Review
A review on CXCR4/CXCL12 axis in oncology: No place to hide

https://doi.org/10.1016/j.ejca.2012.05.005Get rights and content

Abstract

Classical chemotherapeutic anti-cancer treatments induce cell death through DNA damage by taking advantage of the proliferative behaviour of cancer cells. The more recent approach of targeted therapy (usually protein-targeted) has led to many treatments that are currently available or are under development, all of which are designed to strike at the critical driving forces of cancer cells. The interaction of the cancer cells with their microenvironment is one of these fundamental features of neoplasms that could be targeted in such cancer treatments. Haematological and solid tumour cells interact with their microenvironment through membrane chemokine receptors and their corresponding ligands, which are expressed in the tumour microenvironment. Important representatives of this system are the chemokine ligand CXCL12 and its receptor chemokine receptor 4 (CXCR4). This interaction can be disrupted by CXCR4 antagonists, and this concept is being used clinically to harvest haematopoietic stem/progenitor cells from bone marrow. CXCR4 and CXCL12 also have roles in tumour growth and metastasis, and more recently their roles in cancer cell-tumour microenvironment interaction and angiogenesis have been studied. Our review focuses on these roles and summarises strategies for treating cancer by disrupting this interaction with special emphasis on the CXCR4/CXCL12 axis. Finally, we discuss ongoing clinical trials with several classes of CXCR4 inhibitors, and their potential additive value for patients with a (therapy resistant) malignancy by sensitising cancer cells to conventional therapy.

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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