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Page 2 of 11 Tulotta et al. J Cancer Metastasis Treat 2019;5:74 I http://dx.doi.org/10.20517/2394-4722.2019.022

THE TUMOUR MICROENVIRONMENT
Tumours are in constant interaction with the surrounding microenvironment. The tumour
microenvironment consists of stromal cells such as cancer-associated fibroblasts (CAFs), endothelial
cells, mesenchymal stem cells (MSCs), tumour-associated macrophages (TAMs) and neutrophils (TANs),
[1]
adaptive immune cells and extracellular matrix (ECM) . The interaction between cancer and stroma cells
results in either tumour promoting or inhibiting effects and the tumour microenvironment differentially
[2]
contributes to the efficacy of cancer therapies . Tumour cells engage cells from the microenvironment,
either educating resident stromal cells or inducing the recruitment of distal ones to further support
malignant growth, motility and dissemination. Along with the angiogenic switch, where endothelial
cells are educated by malignant cells to form new vasculature to provide oxygen and nutrients, the
immunosuppressive switch phenomenon takes place: the polarization from pro-inflammatory to anti-
inflammatory neutrophils and macrophages (N1 to N2 and M1 to M2), where the sub-type 2 associates
with a tumour-promoting function, links to immunosuppression, characterized by reduced cytotoxic
[3]
T cell and enhanced T regulatory (Treg) and myeloid-derived suppressor (MDSCs) cell infiltration .
Interestingly, the cooperation between different subsets of leukocytes and its role in cancer metastases has
[4]
been recently reported . The plasticity phenomenon in the microenvironment has been described also for
fibroblasts, which respond to a neoplastic lesion in a similar fashion as to a never healing wound . The
[3]
interaction between tumour and the microenvironment is controlled by a plethora of signalling molecules,
such as chemokines, and their complex networking in cancer requires further understanding to inhibit
tumour development.

CXCL12-CXCR4 AXIS IN CANCER AND THE TUMOUR MICROENVIRONMENT
Chemokines are chemotactic cytokines that guide directional cell migration in development and disease
[5]
and more than 50 chemokine ligands and 18 chemokine receptors have been described in Homo sapiens .
Chemokines are classified into four classes, depending on the presence and position of the conserved
cysteine residues (CXC, CC, (X)C and CX3C) at the N-terminus, involved in the formation of disulphide
[6]
bonds between the first and third or second and fourth cysteines . The chemokines belonging to the CXC
subgroup are further classified into angiogenic ELR+ and angiostatic ELR-, whether they are positive or
[7,8]
negative for the Glu-Leu-Arg (ELR) motif at the N-terminus . Chemokine ligands can bind multiple
[8]
chemokine receptors, which possibly work in concert to control signalling activation and inhibition .
CXCR4 is a seven-transmembrane, chemokine, G-protein coupled receptor. The chemokine CXCL12
binds both CXCR4 and CXCR7 receptors in order to guide a directional and collective migration of cell
primordia, during the formation of sensory organs in zebrafish [9-11] . CXCL12 binding to CXCR4 induces
the dissociation of the G protein αβγ trimer and activation of PI3K/AKT/mTOR, MAPK, PKA and PLC/
2+
Ca pathways. Moreover, MAPK cascade activation and CXCR4 internalization occur via β-Arrestin,
independently from G-proteins [Figure 1A]. In addition, CXCR4 can form homodimers, activating the
2+
JAK/STAT pathway and Ca release from intracellular storage into the cytoplasm [Figure 1B]. CXCR4 can
also form heterodimers with CXCR7. Whereas CXCR4 is internalized and degraded after CXCL12 binding,
CXCR7 is internalized and recycled to the plasma membrane. Via β-Arrestin, CXCR7 has either CXCL12
scavenging functions or triggers MAPK signalling activation [Figure 1C]. CXCL12 signalling via CXCR4
and CXCR7 controls cell chemotaxis and migration as well as cell proliferation and survival [12,13] .

In cancer, malignant cells acquire higher CXCR4 levels, compared to normal tissues, and are found to
preferentially metastasise in organs where CXCL12 is secreted, in line with the “seed and soil” theory .
[14]
Enhanced CXCR4 signalling has been identified in several malignancies such as gastrointestinal
[17]
[18]
tumours , melanoma , basal cell carcinoma , head and neck squamous cell carcinoma , lung cancer ,
[16]
[15]
[19]
[22]
[21]
[20]
[23]
breast and ovarian tumours, renal cell carcinoma , prostate cancer , glioblastoma multiforme