Introduction:
Iron is crucial for the growth of cells, but it can also cause problems by creating harmful substances that damage DNA (deoxyribonucleic acid). In cancer, iron plays a significant role in tumor growth and spread. The normal ways cells get, release, and store iron are often disturbed in cancer. This suggests that targeting how the body handles iron could be a new way to treat cancer. Recent research shows that certain immune cells in tumors, called tumor-associated macrophages, are a source of iron. Targeting this iron source could improve cancer therapy.
What Are the Various Risk Factors Associated With Iron in Cancer Development?
Iron is vital for the body's functions, supporting cell growth and proliferation. However, an excess of iron can be harmful, especially when the balance is disrupted due to factors like genetics and lifestyle, potentially increasing the risk of cancer. Some hereditary and lifestyle risks are mentioned below:
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Excessive Iron Intake: Consuming too much iron is linked to various cancers, with colorectal cancer showing the strongest connection. Studies suggest that dietary iron overload, particularly from red and processed meat, may heighten the risk of certain cancers.
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Red Meat: Heme iron found in meat, especially red meat, appears to play a significant role in cancer development, particularly in gastrointestinal cancers. Compounds generated during the production and cooking of meat may contribute to carcinogenesis, with heme iron identified as a key factor.
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Genetic Cause: Hereditary conditions like hemochromatosis and beta-thalassemia, which involve iron imbalance, predispose individuals to cancer. Hemochromatosis, causing iron overload, is associated with an increased risk of liver cancer. Beta-thalassemia, characterized by improper hemoglobin production, may lead to iron overload and a higher risk of certain cancers.
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Smoking and Iron Metabolism: Cigarette smoke, a known cancer risk, is now linked to dysregulated iron metabolism. Changes in iron levels, including iron deposition, are suggested to precede the development of lung cancer and related pulmonary diseases in smokers.
What Are the Strategies to Control Iron in Tumor microenvironment?
Understanding how iron behaves in tumors is crucial for treating cancer. One key player is hepcidin, a gene sensitive to iron levels. Different strategies are being explored to influence hepcidin, such as using antibodies or drugs. There is a focus on reactivating iron release from the reticuloendothelial system, which can be compromised in cancer, leading to anemia. However, these approaches for treating cancer are still being closely examined before complete acceptance.
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Transferrin Receptor (TfR) - Another approach targets proteins like transferrin (Tf) involved in iron uptake by cancer cells. Anti-TfR antibodies, tested about 30 years ago, showed promise in some cancers like leukemia. Yet, concerns arise about their impact on healthy cells and the potential for causing anemia. A Trojan horse strategy using antibodies to deliver drugs directly to cancer cells is being investigated, showing improved drug uptake.
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Ferritin (FT) - Another factor to consider is the absorption of secreted FT by the TfR. FT forms cage-like structures that can assemble and disassemble within cells. This characteristic makes it an interesting subject for cancer-related nanostructure research. Naturally occurring FT structures are preferred over synthetic ones because they have low toxicity and trigger minimal immune responses. FT nanocages are employed to contain substances like Doxorubicin or gold ions, leading to the death of tumor cells.
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Lipocalin-2 (Lcn-2) - Consideration must be given to the fact that cancer cells may have developed new ways to acquire iron using less-known transport proteins. One such protein, Lcn-2, has the ability to scavenge iron-loaded siderophores. Siderophores are small molecules used by bacteria to capture iron. A recent study suggests that bacterial siderophores not only limit bacterial growth but also support the host's iron balance. Lcn-2 plays a crucial role in innate immunity, influencing iron transport. During infectious diseases, Lcn-2 controls neutrophil function. Neutrophils lacking Lcn-2 do not migrate to infection sites or respond to stimuli, but this can be reversed by adding recombinant Lcn-2.
Cells recognize and absorb Lcn-2 through specific receptors, like Lcn-2R. Studies indicate Lcn-2's involvement in breast cancer correlates with reduced survival and responsiveness to chemotherapy. Human breast tumors, especially in advanced stages, show elevated Lcn-2 levels. Experimental studies in mice support the role of Lcn-2 in tumor development. Lcn-2 induces a process called epithelial-to-mesenchymal transition (EMT), promoting invasiveness in cancer cells. Recent findings suggest that Lcn-2 from the surrounding tissue (stroma) also contributes to cancer spread by enhancing EMT and lymphangiogenesis.
What Are the Applications of Iron in Cancer Diagnosis and Management?
The applications of iron in cancer diagnosis and management include:
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Imaging Techniques: Iron oxide nanoparticles find frequent applications as contrast agents in magnetic resonance imaging (MRI). These nanoparticles enhance the visibility of tumors in imaging, providing detailed information about their size, location, and characteristics. For example, Ferumoxytol is an iron oxide nanoparticle used for vascular imaging in cancer diagnosis.
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Targeted Therapies: Certain drugs incorporate iron and are designed to specifically target cancer cells. Examples include iron-based compounds that are selectively taken up by cancer cells, leading to localized cytotoxic effects. This targeted approach minimizes damage to normal tissues. Ferritin-based therapies are being explored for their potential in targeted drug delivery to cancer cells.
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Iron Chelation Therapy: In cases where cancer or its treatment results in iron overload, iron chelation therapy is employed. Deferoxamine and Deferasirox are examples of iron-chelating drugs that bind to excess iron, promoting its elimination from the body. This is crucial in managing conditions such as iron overload resulting from repeated blood transfusions in cancer patients.
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Inflammation and Anemia Management: Iron status is monitored in cancer patients to manage inflammation and anemia associated with the disease or its treatment. Maintaining optimal iron levels is essential for overall patient well-being and can impact the response to treatment.
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Predictive Biomarker: Serum ferritin levels are used as biomarkers in cancer diagnosis and management. Elevated levels may indicate iron overload or inflammation associated with cancer. Monitoring these levels helps in early detection, prognosis assessment, and evaluation of treatment responses.
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Nanoparticle Drug Delivery: Iron nanoparticles are employed in drug delivery systems. These nanoparticles can carry anti-cancer drugs directly to tumor sites, enhancing drug efficacy while minimizing side effects on healthy tissues. This targeted drug delivery approach is a promising strategy in cancer treatment.
Conclusion:
Understanding the complexities of cancer is crucial for prevention and treatment. Recognizing patterns of how cancers depend on iron can lead to more specific therapies. This approach aims to target cancer cells more precisely, making treatments more effective while minimizing harm to healthy cells. Knowing that iron can act as a pro-oxidant and might play a role in cancer development suggests simple and beneficial preventive measures against cancer.
