Iron is a fundamental mineral required for numerous biological processes within the human body. Its presence and metabolism can significantly influence the initiation, progression, and potential treatment responses of various cancers. This article explores how iron impacts cancer cells, from its normal functions to its role in disease development and therapeutic strategies.
Iron’s Essential Functions in the Body
Iron plays widespread roles in maintaining human health. Approximately 70% of the body’s iron is found in hemoglobin, a protein in red blood cells that transports oxygen from the lungs to tissues throughout the body. Myoglobin, a protein in muscle cells, also stores oxygen for muscle use.
Beyond oxygen transport, iron is a component of many proteins and enzymes involved in metabolism. It is a cofactor for enzymes involved in oxidative phosphorylation, which converts nutrients into energy. Iron is also involved in DNA synthesis, electron transport, and maintaining a properly functioning immune system.
How Cancer Cells Acquire and Utilize Iron
Cancer cells exhibit altered iron metabolism due to their rapid growth and increased metabolic demands. They have a higher iron requirement compared to healthy cells, needing it for processes like DNA replication and proliferation. To meet this heightened demand, cancer cells often upregulate mechanisms for iron import.
One primary mechanism involves increasing the expression of transferrin receptor 1 (TFR1) on their surface, allowing them to absorb more iron from the bloodstream. Cancer cells may also alter the activity of iron regulatory proteins (IRPs), particularly IRP2, which helps maintain iron balance within tumor cells. Other acquisition methods include:
Heme importers like HCP1, CD91, and CD193.
Increased ferritinophagy, a process that degrades ferritin-iron complexes to release more bioavailable iron.
These changes collectively lead to an elevated labile iron pool (LIP) within cancer cells, creating an iron-rich environment that supports their aggressive growth, DNA synthesis, and potential to spread.
Iron Overload and Cancer Development
Excessive iron levels, known as iron overload, can contribute to the development and progression of cancer. This condition can arise from genetic disorders like hereditary hemochromatosis, where iron regulation is impaired, or from factors such as frequent blood transfusions or excessive iron supplementation. In individuals with hereditary hemochromatosis, chronic iron overload in the liver can lead to inflammation, fibrosis, and cirrhosis, which are precursors to hepatocellular carcinoma (HCC).
High iron levels promote the generation of reactive oxygen species (ROS) through the Fenton reaction. This leads to oxidative stress, which can damage cellular components, including proteins and DNA, potentially causing mutations that contribute to cancer initiation and growth. Elevated serum iron levels might increase the risk of certain cancers, including liver, breast, and colon cancer. While iron overload supports tumor growth by providing necessary nutrients for replication and survival, cancer cells can also develop enhanced antioxidant defenses to protect themselves from excessive ROS-induced damage.
Therapeutic Strategies Targeting Iron in Cancer
Understanding how cancer cells depend on iron has opened avenues for potential therapeutic strategies. One approach involves iron chelation, which uses agents to remove excess iron from the body or specifically from cancer cells. Iron chelators, such as deferoxamine (DFO) and deferasirox (DFX), aim to induce iron deficiency within tumor cells, thereby inhibiting their proliferation. These agents can bind to the free iron within the labile iron pool, disrupting the metabolic processes essential for cancer cell survival.
Another strategy focuses on modulating ferroptosis, a form of iron-dependent regulated cell death. Lipophilic chelators and their iron complexes are being explored to induce ferroptosis in certain resistant or recurring tumors. Researchers are also investigating ways to target iron uptake pathways, such as disrupting the overexpression of transferrin receptors on cancer cell surfaces, to limit their iron acquisition. These approaches aim to exploit cancer cells’ heightened iron dependence, making them more susceptible to treatment and potentially overcoming drug resistance.
Dietary Iron and Cancer Risk
Dietary iron intake can influence cancer risk, though the relationship is nuanced. Iron from food sources is categorized into two types: heme iron, primarily found in animal products like red meat, poultry, and fish, and non-heme iron, found in plant-based foods such as nuts, grains, vegetables, and fruits. Heme iron is generally more readily absorbed by the body compared to non-heme iron.
Some epidemiological studies suggest a possible link between high dietary heme iron intake and an increased risk of certain cancers, including colorectal cancer. For example, some research indicates that replacing heme iron with non-heme iron may lower colorectal cancer risk. However, the evidence for a direct association between total dietary iron intake and cancer risk remains inconsistent, and women may show different sensitivities than men due to variations in iron metabolism. Individuals should not restrict their iron intake without consulting a healthcare professional. A balanced diet remains the best approach, and any concerns about iron levels should be discussed with a doctor for personalized guidance.