Revisiting Epithelial Carcinogenesis

Abstract

The origin of cancer remains one of the most important enigmas in modern biology. This paper presents a hypothesis for the origin of carcinomas in which cellular aging and inflammation enable the recovery of cellular plasticity that may ultimately result in cancer. The process is described as the result of dedifferentiation undergone by epithelial cells in hyperplasia due to replicative senescence towards a mesenchymal cell state with potential cancerous behavior. In support of the hypothesis, the molecular, cellular, and histopathological evidence was critically reviewed and reinterpreted when necessary to postulate a plausible generic model for the origin and progression of carcinomas. In addition, the implications of this theoretical framework for the current strategies of cancer treatment are discussed against recent evidence of the molecular events underlying the epigenetic switches involved in the resistance of breast carcinomas. Subsequently, is proposed an epigenetic landscape for their progression and a potential mechanism to restrain the degree of dedifferentiation and malignant behavior. Finally, is suggested a novel understanding of the involution and carcinogenesis of tissues associated with aging as a perspective that might inspire integrative approaches in the study and management of chronic diseases.