Oxidative stress, inflammation, and cancer: how are they linked?

Abstract

Extensive research during the past 2 decades has revealed the mechanism by which continued oxidative stress can lead to chronic inflammation, which in turn could mediate most chronic diseases including cancer, diabetes, and cardiovascular, neurological, and pulmonary diseases. Oxidative stress can activate a variety of transcription factors including NF-κB, AP-1, p53, HIF-1α, PPAR-γ, β-catenin/Wnt, and Nrf2. Activation of these transcription factors can lead to the expression of over 500 different genes, including those for growth factors, inflammatory cytokines, chemokines, cell cycle regulatory molecules, and anti-inflammatory molecules. How oxidative stress activates inflammatory pathways leading to transformation of a normal cell to tumor cell, tumor cell survival, proliferation, chemoresistance, radioresistance, invasion, angiogenesis, and stem cell survival is the focus of this review. Overall, observations to date suggest that oxidative stress, chronic inflammation, and cancer are closely linked.

Figure 1. Schematic representation of various activators and inhibitors of reactive oxygen species production

Figure 2. Schematic representation of various transcription factors that are modulated by reactive oxygen species

Figure 3. Model of a balance between pro-oxidants and anti-oxidants

Under normal conditions, anti-oxidants outbalance pro-oxidants, but under oxidative conditions, pro-oxidants prevail over anti-oxidants, which can lead to many inflammatory diseases including cancer.

Figure 4. Model of the sensitivity of normal cells versus cancer cells to reactive oxygen species

Normal cells are hypersensitive to ROS if not adequately protected by anti-oxidant mechanisms, which may lead to cancer formation. Cancer cells, on the other hand, have upregulated antioxidant mechanisms (glutathione, SOD, catalase, and others) that will protect them against ROS, as can be observed in, for example, the case of radioresistance.