The role of nitric oxide and reactive oxygen species in the induction of platelet aggregation by SW480 and SW620 human colon tumor cells

• Grant number: 19/16836-7
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): May 01, 2020
• Effective date (End): September 30, 2023
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Hugo Pequeno Monteiro
• Grantee: Fernanda Lima Torres de Aquino
• Host Institution: Centro de Terapia Celular e Molecular. Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 18/15038-7 - Tumor development under the perspective of redox signaling: temporal modulation of the production of nitric oxide and reactive oxygen species, AP.TEM

Abstract

According to the World Health Organization (WHO), Cancer is the second leading cause of death in the world and in 2018 has caused more than nine million deaths. Among the various types of Cancer, Colorectal Cancer, which includes solid tumors in one segment of the large intestine (the colon) and the rectum, is the third most frequent type of Cancer in men and the second in women in Brazil. The tumor microenvironment is often described as a "non-healing wound" suggesting that the Cancer promotes a chronic inflammatory condition regulated by specialized cells, inflammatory cytokines, and reactive species such as ROS and NO that directly influence cell signaling processes and also act in the epithelial-mesenchymal - EMT and mesenchymal-epithelial - MET transitions, indirectly modulating tumor dissemination. In addition, it is well established that patients with solid tumors have an abnormal activation of the coagulation system, with consequent thromboembolism. This facilitates tumor dissemination through the secretion of bioactive lipids, proteins and the expression of surface molecules present in platelets. These allow the formation of an adequate environment for safe transport, facilitating tumor dissemination. Since distant organ metastasis depends on the interaction between tumor cells and the lymphatic and blood microenvironment. However, the mechanisms involved in the interaction of platelets with tumor cells; molecules involved in the recognition and activation of platelet aggregation; as well as, the modus operandi of how the transport of these cells is made, have not yet been fully elucidated. Thus, studies aimed at understanding the mechanisms involved in platelet aggregation stimulated by tumor cells are essential in the development of therapeutic strategies to prevent and combat an association between progression of CRC and thromboembolism. The aim of the present study is to investigate the role of NOS2-induced NO generation in human CCR cell lines in the regulation of platelet aggregation induced by tumor cells and in the induction of the mesenchymal-epithelial transition in three experimental situations: in cells obtained from primary site-acquired CCR SW480 cells incubated with isolated human platelets; SW620 cells that are metastasis in SW480 cell lymph nodes incubated with isolated human platelets and I12 cells from SW620 cells which had the expression of the permanently silenced NOS2 enzyme incubated with isolated human platelets. The results obtained in this study will allow to experimentally evidence the role of NO and ROS in the activation of platelet aggregation and its possible association with the MET transition. (AU)