Enhanced CRC Growth in Iron-Rich Environment, Facts and Speculations

Abstract

The contribution of nutritional factors to disease development has been demonstrated for several chronic conditions including obesity, type 2 diabetes, metabolic syndrome, and about 30 percent of cancers. Nutrients include macronutrients and micronutrients, which are required in large and trace quantities, respectively. Macronutrients, which include protein, carbohydrates, and lipids, are mainly involved in energy production and biomolecule synthesis; micronutrients include vitamins and minerals, which are mainly involved in immune functions, enzymatic reactions, blood clotting, and gene transcription. Among the numerous micronutrients potentially involved in disease development, the present review will focus on iron and its relation to tumor development. Recent advances in the understanding of iron-related proteins accumulating in the tumor microenvironment shed light on the pivotal role of iron availability in sustaining pathological tumor hallmarks, including cell cycle regulation, angiogenesis, and metastasis.

Keywords: colorectal cancer; intestinal microbiota; iron metabolism.

Figure 1

Schematic mechanisms of intestinal iron transport. The primary mechanism by which iron is absorbed into enterocytes is via the divalent metal ion transporter 1 (DMT1) on the luminal membrane after reduction by duodenal cytochrome b (DCYTB). Once in the intracellular labile iron pool, iron can be used directly for intrinsic cellular metabolic processes, stored as ferritin, or exported into circulation via ferroportin (FPN) after reduction by hephaestin (HEPH), a ferroxidase located on the basolateral membrane of enterocytes. Transferrins mediate the transport of iron through blood plasma.

Figure 2

Iron overload and CRC development. Elevated iron uptake by divalent metal transporter 1 (DMT-1) leads to iron accumulation in the colon resulting in several downstream effects. Increased iron levels enhance the production of reactive oxygen species (ROS), which promotes oxidative stress and DNA damage. This oxidative environment supports oncogene activation, further driving tumorigenesis. Additionally, the pro-inflammatory mediators released in response to iron accumulation amplify local inflammation, while changes in the gut microbiome (dysbiosis) further contribute to CRC growth and progression. Together, these processes create a microenvironment conducive to the development and progression of CRC.