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Cytokine CCL5 and receptor CCR5 axis in glioblastoma multiforme

Miha Koprivnikar Kranjc
Miha Koprivnikar Kranjc
, 
Metka Novak
Metka Novak
, 
Richard G. Pestell
Richard G. Pestell
 and 
Tamara T. Lah
Tamara T. Lah
   | Nov 20, 2019
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Article Category: Review
Published Online: Nov 20, 2019
Page range: 397 - 406
Received: Aug 14, 2019
Accepted: Oct 15, 2019
DOI: https://doi.org/10.2478/raon-2019-0057
© 2019 Miha Koprivnikar Kranjc, Metka Novak, Richard G. Pestell, Tamara T. Lah, published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Figure 1

Chemokine CCL5 promiscuous binding to receptors. A variety of chemokine-receptors are interacting with CCL5/CCR5 in the signalling axis: (A) in addition to the cognate receptor CCR5, CCL5 binds also to CCR3 and CCR1. Non-conventional receptors are GPR75 and CD44. (B) The chemokines which bind to CCR5 are also CCL5, CCL4 and CCL3.
Chemokine CCL5 promiscuous binding to receptors. A variety of chemokine-receptors are interacting with CCL5/CCR5 in the signalling axis: (A) in addition to the cognate receptor CCR5, CCL5 binds also to CCR3 and CCR1. Non-conventional receptors are GPR75 and CD44. (B) The chemokines which bind to CCR5 are also CCL5, CCL4 and CCL3.

Figure 2

Phosphatidylinositol 3-kinase (PI3K)/pAkt-kinase pathway as a central CCL5/CCR5 signalling cascade in cancer cells. Upon CCL5 binding to its cognate receptor CCR5, primarily the PI3K/Akt pathway is triggered. This favours the phosphorylation of PIP2 to PIP3, a secondary messenger responsible for the activation of the Akt kinase, which in turn phosphorylates several downstream effectors. This causes the inhibition of pro-apoptotic effectors and the upregulation of survival genes. Another target of PI3K is the mammalian target of rapamycin complex 1 (mTORC1), which also activates the Akt kinase. However, it has also been shown that a secondary intracellular target, Focal Adhesion kinase (FAK) binding-SRC kinase complex can be activated, resulting in additional PI3K activation (in prostate cancer62).
Phosphatidylinositol 3-kinase (PI3K)/pAkt-kinase pathway as a central CCL5/CCR5 signalling cascade in cancer cells. Upon CCL5 binding to its cognate receptor CCR5, primarily the PI3K/Akt pathway is triggered. This favours the phosphorylation of PIP2 to PIP3, a secondary messenger responsible for the activation of the Akt kinase, which in turn phosphorylates several downstream effectors. This causes the inhibition of pro-apoptotic effectors and the upregulation of survival genes. Another target of PI3K is the mammalian target of rapamycin complex 1 (mTORC1), which also activates the Akt kinase. However, it has also been shown that a secondary intracellular target, Focal Adhesion kinase (FAK) binding-SRC kinase complex can be activated, resulting in additional PI3K activation (in prostate cancer62).

Figure 3

CCL5-CCR5 system and microglia polarization. The pharmacological blockade of CCR5 with maraviroc prevents the activity of glioblastoma-associated anti-inflammatory microglia M2 phenotype in and induces (green arrow) the conversion to prevailing pro-inflammatory M1 microglia phenotype.
CCL5-CCR5 system and microglia polarization. The pharmacological blockade of CCR5 with maraviroc prevents the activity of glioblastoma-associated anti-inflammatory microglia M2 phenotype in and induces (green arrow) the conversion to prevailing pro-inflammatory M1 microglia phenotype.

Figure 4

CCL5 and CCR5 in Glioblastoma microenvironment. (A) Fluorescence immunohistochemical labelling of CCR5 in glioblastoma associated macrophages. Macrophages in the tumour section were immuno-fluorescently labelled to detect antigen CD68 (marker for macrophages), as well as CCR5 expressions in glioblastoma tissue samples of glioblastoma patient. Nuclei were stained with DAPI (blue), CD68 with Alexa Fluor 546 (red) and CCR5 with Alexa Fluor 488 (green) dye. CCR5 is expressed in macrophages, shown in yellow in merged pictures. 40x magnification was used. (B) CCL5 is expressed in proximity to MSC on glioblastoma tissue slide. Immunofluorescence images of GB tissue slides, labelled for CD105 marker of Mesenchymal stem cells (green positive cells) and CCL5 (red). We observe selective localisation of CCL5 in glioblastoma cells and colonalization in the fraction of mesenchymal stem cells, expressing CCL5. This indicates the involvement of MSCs in the CCL5/CCR5 signalling in glioblastoma. CCL5 was also expressed in glioblastoma cells.
CCL5 and CCR5 in Glioblastoma microenvironment. (A) Fluorescence immunohistochemical labelling of CCR5 in glioblastoma associated macrophages. Macrophages in the tumour section were immuno-fluorescently labelled to detect antigen CD68 (marker for macrophages), as well as CCR5 expressions in glioblastoma tissue samples of glioblastoma patient. Nuclei were stained with DAPI (blue), CD68 with Alexa Fluor 546 (red) and CCR5 with Alexa Fluor 488 (green) dye. CCR5 is expressed in macrophages, shown in yellow in merged pictures. 40x magnification was used. (B) CCL5 is expressed in proximity to MSC on glioblastoma tissue slide. Immunofluorescence images of GB tissue slides, labelled for CD105 marker of Mesenchymal stem cells (green positive cells) and CCL5 (red). We observe selective localisation of CCL5 in glioblastoma cells and colonalization in the fraction of mesenchymal stem cells, expressing CCL5. This indicates the involvement of MSCs in the CCL5/CCR5 signalling in glioblastoma. CCL5 was also expressed in glioblastoma cells.
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