Impact of autonomic nervous system in cancer: associated mechanisms and effect of exercise training

• Grant number: 24/02973-0
• Support Opportunities: Research Projects - Thematic Grants
• Start date: February 01, 2025
• End date: January 31, 2030
• Field of knowledge: Biological Sciences - Physiology - Physiology of Effort
• Principal Investigator: Patricia Chakur Brum
• Grantee: Patricia Chakur Brum
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Pesquisadores principais: Anamaria Aranha Camargo ; Gilberto de Castro Junior
• Associated researchers: Christiano Robles Rodrigues Alves ; Cláudia Lúcia de Moraes Forjaz ; Elisângela Pinto Marinho de Almeida ; Juliane Cruz Campos ; Julio Cesar Batista Ferreira ; Leo Edmond Otterbein ; Luiz Henrique Marchesi Bozi ; Mariane Tami Amano ; Silvana Auxiliadora Bordin da Silva ; Telma Fátima da Cunha Moraes ; Vagner Roberto Antunes ; Vanessa Azevedo Voltarelli

Abstract

Recent data indicates that the autonomic nervous system, comprising the sympathetic and parasympathetic divisions, significantly contributes to the initiation and progression of cancer, thereby adversely affecting the patient's prognosis. It functions as a facilitator within the tumor microenvironment, promoting its growth and development. For instance, the sympathetic nervous system plays a role in immunomodulation, as well as cardiac and musculoskeletal changes associated with cancer, triggering systemic diseases, elevating the prevalence of cardiovascular risk factors, and leading to paraneoplastic syndromes like cachexia. While cancer treatment strategies have advanced and are linked to increased survival rates, their impact on cure rates and quality of life remains limited, accompanied by adverse effects such as fatigue, pain, cognitive impairment, cardiotoxicity, and muscle mass loss. Therefore, associated and complementary therapies that contribute to modulating the autonomic nervous system and mitigating the adverse effects of cancer and its treatment are of great scientific interest. Exercise training is an effective tool in modulating the autonomic nervous system, reducing sympathetic nervous activity, improving sympathovagal balance, and enhancing the function and structure of cardiac and skeletal muscles in other chronic diseases, such as heart failure. Evidence also suggests that exercise training influences the tumor microenvironment and immune system cells, resulting in a reduced rate of tumor growth. However, it remains unclear whether these positive effects of exercise training on both the tumor microenvironment and cardiac and skeletal muscles are associated with a decrease in autonomic dysfunction. The molecular mechanisms associated with the autonomic nervous system's action in cancer are not well understood. Nonetheless, our research group has explored some targets that appear to be modulated or interact with the autonomic nervous system and can potentially be influenced by exercise training. One of these targets is hemoxygenase-1, a protein involved in the degradation of the heme group of hemoglobin, releasing byproducts that contribute to preventing cellular damage and myopathy in systemic diseases. Another target is succinate, a metabolite of succinate dehydrogenase, an enzymatic complex in the inner membrane of mitochondria participating in the Krebs cycle and the electron transport chain. In this thematic project proposal, we aim to address gaps in the literature related to the modulation of the autonomic nervous system in cancer, with a focus on adrenergic signaling, through 10 scientific projects conducted in experimental models of cancer and clinical studies. The projects will be divided into two steps: Step 1 will explore the relationship between the autonomic nervous system and cancer, examining its influence on tumor growth, the immune system, morphofunctionality of cardiac and skeletal muscles, and molecular mechanisms. Step 2 will assess the effect of exercise training, aiming to evaluate its potential in reestablishing autonomic homeostasis and favoring control over disease progression. (AU)