Trace Elements and Tumor: Research Progress
Abstract
This review systematically summarizes the core advances in the field of trace elements and tumors, and clarifies the dual roles of key elements such as Zn, Cu, Fe, Se, Mn, and Ni in tumorigenesis (e.g., DNA damage repair), tumor progression (e.g., tumor microenvironment regulation), and therapeutic response—these elements not only possess tumor-suppressive potential but can also contribute to tumorigenesis. Meanwhile, it confirms the breakthrough value of multi-omics technologies and organoid models in deciphering the “element-cell-tumor” interaction mechanisms, which overcomes the limitations of traditional in vitro experiments and also points out the core directions for subsequent clinical research.
References
He H, Zou Z, Wang B, et al., 2020, Copper Oxide Nanoparticles Induce Oxidative DNA Damage and Cell Death via Copper Ion-Mediated P38 MAPK Activation in Vascular Endothelial Cells. Int J Nanomedicine, 15: 3291–3302.
Zhang S, Kang L, Dai X, et al., 2022, Manganese Induces Tumor Cell Ferroptosis through Type-I IFN Dependent Inhibition of Mitochondrial Dihydroorotate Dehydrogenase. Free Radic Biol Med, 193(Pt 1): 202–212.
Jarosz M, Olbert M, Wyszogrodzka G, et al., 2017, Antioxidant and Anti-inflammatory Effects of Zinc. Zincdependent NF-κB Signaling. Inflammopharmacology, 25(1): 11–24.
Rataan A, Geary S, Zakharia Y, et al., 2022, Potential Role of Selenium in the Treatment of Cancer and Viral Infections. Int J Mol Sci, 23(4): 2215.
Chasapis C, Loutsidou A, Spiliopoulou C, et al., 2012, Zinc and Human Health: An Update. Arch Toxicol, 86: 521–534.
Maywald M, Rink L, 2015, Zinc Homeostasis and Immunosenescence. J Trace Elem Med Biol, 29: 24–30.
Choi S, Cui C, Luo Y, et al., 2018, Selective Inhibitory Effects of Zinc on Cell Proliferation in Esophageal Squamous Cell Carcinoma through Orai1. FASEB J, 32: 404–416.
Abnet C, Lai B, Qiao Y, et al., 2005, Zinc Concentration in Esophageal Biopsy Specimens Measured by X-ray Fluorescence and Esophageal Cancer Risk. J Natl Cancer Inst, 97: 301–306.
Liu C, Liang D, Jin J, et al., 2017, Research Progress on the Relationship Between Zinc Deficiency, Related MicroRNAs, and Esophageal Carcinoma. Thorac Cancer, 8: 549–557.
Chen Y, Liu F, Liu H, 2021, Effects of Dietary Zinc Deficiency on Esophageal Squamous Cell Proliferation and the Mechanisms Involved. World J Gastrointest Oncol, 13: 1755–1765.
Fong L, Zhang L, Jiang Y, et al., 2005, Dietary Zinc Modulation of COX-2 Expression and Lingual and Esophageal Carcinogenesis in Rats. J Natl Cancer Inst, 97: 40–50.
Valenzano M, Rybakovsky E, Chen V, et al., 2021, Zinc Gluconate Induces Potentially Cancer Chemopreventive Activity in Barrett’s Esophagus: A Phase 1 Pilot Study. Dig Dis Sci, 66: 1195–1211.
Zhang C, Wu H, Cheng M, et al., 2019, Association of Exposure to Multiple Metals with Papillary Thyroid Cancer Risk in China. Environ Sci Pollut Res Int, 26(20): 20560–20572.
Al-Sayer H, Mathew T, Asfar S, et al., 2004, Serum Changes in Trace Elements During Thyroid Cancers. Mol Cell Biochem, 260(1–2): 1–5.
Bengtsson Y, Demircan K, Rosendahl A, et al., 2022, Zinc and Breast Cancer Survival: A Prospective Cohort Study of Dietary Intake and Serum Levels. Nutrients, 14(13): 2575.
Lin S, Yang H, 2021, Ovarian Cancer Risk According to Circulating Zinc and Copper Concentrations: A Meta-analysis and Mendelian Randomization Study. Clin Nutr, 40(4): 2464–2468.
Shahrokhi N, Golzari Z, Zangiabadian M, et al., 2024, The Association Between Zinc and Prostate Cancer Development: A Systematic Review and Meta-analysis. PLoS One, 19(3): e0299398.
Ge E, Bush A, Casini A, et al., 2022, Connecting Copper and Cancer: From Transition Metal Signalling to Metalloplasia. Nat Rev Cancer, 22: 102–113.
Nasulewicz A, Mazur A, Opolski A, 2004, Role of Copper in Tumour Angiogenesis – Clinical Implications. J Trace Elem Med Biol, 18: 1–8.
Lener M, Scott R, Wiechowska-Kozłowska A, et al., 2016, Serum Concentrations of Selenium and Copper in Patients Diagnosed with Pancreatic Cancer. Cancer Res Treat, 48(3): 1056–1064.
Xue Q, Yan D, Chen X, et al., 2023, Copper-dependent Autophagic Degradation of GPX4 Drives Ferroptosis. Autophagy, 19(7): 1982–1996.
Gou Y, Chen M, Li S, et al., 2021, Dithiocarbazate-copper Complexes for Bioimaging and Treatment of Pancreatic Cancer. J Med Chem, 64(9): 5485–5499.
