Abstract
Cancer is the third most frequent cause of death in the world, and metastasis is responsible for over 90% tumor-associated mortality. The most common locations of metastasis are the lungs and bone marrow. It has been demonstrated that the stromal cell-derived factor-1 (SDF-1)-CXCR4 axis plays an important role in bone-marrow metastasis.In conditions of chronic inflammation or tissue damage, an environment is generated, where circulating stem cells are attracted for tissue/organ regeneration. Similar conditions might attract cancer stem cells directed by inflammation-related molecules and thereby induce metastatic behavior of cells. Therefore, bradykinin (BK), extracellular purines (ATP) and nitric oxide (NO) known to be involved in hematopoiesis and closely inflammation-related molecules will be studied in cancer metastasis to the bone marrow.We have found that BK precursor kininogen expression is increased in mimetic models of radiation therapy. Moreover, BK exerts a "priming" effect in neuroblastoma cells, i.e., augments cellular responses to physiological concentrations of SDF-1. Here, lipid rafts formation, which are lipid membranes enriched for various signaling molecules that facilitate CXCR4 receptor activation, will be also considered. Further, effects of a bradykinin-potentiating peptide (BPP-5a) will be determined chemotaxis of neuroblastoma cells. As an underlying mechanism for BPP-5a action, it is known that this peptide shows strong activity in enhancing BK-induced effects, regardless angiotensin converting enzyme inhibiting, while involving BK receptor activation.It was shown that NO has a pleiotropic effect on platelet aggregation, immune response and signaling of tumor progression, all of which affect the tumor cells metastasis. On one hand, nitric oxide synthase (NOS) activation and elevation in NO production have anti-tumor effects; however, on the other hand, it has also been reported that NO can promote the cancer formation and progression. Therefore, we will study the role of NO in neuroblastoma cells metastasis to the bone marrow following stimulation with the pro-metastatic agents SDF-1, BK and ATP. BPP-10c, an antihypertensive peptide, that induces NO production, will be used in these studies. This peptide increases levels of L-arginine due to argininosuccinate synthase (ASS) activation, a step-limiting enzyme in the L-arginine biosynthesis into NO-citrulline cycle for NO production.Potential therapeutic applications of BPP-10c will also be evaluated for the cancer and metastasis treatment. The reduced ASS expression in various types of cancer is a predictive biomarker for metastasis development; thus is associated with a poor clinical outcome. Therefore, we expect that BPP-10c reverses the neuroblastoma metastatic potential due to activation and induction of enzyme expression in tumor cells.Inter-relationships between purinergic and kallikrein-kinin systems in neuroblastoma cells metastasis have been observed. We have also found that BK "priming" effects result in differential purinergic receptor expression levels, including a significant increased P2X7 subtype expression. Several P2X7 receptor isoforms exist, named P2X7A-J. Thus, to investigate the contribution of each isoform will provide information of the interaction mechanism between the two systems (purines and kinins) for cancer promotion.We also intend to clarify the role of P2X7 receptors as anti-metastatic and pro-metastatic mechanism, depending on the expression site, considering the individual (host), using knockout animals for the P2X7 receptor or cancer cells subjected to RNA interference for down-regulating P2X7 receptor expression in neuroblastoma cells.Thus, this project aims to clarify the mechanisms, by which tumor cells metastasize. Studying how NO, kallikrein-kinin and purinergic systems interfere with tumor biology might open avenues to apply molecular strategies to inhibit metastatic pathways. (AU)
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