Flipside of the Coin: Iron Deficiency and Colorectal Cancer

Abstract

Iron deficiency, with or without anemia, is the most frequent hematological manifestation in individuals with cancer, and is especially common in patients with colorectal cancer. Iron is a vital micronutrient that plays an essential role in many biological functions, in the context of which it has been found to be intimately linked to cancer biology. To date, however, whereas a large number of studies have comprehensively investigated and reviewed the effects of excess iron on cancer initiation and progression, potential interrelations of iron deficiency with cancer have been largely neglected and are not well-defined. Emerging evidence indicates that reduced iron intake and low systemic iron levels are associated with the pathogenesis of colorectal cancer, suggesting that optimal iron intake must be carefully balanced to avoid both iron deficiency and iron excess. Since iron is vital in the maintenance of immunological functions, insufficient iron availability may enhance oncogenicity by impairing immunosurveillance for neoplastic changes and potentially altering the tumor immune microenvironment. Data from clinical studies support these concepts, showing that iron deficiency is associated with inferior outcomes and reduced response to therapy in patients with colorectal cancer. Here, we elucidate cancer-related effects of iron deficiency, examine preclinical and clinical evidence of its role in tumorigenesis, cancer progression and treatment response. and highlight the importance of adequate iron supplementation to limit these outcomes.

Iron Deficiency in Heart Failure: Mechanisms and Pathophysiology

“…Contrastingly, increasing evidence suggests that patients with HF have an increased risk of developing cancer [ 163 , 164 , 170 ]. Interestingly, iron has emerged as a potential cause for tumorigenesis, especially in colorectal cancer [ 171 , 172 , 173 , 174 ]. The contribution of ID to the incidence of cancer in HF patients is not yet elucidated and worth further investigation.…”

Pre-Clinical Insights into the Iron and Breast Cancer Hypothesis

“…Thus, there appeared to be an iron-deficiency-specific effect on the development of mammary cancer. We judge that this is important for population studies since previous cycles of publications suggested that future studies of iron–cancer hypotheses are likely to be reported, if not in breast then minimally in other organ sites [ 62 ]. The more meaningful effects of either low or high iron status on cancer risk should be assessed by making the referent group chosen for comparison be the iron-adequate group, as judged using clinical standards of iron status assessment.…”

The Macrophage Iron Signature in Health and Disease

“…In this setting, GI MΦ are of particular importance, since they are major local producers of cytokines, thus creating the inflammatory microenvironment [45][46][47], and they are also the main iron-retaining cells due to downregulation of the iron exporter FPN1 under inflammation [36,48]. Moreover, impairment of the immune response has been reported both during iron deficiency and overload (reviewed in [49,50]), likely reflecting a narrow range for cellular iron levels promoting proper immune responses, which may have consequences for MΦ immunosurveillance. In fact, several studies have described a link between Helicobacter pylori stomach infection and iron-deficiency anemia [51][52][53], but a clear physiological mechanism and potential relationship with MΦ iron handling remains unexplained.…”