Abstract
CXCR4 expression in neuroblastoma tumors correlates with disease severity. In this study, we describe mechanisms by which CXCR4 signaling controls neuroblastoma tumor growth and response to therapy. We found that overexpression of CXCR4 or stimulation with CXCL12 supports neuroblastoma tumorigenesis. Moreover, CXCR4 inhibition with the high-affinity CXCR4 antagonist BL-8040 prevented tumor growth and reduced survival of tumor cells. These effects were mediated by the upregulation of miR-15a/16-1, which resulted in downregulation of their target genes BCL-2 and cyclin D1, as well as inhibition of ERK. Overexpression of miR-15a/16-1 in cells increased cell death, whereas antagomirs to miR-15a/16-1 abolished the proapoptotic effects of BL-8040. CXCR4 overexpression also increased miR-15a/16-1, shifting their oncogenic dependency from the BCL-2 to the ERK signaling pathway. Overall, our results demonstrate the therapeutic potential of CXCR4 inhibition in neuroblastoma treatment and provide a rationale to test combination therapies employing CXCR4 and BCL-2 inhibitors to increase the efficacy of these agents.Significance: These results provide a mechanistic rationale for combination therapy of CXCR4 and BCL-2 inhibitors to treat a common and commonly aggressive pediatric cancer.Cancer Res; 78(6); 1471-83. ©2017 AACR.
Highlights
Neuroblastoma is the most prevalent extracranial solid tumor in childhood with a median diagnosis age of 17 months
To appreciate the significance of CXCR4 to neuroblastoma development, CXCR4 expression was measured in a tissue array composed of 13 neuroblastoma samples and several cell lines derived from neuroblastoma tumors
We have demonstrated in agreement with previous published data [10] that primary human neuroblastoma tumors express high CXCR4 levels (Fig. 1)
Summary
Neuroblastoma is the most prevalent extracranial solid tumor in childhood with a median diagnosis age of 17 months. Most children are diagnosed at stage 4, at which, 5-year survival is around 26% [1]. Treatment at this stage includes chemotherapy and primary tumor resection followed by autologous hematopoietic transplantation. Despite induction and consolidation protocols, half of the patients will relapse, indicating that minimal residual disease (MRD) is a challenge in neuroblastoma treatment [2]. The initial indication of CXCR4 regulating cell survival came from HIV patients, where it was found to induce programmed cell death. CXCR4 was shown to promote survival through CXCL12-induced signals, supporting the proliferation of many tumor cells [4,5,6,7].
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