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Review
. 2021 Jan 15;22(2):843.
doi: 10.3390/ijms22020843.

The Effect of Hypoxia on the Expression of CXC Chemokines and CXC Chemokine Receptors-A Review of Literature

Jan Korbecki  1 , Klaudyna Kojder  2 , Patrycja Kapczuk  1 , Patrycja Kupnicka  1 , Barbara Gawrońska-Szklarz  3 , Izabela Gutowska  4 , Dariusz Chlubek  1 , Irena Baranowska-Bosiacka  1
Affiliations
Review

The Effect of Hypoxia on the Expression of CXC Chemokines and CXC Chemokine Receptors-A Review of Literature

Jan Korbecki et al. Int J Mol Sci. .

Abstract

Hypoxia is an integral component of the tumor microenvironment. Either as chronic or cycling hypoxia, it exerts a similar effect on cancer processes by activating hypoxia-inducible factor-1 (HIF-1) and nuclear factor (NF-κB), with cycling hypoxia showing a stronger proinflammatory influence. One of the systems affected by hypoxia is the CXC chemokine system. This paper reviews all available information on hypoxia-induced changes in the expression of all CXC chemokines (CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8 (IL-8), CXCL9, CXCL10, CXCL11, CXCL12 (SDF-1), CXCL13, CXCL14, CXCL15, CXCL16, CXCL17) as well as CXC chemokine receptors-CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7 and CXCR8. First, we present basic information on the effect of these chemoattractant cytokines on cancer processes. We then discuss the effect of hypoxia-induced changes on CXC chemokine expression on the angiogenesis, lymphangiogenesis and recruitment of various cells to the tumor niche, including myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), regulatory T cells (Tregs) and tumor-infiltrating lymphocytes (TILs). Finally, the review summarizes data on the use of drugs targeting the CXC chemokine system in cancer therapies.

Keywords: CXC chemokine; HIF-1α; IL-8; NF-κB; SDF-1; cancer; cycling hypoxia; hypoxia; hypoxia-inducible factor; tumor.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Two types of hypoxia in a tumor: chronic hypoxia associated with an excessive distance from the blood vessels and cycling hypoxia associated with changes in the blood flow in the vessels inside the tumor which lead to periodic oxygen deficiencies in various parts of the tumor.
Figure 2
Figure 2
Regulation of hypoxia-inducible factor-1 (HIF-1) transcriptional activity at various oxygen concentrations. (A) In normoxia, HIF-1α is hydroxylated by the oxygen-dependent enzymes prolyl hydroxylase (PHD) and factor inhibiting HIF (FIH). The PHD-catalyzed reaction leads to proteasomal degradation of HIF-1α. In turn, hydroxylation by FIH prevents interaction of HIF-1 with the CBP/p300 coactivator. (B) PHD and FIH require different concentrations of oxygen for their activity and so, in moderate hypoxia, PHD activity decreases while FIH retains its functions. Accumulation of HIF-1α occurs, but due to hydroxylation by FIH, there is no interaction between HIF-1 and the CBP/p300 coactivator, and thus genes dependent on this coactivator are not expressed. (C) In hypoxia, the activities of oxygen-dependent enzymes are reduced. For this reason, HIF-1α is not hydroxylated by PHD or by FIH. This subunit begins to form a transcription factor with HIF-1β, which is responsible for inducing the transcription of hypoxia-dependent genes.
Figure 3
Figure 3
The mechanism of interaction between HIF-1 and HIF-2 in the change of CXCL8 expression in HMEC-1 cells. HIF-1 reduces CXCL8 expression in HMEC-1 cells due to an increase in Bach1 expression, which reduces erythroid 2-related factor (Nrf2) activation. HIF-1 also reduces the expression of c-Myc and destabilizes the c-Myc:Max complex. HIF-2 increases the expression of CXCL8 in these cells, which is related to an increase in c-Myc expression and stabilization of the c-Myc:Max complex.
Figure 4
Figure 4
Association between the CXCL12→CXCR4 axis and vascular endothelial growth factor (VEGF) in angiogenesis induced by chronic hypoxia. Chronic hypoxia increases the expression of VEGF and CXCL12 in a cancer cell, factors that act on endothelial cells. VEGF increases the expression of CXCR4 and thus enhances the sensitivity of these cells to CXCL12. In turn, CXCL12 causes an increase in VEGF expression in endothelial cells. In addition, chronic hypoxia itself can act directly on endothelial cells. It increases the expression of CXCR4, CXCL12 and VEGF, which act in an autocrine manner on these cells. As a result of the described factors, angiogenesis occurs.
Figure 5
Figure 5
Hypoxia as an essential element of cancer mechanisms and as a therapeutic target. Hypoxia leads to an increase in the expression of genes essential for tumor progression, especially CXC chemokines, CXC chemokine receptors, and other genes encoding VEGF-A and programmed death-ligand 1 (PD-L1). As hypoxia occurs mainly in the tumor, cancer-specific therapy can be developed by using hyperbaric oxygen therapy and HIF inhibitors. Researchers are also investigating the potential of inactivating specific proteins whose expression is increased by hypoxia.
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References

    1. Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018;68:394–424. doi: 10.3322/caac.21492. - DOI - PubMed
    1. GBD 2017 Causes of Death Collaborators Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1736–1788. doi: 10.1016/S0140-6736(18)32203-7. - DOI - PMC - PubMed
    1. Wang M., Zhao J., Zhang L., Wei F., Lian Y., Wu Y., Gong Z., Zhang S., Zhou J., Cao K., et al. Role of tumor microenvironment in tumorigenesis. J. Cancer. 2017;8:761–773. doi: 10.7150/jca.17648. - DOI - PMC - PubMed
    1. Mu X., Shi W., Xu Y., Xu C., Zhao T., Geng B., Yang J., Pan J., Hu S., Zhang C., et al. Tumor-derived lactate induces M2 macrophage polarization via the activation of the ERK/STAT3 signaling pathway in breast cancer. Cell Cycle. 2018;17:428–438. doi: 10.1080/15384101.2018.1444305. - DOI - PMC - PubMed
    1. Lian G., Chen S., Ouyang M., Li F., Chen L., Yang J. Colon Cancer Cell Secretes EGF to Promote M2 Polarization of TAM through EGFR/PI3K/AKT/mTOR Pathway. Technol. Cancer Res. Treat. 2019;18 doi: 10.1177/1533033819849068. - DOI - PMC - PubMed

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