Abstract
Neuroblastoma (NB) is a typical childhood and heterogeneous neoplasm for which efficient targeted therapies for high-risk tumors are not yet identified. The chemokine CXCL12, and its receptors CXCR4 and CXCR7 have been involved in tumor progression and dissemination. While CXCR4 expression is associated to undifferentiated tumors and poor prognosis, the role of CXCR7, the recently identified second CXCL12 receptor, has not yet been elucidated in NB. In this report, CXCR7 and CXCL12 expressions were evaluated using a tissue micro-array including 156 primary and 56 metastatic NB tissues. CXCL12 was found to be highly associated to NB vascular and stromal structures. In contrast to CXCR4, CXCR7 expression was low in undifferentiated tumors, while its expression was stronger in matured tissues and specifically associated to differentiated neural tumor cells. As determined by RT-PCR, CXCR7 expression was mainly detected in N-and S-type NB cell lines, and was slightly induced upon NB cell differentiation in vitro. The relative roles of the two CXCL12 receptors were further assessed by overexpressing CXCR7 or CXCR4 receptor alone, or in combination, in the IGR-NB8 and the SH-SY5Y NB cell lines. In vitro functional analyses indicated that, in response to their common ligand, both receptors induced activation of ERK1/2 cascade, but not Akt pathway. CXCR7 strongly reduced in vitro growth, in contrast to CXCR4, and impaired CXCR4/CXCL12-mediated chemotaxis. Subcutaneous implantation of CXCR7-expressing NB cells showed that CXCR7 also significantly reduced in vivo growth. Moreover, CXCR7 affected CXCR4-mediated orthotopic growth in a CXCL12-producing environment. In such model, CXCR7, in association with CXCR4, did not induce NB cell metastatic dissemination. In conclusion, the CXCR7 and CXCR4 receptors revealed specific expression patterns and distinct functional roles in NB. Our data suggest that CXCR7 elicits anti-tumorigenic functions, and may act as a regulator of CXCR4/CXCL12-mediated signaling in NB.
Highlights
Neuroblastoma (NB) is a typical pediatric neoplasm derived from embryonic neural crest cells
Expression of CXCR7 and CXCL12 in NB Tissues A NB TMA including a panel of 156 primary NB tumors, 56 metastatic and 65 control normal tissues, such as adrenal glands (AG) and sympathetic ganglia (SG), was screened for CXCR7 and CXCL12 expression
Neuroblasts and tumor ganglion cells were included in the neural compartment of tumors, while adrenal medulla and normal ganglion cells represented the neural part of AG and SG, respectively
Summary
Neuroblastoma (NB) is a typical pediatric neoplasm derived from embryonic neural crest cells. The disease displays a remarkable clinical diversity, ranging from spontaneous regression to fatal progression and dissemination to privileged sites, such as bone-marrow and liver [1,2]. Chemokines and their receptors have been originally described as essential mediators of leukocyte directional migration, during infection and inflammation, and have further emerged as crucial players in all stages of tumor development [3,4,5,6]. The binding of chemokines to their cognate receptors elicits typical cellular responses, such as directional migration, through activation of classical MAP-kinase or PI3-kinase/PKB signaling cascades [7]. Both tumor and stromal cells express a large pattern of chemokine/chemokine receptor axes, which may represent major paracrine/autocrine complex players within the tumor and its microenvironment [8]
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