Regulation of the Chemokine Receptor CXCR4 by Hypoxia

By T. Schioppa, B. Uranchimeg, Alessandra Saccani, Subhra K. Biswas, A. Doni, A. Rapisarda, S. Bernasconi, S. Saccani, M. Nebuloni, L. Vago and 3 more. Journal of Experimental Medicine, 2003

910 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/2f0499bcfef75bef4c6931010f467141168b7776

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In Cancer Research

1. M. Karin
2. A. Mantovani
3. V. Nizet
4. A. Sica
5. F. Greten
6. M. C. Simon
7. F. Balkwill
8. P. Allavena

In Immunology

1. A. Mantovani
2. A. Sica
3. M. Karin
4. P. Allavena
5. F. Balkwill
6. C. Garlanda
7. F. Greten
8. G. Solinas

In Oncology

1. A. Mantovani
2. M. Karin
3. A. Sica
4. P. Allavena
5. F. Balkwill
6. C. Garlanda
7. F. Greten
8. G. Solinas

Citations in the corpus

• Role of tumor-associated macrophages in tumor progression and invasion (2006, background): “Moreover, a recent work has shown that HIF-1 activation may play a role in the induction of the CXCR4 ligand, CXCL12 [45], a chemokine involved in cancer metastasis [46].”
• Role of chemokines in tumor growth. (2007, background): “HIF-1-α then induces the expression of CXCR4 [57,58].”
• Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor κB (2009, methodology): “ChIP was performed with a polyclonal anti-RNA Pol II, p65 NF- B (C-20) sc-372, and p50 NF- B (C-19) sc-1190 antibody (Santa Cruz Biotechnology) (44).”
• Cancer and the chemokine network (2004, background): “Further proof of the link between hypoxia and CXCR4 came from a study that showed positive regulation of CXCR4 by hypoxia in a range of normal and malignant cell”
• Regulation of CXCR4 signaling. (2007, background): “Hypoxia induces the activation of hypoxia inducible factor 1 (HIF-1) which in turn promotes expression of a number of target genes [138] including CXCR4 [139–141].”
• Hypoxia and hypoxia-inducible factors (HIFs): master regulators of metastasis (2010, background): “metastatic homing by inducing CXCR4 expression in renal cell carcinoma (27), ovarian cancer (28), breast cancer (25), and NSCLC (29).”
• Macrophages in Tumor Microenvironments and the Progression of Tumors (2012, background): “In addition, it has been reported that the HIF-1-dependent chemokine CXCL-12 acts as a potent chemoattractant that promotes endothelial cell infiltration when specifically combined with its sole receptor, CXCR4 [52].”
• Hypoxia-induced angiogenesis: good and evil. (2011, background): “SDF-1/CXCR4 and VEGF/VEGF-R2 signaling regulate the recruitment of these cells.(146) Ectopic expression of HIF-1α enhances the mobilization and recruitment of CACs to ischemic sites in the FAL model by upregulating SDF-1 and VEGF.”
• Tumor-Associated Macrophages as Major Players in the Tumor Microenvironment (2014, background): “HIF-1α also induces CXCL12 expression in direct proportion to the reduced oxygen tension at hypoxic sites [55].”
• NF-κB: linking inflammation and immunity to cancer development and progression (2005, background): “Macrophage progenitors (monocytes) migrate to hypoxic sites, such as the growing tumour mass, in response to upregulation of CXC-chemokine receptor 4 (CXCR4) at the cell surfac”