Abstract
Bone marrow metastasis occurs in approximately 350,000 patients that annually die in the U.S. alone. In view of the importance of tumor cell migration into the bone marrow, we have here investigated effects of various concentrations of stromal cell-derived factor-1 (SDF-1), bradykinin- and ATP on bone marrow metastasis. We show for first time that bradykinin augmented chemotactic responsiveness of neuroblastoma cells to SDF-1 and ATP concentrations, encountered under physiological conditions. Bradykinin upregulated VEGF expression, increased metalloproteinase activity and induced adhesion of neuroblastoma cells. Bradykinin augmented SDF-1-induced intracellular Ca2+ mobilization as well as resensitization and expression of ATP-sensing P2X7 receptors. Bradykinin treatment resulted in higher gene expression levels of the truncated P2X7B receptor compared to those of the P2X7A full-length isoform. Bradykinin as pro-metastatic factor induced tumor proliferation that was significantly decreased by P2X7 receptor antagonists; however, the peptide did not enhance cell death nor P2X7A receptor-related pore activity, promoting neuroblastoma growth. Furthermore, immunodeficient nude/nude mice transplanted with bradykinin-pretreated neuroblastoma cells revealed significantly higher metastasis rates compared to animals injected with untreated cells. In contrast, animals receiving Brilliant Blue G, a P2X7 receptor antagonist, did not show any specific dissemination of neuroblastoma cells to the bone marrow and liver, and metastasis rates were drastically reduced. Our data suggests correlated actions of kinins and purines in neuroblastoma dissemination, providing novel avenues for clinic research in preventing metastasis.
Highlights
Neuroblastoma is the most common pediatric extracranial solid tumor and present as metastatic disease in about 50% of patients (Kucia et al, 2005a)
We have focused on biological responses to stimulation of exogenously administered BK on neuroblastoma cell lines, such as chemotaxis in response to stromal-derived factor-1 (SDF-1) and adenosine triphosphate (ATP), expression and sensitization of CXCR4 and purinergic receptors, ATP-induced pore formation, cell proliferation, adhesion, Matrix metalloproteinases (MMPs) activities, VEGF expression and cytoskeleton rearrangement in vitro, as well as induction of neuroblastoma cell dissemination in vivo
We postulate that BK, secreted by the bone marrow (BM), enhances adhesion, invasion, angiogenesis and sensitizes CXCR4 to promote metastasis of neuroblastoma cells to the BM (Figure 1C)
Summary
Neuroblastoma is the most common pediatric extracranial solid tumor and present as metastatic disease in about 50% of patients (Kucia et al, 2005a). Kinin and Purine in the Metastasis targets causing neuroblastoma metastatic dissemination is of particular interest for advanced stage neuroblastoma patients, which despite aggressive treatment still show overall survival rate less than 40%. Chemo- and radiotherapy are the most important and effective therapeutic modalities used in cancer treatment, these are associated with undesired expression and release of several pro-metastatic factors, such as molecules related to inflammatory processes creating a favorable microenvironment for seeding of tumor cells that have survived treatment (Ratajczak et al, 2013). The C-X-C chemokine receptor type 4 (CXCR4) and its ligand, α-chemokine stromal-derived factor-1 (SDF-1), secreted by BM stroma supposedly participate in establishment of BM metastasis by neuroblastoma cells (Geminder et al, 2001). We here propose the existence of other mechanisms regulating neuroblastoma trafficking to the BM and/or increasing responsiveness of neuroblastoma to SDF-1 by sensitization or overexpression of the CXCR4
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