Abstract
Neuroblastoma accounts for 15% of childhood cancer deaths and presents with metastatic disease of the bone and the bone marrow at diagnosis in 70% of the cases. Previous studies have shown that the Mesenchymal Stromal Cell (MSC) secretome, triggers metastases in several cancer types such as breast and prostate cancer, but the specific role of the MSC factors in neuroblastoma metastasis is unclear. To better understand the effect of MSC secretome on chemokine receptors in neuroblastoma, and its role in metastasis, we studied a panel of 20 neuroblastoma cell lines, and compared their invasive potential towards MSC-conditioned-RPMI (mRPMI) and their cytokine receptor expression profiles. Western blot analysis revealed the expression of multiple CXCR4 isoforms in neuroblastoma cells. Among the five major isoforms, the expression of the 47 kDa isoform showed significant correlation with high invasiveness. Pretreatment with mRPMI up-regulated the expression of the 47 kDa CXCR4 isoform and also increased MMP-9 secretion, expression of integrin α3 and integrin β1, and the invasive potential of the cell; while blocking CXCR4 either with AMD 3100, a CXCR4 antagonist, or with an anti-47 kDa CXCR4 neutralizing antibody decreased the secretion of MMP-9, the expression of integrin α3 and integrin β1, and the invasive potential of the cell. Pretreatment with mRPMI also protected the 47 kDa CXCR4 isoform from ubiquitination and subsequent degradation. Our data suggest a modulatory role of the MSC secretome on the expression of the 47 kDa CXCR4 isoform and invasion potential of the neuroblastoma cells to the bone marrow.
Highlights
Neuroblastoma, a biologically heterogeneous tumor originating from the sympathetic nervous system, is the most common extra-cranial solid tumor in childhood and the most frequently diagnosed neoplasm during infancy [1, 2, 3]
We found an isoform-specific-over-expression of CXCR4, in neuroblastoma cell lines, upon exposure to the Mesenchymal Stromal Cell (MSC) secretome, and a protective role of the MSC secretome in the expression of the 47 kDa CXCR4 isoform
Neuroblastoma cell lines are heterogeneous in their invasive potential Neuroblastoma cells were assayed for their invasive potentials using a transwell invasion experiment setting
Summary
Neuroblastoma, a biologically heterogeneous tumor originating from the sympathetic nervous system, is the most common extra-cranial solid tumor in childhood and the most frequently diagnosed neoplasm during infancy [1, 2, 3]. The most common metastatic sites include the bone, bone marrow, liver and non-contiguous lymph nodes [1, 4]. Treatment of patients with disseminated neuroblastoma is one of the greatest challenges for pediatric oncologists, as the 5 year survival rate remains as low as 40–45%, despite advanced treatment options [5]. Disseminated disease often leads to fatal outcomes, and children with bone metastasis have a
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