Iron metabolism in colorectal cancer: a balancing act

Abstract

Background Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second deadliest malignancy worldwide. Current dietary habits are associated with increased levels of iron and heme, both of which increase the risk of developing CRC. The harmful effects of iron overload are related to the induction of iron-mediated pro-tumorigenic pathways, including carcinogenesis and hyperproliferation. On the other hand, iron deficiency may also promote CRC development and progression by contributing to genome instability, therapy resistance, and diminished immune responses. In addition to the relevance of systemic iron levels, iron-regulatory mechanisms in the tumor microenvironment are also believed to play a significant role in CRC and to influence disease outcome. Furthermore, CRC cells are more prone to escape iron-dependent cell death (ferroptosis) than non-malignant cells due to the constitutive activation of antioxidant genes expression. There is wide evidence that inhibition of ferroptosis may contribute to the resistance of CRC to established chemotherapeutic regimens. As such, ferroptosis inducers represent promising therapeutic drugs for CRC. Conclusions and perspectives This review addresses the complex role of iron in CRC, particularly in what concerns the consequences of iron excess or deprivation in tumor development and progression. We also dissect the regulation of cellular iron metabolism in the CRC microenvironment and emphasize the role of hypoxia and of oxidative stress (e.g. ferroptosis) in CRC. Finally, we underline some iron-related players as potential therapeutic targets against CRC malignancy.

Clinicopathological Differences between Right and Left Colorectal Cancer by Sex

“…Consequently, the more frequent occurrence of anemia in RCC may be due to IDA caused by prolonged low-grade loss of iron-rich blood close to the base of the RCC, leading to the gradual depletion of body iron stores [21,22]. Iron deficiency is essential in deoxyribonucleic acid damage by reducing Fe-S clusters, leading to genomic instability [23].…”

Insight into Iron, Oxidative Stress and Ferroptosis: Therapy Targets for Approaching Anticancer Strategies

“…Consistently, higher levels of dietary iron have also been associated with the development of colorectal cancer [ 69 ]. Moreover, patients with colorectal cancer, as well as cancer cells themselves, have deregulated iron metabolism, confirming this metal’s direct involvement in cancer development and progression [ 70 , 71 ]. More generally, current dietary habits associated with iron overload can be associated with an increased risk of developing neoplasms because of the induction of iron-mediated protumorigenic pathways, including hyperproliferation [ 64 ].…”

The Regulation of Ferroptosis by Noncoding RNAs

“…Iron is an essential trace element for virtually all living organisms. It plays important roles in many physiological and cellular processes, including oxygen transport, energy production, and cellular proliferation [1,2]. Because of its importance, iron levels are finely tuned in living organisms, and iron overload can damage an organism through a variety of mechanisms, including the induction of a kind of regulated cell death, ferroptosis.…”