Iron imbalance in cancer: Intersection of deficiency and overload.

Abstract

Iron, an essential trace element, plays a complex role in tumour biology. While iron causes cancer clearance through toxic free radical generation, iron‐induced free radical flux also acts as a cancer promoter. These fates majorly guided through cellular response towards pro‐oxidant and antioxidant settings in a tumour microenvironment, designate iron‐induced oxidative stress as a common yet paradoxical factor in pro‐tumorigenesis as well as anti‐tumorigenesis, posing a challenge to laying down iron thresholds favouring tumour clearance. Additionally, complexity of iron's association with carcinogenesis has been extended to iron‐induced ROS's involvement in states of both iron deficiency and overload, conditions identified as comparable, inevitable and significant coexisting contributors as well as outcomes in chronic infections and tumorigenesis. Besides, iron overload may also develop as an unwanted outcome in certain cancer patients, as a result of symptomatic anaemia treatment owed to irrational iron‐restoration therapies without a prior knowledge of body's iron status with both conditions synergistically acting towards tumour aggravation. The co‐play of iron deficiency and overload along with iron's pro‐tumour and antitumour roles with intersecting mechanisms, thus presents an unpredictable regulatory response loop in a state of malignancy. The relevance of iron's thresholds beyond which it proves to be beneficial against tumorigenesis hence becomes questionable. These factors pose a challenge, over establishing if iron chelation or iron flooding acts as a better approach towards antitumour therapies. This review presents a critical picture of multiple contrasting features of iron's behaviour in cancer, leading towards two conditions lying at opposite ends of a spectrum: iron deficiency and overload in chronic disease conditions including cancer, hence, validating the critical significance of diagnosis of patients' iron status prior to opting for subsequent therapies.