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Figure 2. Intermittent hypoxia within the primary tumor microenvironment as a driver of mitochondrial ROS production and metastatic reprogramming. Mitochondrial ROS is produced extensively in cells undergoing rounds of intermittent hypoxia. In a similar manner to ischaemia/reperfusion in normal cells, the intermittent hypoxia of early primary cancer cells causes readjustments in redox homeostasis by increasing ROS activated NRF2 release from the outer redox hub (KEAP1/PGAM5) on the mitochondria, NRF2 transport to the nucleus and transcriptional activation of a large number of antioxidant defense response, including the GSH and Trx systems to counteract and detoxify the ROS. In addition, Bcl-2 and Bcl-XL are stabilized to promote cell survival under the conditions of pro-oxidative stress. NRF: nuclear respiratory factor; ROS: reactive oxygen species; Trx: thioredoxin; GSH: reduced glutathione
