Background: The CXCR4/CXCR7/CXCL12 chemokine axis has been involved in the progression and organ-specific dissemination of various cancers. In NB, CXCR4 expression was shown to be associated to highly aggressive undifferentiated tumors, while CXCR7 expression was detected in more differentiated and mature neuroblastic tumors. As investigated in vivo, using an orthotopic model of tumor cell implantation of chemokine receptor-overexpressing NB cells (IGR-NB8), the CXCR4/CXCR7/CXCL12 axis was shown to regulate NB primary and secondary growth, although without any apparent influence on organ selective metastasis.
Methods: The selective role of CXCR4 and CXCR7 receptors in the homing phase of metastatic dissemination was addressed using an intravenous model of tumor cell implantation into NOD-scid-gamma mice.
Results: Tail vein injection of transduced IGR-NB8 cells overexpressing CXCR4, CXCR7 or both receptors revealed that all transduced cell variants preferentially invaded adrenal gland and typical NB metastatic target organs, such as liver and bone marrow (BM). However, CXCR4 expression favored NB cell dissemination to liver and lungs, while CXCR7 was able to strongly promote NB cell homing to adrenal gland and liver. Finally, coexpression of CXCR4 and CXCR7 receptors significantly and selectively increased NB dissemination toward BM.
Conclusion: CXCR4 and CXCR7 receptors may be involved in a complex and organ-dependent control of NB growth and selective homing, making these receptors and their inhibitors, potential new therapeutic targets.