The Roles of ROS in Cancer Heterogeneity and Therapy

Abstract

Cancer comprises a group of heterogeneous diseases encompassing high rates of morbidity and mortality. Heterogeneity, which is a hallmark of cancer, is one of the main factors related to resistance to chemotherapeutic agents leading to poor prognosis. Heterogeneity is profoundly affected by increasing levels of ROS. Under low concentrations, ROS may function as signaling molecules favoring tumorigenesis and heterogeneity, while under high ROS concentrations, these species may work as cancer modulators due to their deleterious, genotoxic or even proapoptotic effect on cancer cells. This double-edged sword effect represented by ROS relies on their ability to cause genetic and epigenetic modifications in DNA structure. Antitumor therapeutic approaches may use molecules that prevent the ROS formation precluding carcinogenesis or use chemical agents that promote a sudden increase of ROS causing considerable oxidative stress inside tumor mass. Therefore, herein, we review what ROS are and how they are produced in normal and in cancer cells while providing an argumentative discussion about their role in cancer pathophysiology. We also describe the various sources of ROS in cancer and their role in tumor heterogeneity. Further, we also discuss some therapeutic strategies from the current landscape of cancer heterogeneity, ROS modulation, or ROS production.

Figure 1

Quiescent and/or self-renewing stem cells display low levels of ROS due to their basal metabolism associated to an efficient antioxidant machinery. ROS can result from increased metabolism associated with dysfunctional mitochondria, oncogene activation, or cytokine/growth factor signaling that triggers ROS-producing enzymes: NADPH oxidases, cycloxygenases (COX), and lipoxygenases (LOX). ROS-induced Wnt/β-catenin signal in cancer stem-like cells. The exposure to oxidative stress activates Wnt pathway and upregulates c-Myc. In CSCs, c-Myc expression level varies from cell-to-cell contributing to cancer heterogeneity. Wnt activate downstream signaling molecules that promote the stabilization and accumulation of the β-catenin in the nucleus and leading to EMT, a hallmark of cancer.