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Chemokines are a family of cytokines which can induce gradient-dependent directional chemotaxis and are secreted by a variety of stromal and epithelial cells. These small proteins (8–10 kDa) have a common structural feature of conserved cysteine residues at the N-terminus. Up to now, nearly 50 chemokines have been discovered. Chemokines exert the biological effect through interaction with chemokine receptors, seven transmembrane G-protein-coupled receptors, present on the target cells. Chemokine receptors are grouped into four different families as CXC, CC, CX3C, and XC based on the chemokines they primarily interact with for signaling. To date, nearly 20 chemokine receptors have been identified. Many chemokines, compared to chemokine receptors, implies considerable redundancy in chemokine receptor interactions with multiple ligands binding to the same receptor and vice versa. The chemokine receptor 4 (CXCR4) is unique in that it solely interacts with the endogenous ligand CXCL12.
The overview of CXCR4/CXCL12 axis
CXCR4 is a G-protein coupled chemokine receptor, encoded on chromosome 2. CXCR4 exerts its biological function by binding its ligand CXCL12. The binding of CXCL12 to CXCR4 initiates divergent signaling pathways downstream of ligand binding, which can result in many responses such as chemotaxis, increase in intracellular calcium, cell survival and/or proliferation, and gene transcription. There are some of the key signaling pathways thought to be involved in CXCR4 signal transduction (Figure 1). The precise nature of these pathways may be tissue-dependent and may differ between cell types.
During embryonic development, CXCR4 is expressed on progenitor cells, allowing the migration from their place of origin to their final destination where they will differentiate into tissues and organs. CXCR4/CXCL12 deficient mice show a lethal phenotype, confirming the importance of CXCR4/CXCL12 in embryonic development. Phagocytic cells from the innate immune system, such as macrophages and neutrophils, express CXCR4. That allows them to migrate along a gradient of the CXCL12 present at the site of inflammation. In the late 1990s, CXCR4 expressed on CD4+ T-cells was discovered to serve as a co-entry receptor for human immunodeficiency virus HIV-1.
Role of CXCR4/CXCL12 in tumour growth and metastasis
Nowadays, CXCR4 overexpression is known in over 20 human tumour types, including prostate, oesophageal, melanoma, ovarian, neuroblastoma, and renal cell carcinoma. The tumour growth-stimulating role of CXCR4 was confirmed by showing that CXCR4 antagonists inhibit tumour growth in many experimental orthotopic, subcutaneous human xenograft and transgenic mouse models. In a transgenic breast cancer mouse model, treatment with the CXCR4 inhibition CTCE-9908 resulted in a 56% reduction in primary tumour growth rate compared to controls receiving scrambled protein. Furthermore, this coincided with a 42% reduction in vascular endothelial growth factor (VEGF) protein expression and 30% reduction in p-AKT/AKT expression.
Preclinical pancreatic, melanoma, thyroid, prostate, and colon cancer24 models revealed that directed metastasis of cancer cells is mediated by CXCR4 activation and migration of cancer cells towards CXCL12 expressing organs. For example, bone marrow, lungs, liver and lymph nodes exhibit peak expression levels of CXCL12 mRNA and represent the most common organs for homing of breast cancer metastasis. Experimental metastatic mouse models provided evidence that targeting CXCR4 impairs the spread of cancer cells and development of metastasis in breast cancer colon cancer, and prostate cancer, osteosarcoma, hepatocellular carcinoma and melanoma. Taken together, these data indicate that CXCR4 plays a vital role in tumour growth and metastasis (Figure 2).
Figure 2. Multiple functions of CXCR4/ CXCL12 axis in tumour biology
CXCR4 and CXCL12 induction by anti-cancer treatment
Invasive tumour growth induced by anti-angiogenic treatments such as bevacizumab and sunitinib is an intriguing phenomenon observed in preclinical in vivo studies. Interestingly, recent publications reported upregulation of CXCR4 and CXCL12 occurring after certain types of anticancer therapy, particularly after anti-angiogenic treatment targeting the VEGF/VEGFR pathway. The effect of the anti-VEGF-A antibody bevacizumab on the expression of CXCL12 and CXCR4 was studied in rectal cancer patients. Gene expression profiles in the tumour cells and tumour-associated macrophages were studied in biopsies before monotherapy with bevacizumab and 12 days after treatment. It was shown that anti-VEGF-A treatment with bevacizumab upregulated CXCL12 and CXCR4 mRNA expression in tumour cells.
As shown in a study of 53 rectal cancer patients undergoing preoperative chemoradiotherapy, high baseline expression of CXCR4 and CXCL12 mRNA in primary rectal cancer was associated with distant recurrence and poor prognosis. Therefore, it was postulated that CXCR4 inhibition might improve patient outcome. Chemotherapy can also lead to the specific enrichment of CXCR4-expressing chemoresistant tumour cells, as shown in an orthotopic metastatic melanoma model. And many data has demonstrated that treatment with VEGF/VEGFR targeting agents, radiotherapy or taxanes can upregulate CXCR4 and CXCL12 in several tumour types, resulting in enhanced invasive and metastatic tumour growth. Moreover, enhanced serum CXCL12 post-treatment levels lead to recruitment of haematopoietic progenitor cells to the tumour, followed by augmented tumour vascularisation.
Chemokines were recognized originally for their ability to dictate the migration and activation of leukocytes. However, CXCL12-CXCR4 signaling is involved in a number of functions within and outside the immune system and affects morphology of immature endothelial cells and neurons, as well as homing and maintenance of tissue stem cells, including HSCs, indicating that CXCL12 and CXCR4 are the best candidates for the primordial chemokine and receptor. Considering that cell homing and maintenance comprise the multistep processes, including survival, proliferation, transendothelial migration and localization to specific microenvironments, CXCL12 might be a key regulator in the temporal and spatial program of maintenance of particular types of tissue cells, including stem and progenitor cells, in the development and pathophysiology of disease. Further study of cellular and molecular mechanisms of the regulation and signal transduction pathways downstream of CXCL12 holds great promise for massive impact on developmental biology, immunology, stem cell biology and medicine.
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