Tumor Microenvironment and Metabolism: Role of the Mitochondrial Melatonergic Pathway in Determining Intercellular Interactions in a New Dynamic Homeostasis.

There is a growing interest in the role of alterations in mitochondrial metabolism in the pathoetiology and pathophysiology of cancers, including within the array of diverse cells that can form a given tumor microenvironment. The 'exhaustion' in natural killer cells and CD8+ t cells as well as the tolerogenic nature of dendritic cells in the tumor microenvironment seems determined by variations in mitochondrial function. Recent work has highlighted the important role played by the melatonergic pathway in optimizing mitochondrial function, limiting ROS production, endogenous antioxidants upregulation and consequent impacts of mitochondrial ROS on ROS-dependent microRNAs, thereby impacting on patterned gene expression. Within the tumor microenvironment, the tumor, in a quest for survival, seeks to 'dominate' the dynamic intercellular interactions by limiting the capacity of cells to optimally function, via the regulation of their mitochondrial melatonergic pathway. One aspect of this is the tumor's upregulation of kynurenine and the activation of the aryl hydrocarbon receptor, which acts to metabolize melatonin and increase the N-acetylserotonin/melatonin ratio, with effluxed N-acetylserotonin acting as a brain-derived neurotrophic factor (BDNF) mimic via its activation of the BDNF receptor, TrkB, thereby increasing the survival and proliferation of tumors and cancer stem-like cells. This article highlights how many of the known regulators of cells in the tumor microenvironment can be downstream of the mitochondrial melatonergic pathway regulation. Future research and treatment implications are indicated.