The Tumor Microenvironment: Characterization, Redox Considerations, and Novel Approaches for Reactive Oxygen Species-Targeted Gene Therapy

The tumor microenvironment is a complex system that involves the interaction between malignant and neighbor stromal cells embedded in a mesh of extracellular matrix (ECM) components. Stromal cells (fibroblasts, endothelial, and inflammatory cells) are co-opted at different stages to help malignant cells invade the surrounding ECM and disseminate. Malignant cells have developed adaptive mechanisms to survive under the extreme conditions of the tumor microenvironment such as restricted oxygen supply (hypoxia), nutrient deprivation, and a prooxidant state among others. These conditions could be eventually used to target drugs that will be activated specifically in this microenvironment. Preclinical studies have shown that modulating cellular/tissue redox state by different gene therapy (GT) approaches was able to control tumor growth. In this review, we describe the most relevant features of the tumor microenvironment, addressing reactive oxygen species-generating sources that promote a prooxidative microenvironment inside the tumor mass. We describe different GT approaches that promote either a decreased or exacerbated prooxidative microenvironment, and those that make use of the differential levels of ROS between cancer and normal cells to achieve tumor growth inhibition. Antioxid. Redox Signal. 19, 854–895. I. The Tumor Microenvironment A. Tumor microenvironment components 1. Malignant cells 2. Tumor-associated stromal cells a. Fibroblasts b. Tumor vasculature-associated cells c. Inflammatory cells 3. Extracellular matrix B. Tumor microenvironmental characteristics 1. Hypoxia a. General characteristics b. Molecular control of hypoxia 2. Tumor angiogenesis a. General characteristics b. Molecular control 3. Tumor metabolism a. General characteristics b. Molecular control 4. Tumor acidosis a. General characteristics b. Molecular control II. Redox Characterization of the Tumor Microenvironment A. ROS and cell sources B. Control of cellular redox homeostasis: the antioxidant system C. Altered ROS production in cancer cells 1. ROS production due to genetic alterations 2. mtROS produced by malignant cells 3. Deregulation of antioxidant mechanisms in cancer cells 4. ROS generated by the aberrant activity of malignant cells a. Cancer cell metabolism b. Cancer cell survival and proliferation c. Metastatic dissemination d. Cancer cell death 5. CSCs and redox consideration D. ROS generated by the tumor microenvironment 1. ROS generated by CAFs 2. ROS generated by inflammatory cells 3. ROS generated by ECs and the angiogenic process 4. ROS generated by the hypoxic microenvironment E. In vivo evidence of ROS generation in tumors III. ROS and Cancer Gene Therapeutics A. Introduction 1. Threshold ROS concept for cancer therapy 2. An overview of ROS-based cancer gene therapeutics B. GT strategies to modulate extra- or intracellular ROS levels 1. Decreasing ROS extra- or intracellular levels by GT strategies a. Overexpression of the antioxidant enzyme system in cancer cells b. Overexpression of the antioxidant enzyme system in the tumor stroma c. Knocking down NOXs d. Knocking down other ROS cell sources 2. Increasing intracellular levels of ROS by GT strategies in cancer cells a. Knocking down the antioxidant enzyme system (1) Superoxide dismutases (2) Peroxiredoxins (3) Glutathione peroxidases (4) The Trx system b. Overexpression of the antioxidant enzyme SOD c. Knocking down additional redox-associated cellular genes C. ROS-response elements to drive cancer gene therapeutics IV. Concluding Remarks and Future Perspectives