Abstract
Abstract Neuroblastoma; a pediatric cancer of the sympathetic nervous system, which accounts for 15% of childhood cancer deaths, presents with metastatic disease of the bone and the bone marrow at diagnosis in 70% of the cases. Although studies have shown that the CXCL12 chemokine receptor CXCR4 mediates the process of metastasis in many cancer types, its role in the bone marrow metastasis of neuroblastoma is unclear. In an effort to better understand the role of the CXCR4- CXCL12 axis in bone marrow metastasis of neuroblsatoma, we screened 20 neuroblastoma cell lines for their invasive potential, and expression of CXCR4, and sought to identify a correlation between tumor invasiveness and CXCR4 expression. Western blot analyses of cell lysates revealed the presence of multiple CXCR4 isoforms with 3 prominent species at about 35 kda, 47 kda and 62 kda. Cell lines expressing the 47 kda isoform showed higher secretion of MMP9 in gelatin zymography and higher migration and invasion towards mesenchymal stem cells (MSCs) and MSC-conditioned-RPMI, in transwell migration/invasion studies. Far western blot analysis with immuno-precipitated CXCR4, showed that the 47kda protein bound with CXCL12 at a higher rate. Blocking CXCR4 with AMD3100 or a neutralizing antibody against the 47 Kda isoform decreased the secretion of MMP9, the expression of integrin α3 and integrin β1 and the invasive potential of the cell. These data suggest that the 47 kda CXCR4 plays a prominent role in the bone marrow metastasis of neuroblastoma and could possibly be used as a diagnostic marker for highly invasive neuroblastoma and the development of minimal residual disease. Citation Format: Vipin Shankar, Lei Qi, Kentaro Kihira, Yoshihiro Komada, Hiroki Hori. 47 kda CXCR4: A marker for highly invasive neuroblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 41. doi:10.1158/1538-7445.AM2014-41
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