The integrated theory of carcinogenesis: cancer as dysregulated persistence under chronic systemic stress

Cancer may arise less from broken genes than from a collapse of regulatory control. Mutation-based models do not fully explain why normal tissues tolerate large mutational burdens, why some tumors lack recurrent drivers, or why malignant nuclei can be reprogrammed in healthy cytoplasm. This article proposes the Integrated Theory of Carcinogenesis (ITC), which reframes cancer as dysregulated persistence under chronic systemic stress. A central mediator in this model is mitochondrial uncoupling protein 2 (UCP2), a stress-responsive regulator of metabolism and redox balance. Sustained oxidative, inflammatory, metabolic, and neurohormonal stress is proposed to preserve UCP2 expression, suppress differentiation, resist apoptosis, and stabilize stem-like states. Mutations remain an important part of the narrative; however, within the ITC they are interpreted mainly as downstream consequences or context-dependent accelerators within a destabilized regulatory landscape. By positioning UCP2 as a central molecular hinge between systemic dysregulation and malignant transformation, the ITC offers a unifying explanation for longstanding anomalies and outlines testable paths toward prevention and therapy, including metabolic and lifestyle interventions.