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Page 4 of 11 Tulotta et al. J Cancer Metastasis Treat 2019;5:74 I http://dx.doi.org/10.20517/2394-4722.2019.022

Figure 2. CXCR4 drives the interaction between cancer and stromal cells. The CXCR4-CXCL12 axis signals in a bi-directional fashion.
CXCR4 is expressed by both tumour cells and cells that form the surrounding stroma [fibroblast, T cells, T reg cells, myeloid derived
suppressors cells (MDSCs), macrophages and neutrophils], embedded in the extracellular matrix (ECM). The CXCR4 cognate ligand
CXCL12 is secreted by both cancer cells and cells in the microenvironment

areas after chemotherapies and are suggested to display pro-angiogenic functions that drive tumour-
[37]
relapse . Moreover, CXCL12 expressing glioblastoma cells induce VEGF production and angiogenesis in
[38]
microvessel enriched areas with high CXCR4 levels . In addition, CXCR4-expressing peripheral blood
monocytes respond to CXCL12-secreting multiple myeloma (MM) tumour cells and acquire M2 associated
properties . Finally, the inhibition of CXCR4 signalling by oncolytic virotherapy limits the infiltration of
[39]
[40]
Treg, decreasing immunosuppression .
Considering the major and intricate role of this chemokine receptor in cancer, its targeting represents an
important pharmacological approach that is currently under development, through the use of CXCR4
antagonists, antibodies and CXCL12 binding agents. Importantly, the role of the stromal CXCR4 signalling
needs to be considered in drug treatments that target CXCR4 to inhibit cancer spreading.

In 2018, the Nobel prize in Physiology and Medicine was awarded to J.P. Allison and T. Honjo for the
[41]
development of immune-checkpoint blockade . This revolutionary discovery clearly underlines the well-
known pivotal role of the immune system in cancer. Inhibition of CXCR4 signalling has been found to
improve the efficacy of immunotherapies in metastatic breast cancer, by alleviation of desmoplasia and
[42]
increased T cell infiltration in preclinical in vivo models .
Limiting cancer spreading by targeting CXCR4 signalling in the tumour microenvironment is a promising
approach that requires further investigations to become an alternative therapeutic form of intervention.