fig1

Figure 1. Tumorigenesis requires hypoxic driven metabolic reprogramming for metastatic progression. The progression of malignant states during carcinogenesis involves changes occurring within the tumor microenvironment, including regions of hypoxia, hypoglycemia and acidosis. These regions are where cancer cells evolve into pre-metastatic states after selection by the harmful conditions, resulting in the altered capacity for increased ROS production and protection from the greater oxidative stress. Eventually, other mutations (such as in cell cycle regulatory proteins, p53 or ARF) occur which allow the cells to adapt by further metabolic reprogramming to emerge as highly pro-oxidative metastatic cells. HIF: hypoxia-induced factor; PGC1α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; NRF: nuclear respiratory factor; ROS: reactive oxygen species