Abstract
Neuroblastoma (NB) is a heterogeneous, and particularly malignant childhood neoplasm in its higher stages, with a propensity to form metastasis in selected organs, in particular liver and bone marrow, and for which there is still no efficient treatment available beyond surgery. Recent evidence indicates that the CXCR4/CXCL12 chemokine/receptor axis may be involved in promoting NB invasion and metastasis. In this study, we explored the potential role of CXCR4 in the malignant behaviour of NB, using a combination of in vitro functional analyses and in vivo growth and metastasis assessment in an orthotopic NB mouse model. We show here that CXCR4 overexpression in non-metastatic CXCR4-negative NB cells IGR-NB8 and in moderately metastatic, CXCR4 expressing NB cells IGR-N91, strongly increased tumour growth of primary tumours and liver metastases, without altering the frequency or the pattern of metastasis. Moreover shRNA-mediated knock-down experiments confirmed our observations by showing that silencing CXCR4 in NB cells impairs in vitro and almost abrogates in vivo growth. High levels of CXCL12 were detected in the mouse adrenal gland (the primary tumour site), and in the liver suggesting a paracrine effect of host-derived CXCL12 on NB growth. In conclusion, this study reveals a yet unreported NB-specific predominant growth and survival-promoting role of CXCR4, which warrants a critical reconsideration of the role of CXCR4 in the malignant behaviour of NB and other cancers.
Highlights
Neuroblastoma (NB), the most common and deadly solid tumour in childhood, originates from primitive cells of the sympathetic nervous system
Constitutive cell surface CXCR4 expression, measured by flow cytometry (FC) in a panel of NB cell lines was variable among the cell lines tested
Recent reports suggest a role for CXCR4 and its ligand CXCL12 in the malignant behaviour of cancer cells
Summary
Neuroblastoma (NB), the most common and deadly solid tumour in childhood, originates from primitive cells of the sympathetic nervous system. Chemokines are small, cytokine-like proteins forming a large superfamily, originally discovered as essential mediators of leukocyte chemoattraction in inflammation and immune cell homing and recirculation Upon binding to their cognate seven-transmembrane spanning G-protein-coupled receptors, they induce integrin activation and cytoskeletal rearrangement promoting cell adhesion and directional migration [4,5,6]. Recent reports indicate that CXCR4 is commonly expressed on NB metastasis in the bone marrow and that it may be actively contributing to NB tumour cell homing to the bone marrow [12]. These observations are still controversially discussed [13]
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