Integrated Analysis of Cancer Risk from Metabolic Dysfunction: Biological Mechanisms and Tipping Points

Abstract

Abstract Obesity and metabolic syndrome are associated with the incidence of cancer, and they are rising epidemics. Therefore, clarification of the biological mechanisms of metabolic cancer risk is needed to guide strategies to intercept any elevated cancer risk resulting from metabolic syndrome. This study addressed whether interactions among known biological mechanisms elevate cancer risk, and which mechanisms offer the best leverage points for preventing any resulting cancer risk. It used a systems approach to examine the network of biological mechanisms, with special attention to clinically important feedbacks and tipping points. The results show that while no single mechanism leads from metabolic dysfunction to cancer risk, the integrated network of known mechanisms does. Metabolic syndrome collectively, and most of its components individually, induce documented oncogenic pathways. A network of such pathways leads from metabolic dysfunction to oncogenesis. This network includes self-reinforcing feedback loops, mostly centered on systemic metabolic inflammation, that can create tipping points into chronically dysfunctional metabolism with elevated cancer risk. Optimal interventions to reduce cancer risk should preempt these tipping points by targeting elements of metabolic dysfunction upstream of known feedback loops.