Hurtado M, Prokai L, Sankpal U, et al., 2020, Next Generation Sequencing and Functional Pathway Analysis to Understand the Mechanism of Action of Copper-Tolfenamic Acid Against Pancreatic Cancer Cells. Process Biochem, 89: 155–164.
Chen F, Cole P, Mi Z, et al., 1992, Dietary Trace Elements and Esophageal Cancer Mortality in Shanxi, China. Epidemiology, 3: 402–406.
Sohrabi M, Nikkhah M, Sohrabi M, et al., 2021, Evaluating Tissue Levels of the Eight Trace Elements and Heavy Metals Among Esophagus and Gastric Cancer Patients: A Comparison Between Cancerous and Non-Cancerous Tissues. J Trace Elem Med Biol, 68: 126761.
Zhuang X, Kang Y, Zhao L, et al., 2022, Design and Synthesis of Copper Nanoparticles for the Treatment of Human Esophageal Cancer: Introducing a Novel Chemotherapeutic Supplement. J Exp Nanosci, 17: 274–284.
Mir M, Dar N, Salam I, et al., 2007, Studies on Association Between Copper Excess, Zinc Deficiency and TP53 Mutations in Esophageal Squamous Cell Carcinoma From Kashmir Valley, India—A High Risk Area. Int J Health Sci, 1: 35–42.
Sohrabi M, Nikkhah M, Sohrabi M, et al., 2021, Evaluating Tissue Levels of the Eight Trace Elements and Heavy Metals Among Esophagus and Gastric Cancer Patients: A Comparison Between Cancerous and Non-Cancerous Tissues. J Trace Elem Med Biol, 68: 126761.
Zhu J, Zhao Y, Wu G, et al., 2022, Ferroptosis-Related lncRNA Signature Correlates With the Prognosis, Tumor Microenvironment, and Therapeutic Sensitivity of Esophageal Squamous Cell Carcinoma. Oxid Med Cell Longev, 2022: 7465880.
Ma J, Li Q, Fang X, et al., 2018, Increased Total Iron and Zinc Intake and Lower Heme Iron Intake Reduce the Risk of Esophageal Cancer: A Dose-Response Meta-Analysis. Nutr Res, 59: 16–28.
Hung N, Shen C, Hu Y, et al., 2015, Risk of Cancer in Patients With Iron Deficiency Anemia: A Nationwide Population-Based Study. PLoS One, 10: E0119647.
Zhao H, Ao L, Sorina, et al., 2025, Ferroptosis and Gastric Cancer: From Molecular Mechanisms to Clinical Implications. Front Immunol, 16: 1581928.
Wang Y, Tang C, Wang K, et al., 2025, The Role of Ferroptosis in Breast Cancer: Tumor Progression, Immune Microenvironment Interactions and Therapeutic Interventions. Eur J Pharmacol, 996: 177561.
Rayman M, 2012, Selenium and Human Health. Lancet, 379: 1256–1268.
Ahsan A, Liu Z, Su R, et al., 2022, Potential Chemotherapeutic Effect of Selenium for Improved Canceration of Esophageal Cancer. Int J Mol Sci, 23: 5509.
Steevens J, Brandt P, Goldbohm R, et al., 2010, Selenium Status and the Risk of Esophageal and Gastric Cancer Subtypes: The Netherlands Cohort Study. Gastroenterology, 138(5): 1704–1713.
Noè R, Inglese N, Romani P, et al., 2023, Organic Selenium Induces Ferroptosis in Pancreatic Cancer Cells. Redox Biol, 68: 102962.
Khalkar P, Díaz-Argelich N, Antonio P, et al., 2018, Novel Methylselenoesters Induce Programed Cell Death via Entosis in Pancreatic Cancer Cells. Int J Mol Sci, 19(10): 2849.
Moro C, Selvam A, Ghaderi M, et al., 2022, Drug-Induced Tumor-Specific Cytotoxicity in a Whole Tissue Ex Vivo Model of Human Pancreatic Ductal Adenocarcinoma. Front Oncol, 18(12): 965182.
Karelia D, Kim S, Pandey M, et al., 2021, Novel Seleno-Aspirinyl Compound AS-10 Induces Apoptosis, G1 Arrest of Pancreatic Ductal Adenocarcinoma Cells, Inhibits Their NF-κB Signaling, and Synergizes With Gemcitabine Cytotoxicity. Int J Mol Sci, 22(9): 4966.
Gerin M, Siemiatycki J, Richardson L, et al., 1984, Nickel and Cancer Associations From a Multicancer Occupation Exposure Case-Referent Study: Preliminary Findings. IARC Sci Publ, (53): 105–115.
Yu M, Zhang J, 2017, Serum and Hair Nickel Levels and Breast Cancer: Systematic Review and Meta-Analysis. Biol Trace Elem Res, 179(1): 32–37.
Wang Y, Yang C, Hu R, et al., 2015, Assembling Mn:ZnSe Quantum Dots-siRNA Nanoplexes for Gene Silencing in Tumor Cells. Biomater Sci, 3(1): 192–202.
Tong S, Yu Z, Yin F, et al., 2022, Manganese-Based Prussian Blue Nanoparticles Inhibit Tumor Proliferation and Migration via the MAPK Pathway in Pancreatic Cancer. Front Chem, 24(10): 1026924.
Guan G, Liu H, Xu J, et al., 2023, Ultrasmall PtMn Nanoparticles as Sensitive Manganese Release Modulator for Specificity Cancer Theranostics. J Nanobiotechnology, 21(1): 434.
