Cancer bioenergetics as emerging holistic cancer theory: the role of metabolic fluxes and transport proteins involved in metabolic pathways in the pathogenesis of malignancies. State-of-the-art and future prospects

Abstract

Cancer represents a global health concern, imposing a severe burden both from a societal and clinical perspective. Despite the latest advancements and achievements in the treatment and management of malignancy, cancer still imposes a dramatically high burden worldwide. Different theories (biophysical or biochemical, genetic or epigenetic) related to the origin of tumor cells have been put forth. These theories can also be subdivided into reductionist and emergentist/holistic theories. In the current overview, we will focus only on the cancer metabolic theory, one of the emergentist/holistic theories: it is holistic in that maintains that pathways, cascades and networks controlling energy metabolism, as well as those devoted to cell growth, cell cycle, replication, division and other cellular processes are highly interwoven and interconnected, and cannot be understood if not assuming a systems biology perspective. Cells should be seen as metabolic factories, in which metabolic fluxes and circuits (anabolic and catabolic) are plastically re-wired on the basis of the internal/external stimuli (cell make-up and genetic determinants, micro-environment, etc.). Complex regulatory and meta-regulatory systems exist that finely tune the functioning of cell, cell-cell communication and its interaction with the surrounding environment. At the tissue level, not all tissues share the same degree of metabolic plasticity (metabolic rigidity vs. metabolic flexibility), even though some metabolic coupling systems exist in order to guarantee an overall minimum extent of metabolic plasticity. The same broad picture of molecular events is necessary when describing the impairment and dysregulation of these processes, leading to multi-stage phenomena, including carcinogenesis.