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Investigation of purinergic and nitrergic signaling in the maintenance of the Cancer Stem Cells (CSCs) in neuroblastoma tumor mass and metastatic mechanisms tissue-specific

Grant number: 16/22124-1
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): April 01, 2017
Effective date (End): September 30, 2018
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Claudiana Lameu
Grantee:Poliana Cristina de Melo Martins
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil


In an adult the tissues are renewed by differentiation and proliferation of stem-cells and changes in the regulation of self-renewal can initiate the development of cancer. Cells involved in tumor maintenance are described in tumor mass, especially proliferating cells and Cancer Stem Cells (CSCs) with normal stem cell properties. In this research the misappropriation of mechanisms that regulate the tissue repair and self-renewal of stem cells for tumor maintenance will be investigated, with emphasis on the action of purinergic and nitrergic systems in maintaining CSCs in neuroblastoma, and the synergism of these signaling systems in the chemotaxis of neuroblastoma cells in vitro and in vivo metastasis. Studies developed by Prof. Lameu show the involvement of purinergic system in the regulation of neural differentiation of normal stem cells, and an interrelation between the purinergic system and the kallikrein-kinin system in the control of neuroblastoma metastases to bone marrow, where the main agonist purinergic system (ATP) significantly increased chemotactic response of neuroblastoma cells to different concentrations of bradykinin (BK). The reverse also resulted in a significant increase in migration of neuroblastoma cells. Relative to nitrergic system will be evaluated the involvement of nitric oxide-citrulline cycle (NO) in the regulation of proliferation and differentiation of SSCs. In this cycle the Argininosuccinate Synthase enzyme (AS) is an essential because it limits the delivery of L-arginine substrate for NO synthesis by the enzyme NO synthase (NOS). Lameu et al. (2012) reported that the inhibition of NOS and AS 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 signaling of NO in the undifferentiated and differentiated cells balance. The role of these enzymes in maintaining the neuroblastoma CSC and the influence of these system neuroblastoma metastases to bone marrow. The fundamental role of these enzymes cyclo-citrulline in maintaining the neuroblastoma CSC and the influence of this system neuroblastoma metastases to bone marrow will be also evaluated. (AU)

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