors. We have quantified macrophage infiltration using Chalkley count morphometry in a series of invasive breast carcinomas to investigate the relationship between tumor-associated macrophage infiltration and tumor angiogenesis, and prognosis. There was a significant positive correlation between high vascular grade and increased macrophage index (P = 0.03), and a strong relationship was observed between increased macrophage counts and reduced relapse-free survival (P = 0.006) and reduced overall survival (P = 0.004) as an independent prognostic variable. These data indicate a role for macrophages in angiogenesis and prognosis in breast cancer and that this cell type may represent an important target for immunoinhibitory therapy in breast cancer.
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                Author and article information

                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                3 November 2003
                : 198
                : 9
                : 1391-1402
                Affiliations
                [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
                Author notes

                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@ 123456marionegri.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@ 123456dtpax2.ncifcrf.gov

                Article
                20030267
                10.1084/jem.20030267
                2194248
                14597738
                8c8b51b1-e374-44b3-a3b4-69a420398532
                Copyright © 2003, The Rockefeller University Press
                Categories
                Article

                Medicine
                hypoxia-inducible factor 1 (hif-1),low oxygen concentration,sdf-1/cxcl12 receptor (cxcr4),cell migration

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