Controversial role of lactoferrin in cancer: A narrative review

Lactoferrin (Lf) is a positively charged iron-binding glycoprotein that has piqued the scientific community's interest due to its pleiotropic behavior, exhibiting a wide range of biological activities, including antimicrobial, antioxidant, anti-inflammatory, immunomodulatory, and anticancer effects. This narrative review explores the current understanding of Lf’s role in cancer, focusing on the endogenously expressed human full-length and ΔLf isoforms, and the effects of treatment with exogenous human and bovine Lf. We evaluated and compared the mechanisms by which Lf influences tumorigenesis and cancer progression, focusing on its impact on key processes such as cell growth, apoptosis, angiogenesis, cell migration, and invasiveness. Notably, the mechanisms of action of human and bovine Lf show some divergences, presumably due to slight structural differences that may lead to opposing effects. Insights from this comparison may help identify new Lf variants with enhanced anticancer activity. Indeed, both human and bovine Lf showed substantial anticancer activity, prompting researchers to investigate their potential utility in cancer prevention and progression. However, some studies have indicated that high levels of human Lf expression may be linked to increased carcinogenesis and metastasis, reflecting its intricate and context-dependent role in cancer. Thus, we emphasize the need for a deeper comprehension of Lf biology and its regulation to enhance understanding of Lf's role in cancer and identify more targeted therapeutic strategies, encouraging further research in this area.