In an adult individual, the tissues are renewed by differentiation and proliferation of stem-cells. Changes in the regulation of self-renewal induce events which can initiate the development of cancer, such as neuroblastoma, a malignant neuroepithelial tumor originating from stem cells that are precursors of the sympathetic nervous system. Cancer stem cells (CSCs) which are present in tumor mass, are defined as self-renewing tumor cells capable of initiating tumor formation and sustaining tumor growth. Another striking feature of CSC is their resistance to conventional anticancer therapies such as chemo and radiotherapy. In this project, the role of the nitrergic system in the maintenance of CSCs in the tumor mass of the neuroblastoma and the resistance to the chemotherapeutic treatments will be studied. Nitric oxide (NO) is the key molecule of the nitrergic system. This gas molecule is produced within the citrulline-NO cycle, where argininosuccinate synthase (ASS) is an essential enzyme, since it is the rate-limiting step in the supply of L-arginine substrate for the synthesis of NO by the NO synthase enzyme (NOS). Lameu et al. (2012) have reported that the inhibition of NOS and ASS maintain the neural stem cells in a proliferative and undifferentiated state, while the supply of substrate for NO production leads to neuronal differentiation. These results show the importance of NO signaling in the balance between undifferentiated and differentiated cells, at least for normal stem cells. The fundamental role of these key-enzymes from the NO-citrulline cycle in maintaining the neuroblastoma CSC and the influence of this system over neuroblastoma resistance to chemotherapeutic agents will be also evaluated.
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