Reactive Oxygen Species in the Tumor Microenvironment: An Overview

Abstract

Reactive oxygen species (ROS) are important signaling molecules in cancer. The level of ROS will determine physiological effects. While high levels of ROS can cause damage to tissues and cell death, low levels of ROS can have a proliferative effect. ROS are produced by tumor cells but also cellular components that make up the tumor microenvironment (TME). In this review, we discuss the mechanisms by which ROS can affect the TME with particular emphasis on tumor-infiltrating leukocytes. Greater insight into ROS biology in this setting may allow for therapeutic manipulation of ROS levels in order to remodel the tumor microenvironment and increase anti-tumor activity.

Keywords: ROS; metabolism; mitochondria; stroma; tissue infiltrating lymphocytes; tumor microenvironment; tumorigenesis.

Figure 1

The mitochondria are the major contributor to cellular reactive oxygen species (ROS) levels while oxidative enzymes (e.g., NAPDH oxidases, cyclooxygenases, lipooxygenases and thymidine phosphorylase) also contribute to cellular ROS pooles. Mitochondrial ROS have many effects on cellular biology including, Mitogen-activated protein kinase (MAPK) (e.g., extracellular-signal-regulated kinase (ERK), p38 MAPK, Jun N-terminal kinase (JNK)), induction of transcription factors (e.g., nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κβ), hypoxia-inducible transcription factors (HIF), activator protein 1 (AP-1), nuclear respiratory factor (NRF), heat shock factor 1 (HSF-1)) and deregulation of protein phosphatases (e.g., phosphatase and tensin homolog (PTEN)). This leads to enhancement of angiogenesis in the case of HIF, survival, growth, altered metabolism and other cellular processes through MAPKs, transcriptional factors and protein phosphatase and immune cell function and regulation.

Figure 2

(A) Reactive oxygen species (ROS) generated by the mitochondria and/or exogenous sources within a tumor cell affect tumor immunity to promote a more tumorigenic environment. Mitochondrial ROS (mROS) can stimulate differentiation of cancer-associated fibroblasts (CAFs) and ROS produced by the tumor cell can facilitate uptake of exosomes through caveolin-1 inhibition leading to metabolic reprogramming of certain CAFs. ROS can also affect the function of tumor-infiltrating T-cells depending on the level of mROS. Myeloid-derived suppressor cells (MDSCs) and tumor-associated Macrophages (TAMs) also produce ROS that can affect the function of other immune cells and ROS can affect regulatory T-cell function as well. (B) The amount of ROS corresponds to differing effects on biological function. While cytostatic levels of ROS lead to maintenance of biological processes, cytotoxic levels of ROS lead to cell death as well as immune deregulation. Tumor promotion through ROS occurs when ROS reach super-physiological or cytostatic levels while avoiding levels conducive to cell death. As mentioned previously, oxidative stress can arise from tumor cells.