ReviewA review on CXCR4/CXCL12 axis in oncology: No place to hide
Introduction
The growing appreciation of the role of the microenvironment in driving the cancer cell biology has improved the understanding of oncologic disease and accelerated the identification of new therapeutic targets. The chemokine receptor 4 (CXCR4) and its chemokine ligand 12 (CXCL12) are two key factors in the cross-talking between cancer cells and their microenvironment, what makes them promising targets for cancer therapy. In this review, we summarise the role of CXCR4 and CXCL12 in tumour growth, metastasis, angiogenesis, and cancer cell-microenvironment interaction. Furthermore, we discuss the potential benefits of targeting CXCR4 with specific inhibitors to disrupt CXCR4-dependent tumour-stroma interactions. The relevance of CXCR4 inhibition in the clinical setting is discussed, including past and ongoing clinical trials with several classes of CXCR4 inhibitors that could sensitise cancer cells for therapy.
Section snippets
The CXCR4/CXCL12 axis
Chemokine receptors form a large family of proteins that mediate chemotaxis of cells towards a gradient of chemokines. CXCR4 is a G-protein coupled chemokine receptor, encoded on chromosome 2.1 The receptor has a seven-transmembrane structure with seven helical regions connected by six extramembrane loops.2 CXCR4 exerts its biological effect by binding its ligand CXCL12, 3, 4 activating the downstream protein kinase B (AKT)/mitogen-activated protein kinases (MAPK) signalling pathway, leading to
Role of CXCR4/CXCL12 in tumour growth and metastasis
A decade ago, researchers demonstrated the overexpression – relative to normal breast tissue – of CXCR4 by human breast cancer cell lines and primary and metastatic breast tumours (Fig. 2).9 Today, CXCR4 overexpression is known in more than 20 human tumour types, including ovarian,10 prostate,11 oesophageal,12 melanoma,13 neuroblastoma,14 and renal cell carcinoma.15 Furthermore, the tumour growth-stimulating role of CXCR4 was confirmed by showing that CXCR4 antagonists inhibit tumour growth in
Clinical experience with CXCR4 inhibition
The first clinical trials with CXCR4 inhibitor, AMD3100 were designed for treatment of human immunodeficiency virus (HIV). Interestingly, a rapid increased amount of white blood cells within 6–9 h after the AMD3100 injection was observed in the phase I clinical trials in healthy volunteers.63 This finding led to the discovery that AMD3100 mobilises CD34+ human haematopoietic stem and progenitor cells from the bone marrow to peripheral blood.64 Finally, AMD3100 (Mozobil, plerixafor) was approved
Conclusions
The interaction of cancer cells with their microenvironment, which protects the malignant cells from genotoxic stresses such as chemotherapy, is an attractive target to improve anti-cancer treatment. CXCR4 and CXCL12, which are expressed on both tumour and tumour surrounding cells, play an important role in the communication of cancer cells with their microenvironment. CXCR4 antagonists are potentially interesting drugs for sensitising tumour cells to chemotherapy. Further studies are warrant
Conflict of interest statement
All authors report no financial or personal relationships with other people or organisations that could inappropriately influence their work. None of the authors reports any conflict of interests. There are no sources of funding of this manuscript.
Urszula M. Domanska, Roeliene C. Kruizinga, Wouter B. Nagengast, Hetty Timmer-Bosscha, Gerwin Huls, Elisabeth G.E. de Vries, Annemiek M.E. Walenkamp.
Financial support
RCK received a grant from J.K. de Cock Foundation and an UEF-JSM Talent Grant – no role in decision to submit the article for publication. AMEW received CXCR4 inhibitor (AMD3100) from Genzyme for preclinical use (no financial support) – no role in decision to submit the article for publication.
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These authors contributed equally.