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.
Department of Micro and Nanotechnology, National Atomic Energy Commission, Buenos Aires 1650, Argentina. lpolicastro@leloir.org.ar
Lucia Laura
LL
Policastro
Irene Laura
IL
Ibañez
Cintia
C
Notcovich
Hebe Alicia
HA
Duran
Osvaldo Luis
OL
Podhajcer
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006801:Humans; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D059016:Tumor Microenvironment
D000975:Antioxidants; D017382:Reactive Oxygen Species; D010088:Oxidoreductases