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Review
. 2018 May 16;19(5):1477.
doi: 10.3390/ijms19051477.

Inhibition of the CCL5/CCR5 Axis against the Progression of Gastric Cancer

Donatella Aldinucci  1 , Naike Casagrande  2
Affiliations
Review

Inhibition of the CCL5/CCR5 Axis against the Progression of Gastric Cancer

Donatella Aldinucci et al. Int J Mol Sci. .

Abstract

Despite the progress made in molecular and clinical research, patients with advanced-stage gastric cancer (GC) have a bad prognosis and very low survival rates. Furthermore, it is challenging to find the complex molecular mechanisms that are involved in the development of GC, its progression, and its resistance to therapy. The interactions of chemokines, also known as chemotactic cytokines, with their receptors regulate immune and inflammatory responses. However, updated research demonstrates that cancer cells subvert the normal chemokine role, transforming them into fundamental constituents of the tumor microenvironment (TME) with tumor-promoting effects. C-C chemokine ligand 5 (CCL5) is a chemotactic cytokine, and its expression and secretion are regulated in T cells. C-C chemokine receptor type 5 (CCR5) is expressed in T cells, macrophages, other leukocytes, and certain types of cancer cells. The interaction between CCL5 and CCR5 plays an active role in recruiting leukocytes into target sites. This review summarizes recent information on the role of the CCL5 chemokine and its receptor CCR5 in GC cell proliferation, metastasis formation, and in the building of an immunosuppressive TME. Moreover, it highlights the development of new therapeutic strategies to inhibit the CCL5/CCR5 axis in different ways and their possible clinical relevance in the treatment of GC.

Keywords: CCL5; CCR5; CCR5 antagonists; gastric cancer; invasion; tumor microenvironment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Effects of the C-C chemokine ligand 5 (CCL5) and C-C chemokine receptor type 5 (CCR5) interactions on cancer. CCL5 secreted by tumor cells or by cancer-associated fibroblasts (CAFs) recruits monocytes, T cells, eosinophils, and mast cells in the tumor microenvironment (TME). CCL5 induces tumor cell proliferation via the mammalian target of rapamycin (mTOR) pathway and increases ATP production, enhances tumor cell migration/invasion through αvβ3 integrin activation and matrix metalloproteinases-2/9 (MMP-2/9) upregulation, promotes angiogenesis by inducing vascular endothelial growth factor (VEGF) secretion; targeting the CCR5/CCL5 axis reprograms the immunosuppressive M2-tumor-associated macrophage (TAM) to anti-tumoral M1-TAM. Thin arrow, up-regulation; bold arrow, repolarization; red cross, inhibition.
Figure 2
Figure 2
A schematic representation of the proposed role of CCL5 in gastric cancer (GC). (1) By activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Helicobacter pylori may induce CCL5 expression in GC cells. (2) By secreting CCL5, M2-TAMs may activate signal transducer and activator of transcription 3 (STAT3) and DNA methyltransferase (DNMT) and inhibit gelsolin (GSN) expression, leading to enhanced GC cancer cell proliferation and invasion/metastasis formation. CCL5 up-regulation (3) Krüppel-like factors 5 (KLF5) overexpression in CAFs enhances the secretion of CCL5, which induces GC cell invasion and proliferation. (4) By secreting CCL5, CD4+ tumor-associated lymphocytes (TILs) may enhance GC cell proliferation and invasion. (5) By secreting CCL5, GC cells may recruit T-regulatory cells (T-regs), monocytes, and macrophages in the TME. (6) Increased CCL5 in GC metastatic tissues and serum may enhance GC cell invasion. Thin up-arrow, CCL5 up-regulation; red cross, inhibition; curved arrow, binding of CCL5 to CCR5 (3, 4); curved arrow, cell migration to GC cells (5).
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References

    1. Mantovani A. Molecular pathways linking inflammation and cancer. Curr. Mol. Med. 2010;10:369–373. doi: 10.2174/156652410791316968. - DOI - PubMed
    1. Hanahan D., Coussens L.M. Accessories to the crime: Functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21:309–322. doi: 10.1016/j.ccr.2012.02.022. - DOI - PubMed
    1. Kershaw M.H., Westwood J.A., Darcy P.K. Gene-engineered T cells for cancer therapy. Nat. Rev. Cancer. 2013;13:525–541. doi: 10.1038/nrc3565. - DOI - PubMed
    1. Shalapour S., Karin M. Immunity, inflammation, and cancer: An eternal fight between good and evil. J. Clin. Investig. 2015;125:3347–3355. doi: 10.1172/JCI80007. - DOI - PMC - PubMed
    1. Shrihari T.G. Dual role of inflammatory mediators in cancer. Ecancermedicalscience. 2017;11:721. doi: 10.3332/ecancer.2017.721. - DOI - PMC - PubMed

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