Alpha-fetoprotein: A Multifaceted Player in Cancer Biology

Abstract

Alpha-fetoprotein (AFP), a major oncofetal protein, plays a pivotal role in cancer biology, extending beyond its initial identification in fetal development. Alpha-fetoprotein has multifaceted physiological functions mediated by its' complex structure interacting with specific receptors and ligands. The involvement of AFP in carcinogenesis encompasses a broad spectrum of pathophysiological mechanisms, including cell proliferation, apoptosis, metastasis, and immune modulation. Alpha-fetoprotein contributes to the pathological landscape of several cancers, especially hepatocellular carcinoma and germ cell tumors, through an intricate network of signaling pathways. Recent studies highlight the expanding clinical applications of AFP, suggesting its potential to improve the diagnosis and treatment of cancer as well as monitoring genetic diseases, such as neural tube defects and Down syndrome. This comprehensive overview of AFP aims to elucidate the complex biological interactions and clinical implications in cancer management.

How to cite this article: Ucdal M, Yazarkan Y, Sonmez G, et al. Alpha-fetoprotein: A Multifaceted Player in Cancer Biology. Euroasian J Hepato-Gastroenterol 2025;15(1):72-82.

Keywords: Alpha-fetoprotein; Cancer biomarker; Hepatocellular carcinoma.

Fig. 1

The dynamic changes in AFP levels throughout fetal development, pregnancy, and the postpartum period AFP, alpha-fetoprotein; PP, postpartum

Fig. 2

The complex molecular mechanisms governing AFP gene expression regulation. The cascade initiates with membrane-bound receptor activation by diverse extracellular ligands (Wnt, TGF-β, HGF, insulin, and thyroid hormones). These receptor-ligand interactions trigger distinct intracellular signaling pathways: Wnt/β-catenin pathway through the frizzled receptor, TGF-β/suppressor of mothers against decapentaplegic (SMAD) complex formation, HGF/c-Met signaling via MAPK/extracellular signal-regulated kinase (ERK) activation, and insulin receptor-mediated PI3K/protein kinase B (Akt) cascade. The convergence of these pathways leads to the activation of key hepatic transcription factors (HNF1α, HNF4α, and C/EBPα), which subsequently bind to specific regulatory elements within the AFP gene promoter. This coordinated transcriptional regulation ultimately results in AFP mRNA synthesis and subsequent protein production

Fig. 3

This figure illustrates the regulatory pathways involved in the suppression of AFP gene expression and the activation of mature liver-specific genes. Various extracellular factors, including glucocorticoids, retinoic acid, inflammatory factors, and TGF-β, interact with specific receptors, triggering intracellular signaling cascades that converge on transcriptional regulators like nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), p53, and the SMAD complex. These factors, along with epigenetic modifiers such as histone deacetylase (HDAC) and methylation (Me), shift transcriptional activity from AFP genes toward mature liver gene expression, indicating hepatic differentiation and reduced AFP production

Fig. 4

Alpha-fetoprotein exerts complex regulatory effects on cancer cell pathways through its interaction with AFPR. This binding initiates diverse signaling cascades, notably triggering PI3K-mediated conversion of PIP2 to PIP3, leading to Akt pathway activation. Subsequent downstream signaling through mTOR enhances cellular survival mechanisms, while EpCAM, MMP9, MMP2, and CXCR4 mediate invasive and metastatic processes. Cellular calcium dynamics are modulated through ion channel regulation, affecting NFkB signaling, while AFP's interaction with TNF/TNFR system influences inflammatory and immune responses. Additionally, AFP modulates apoptotic pathways through regulation of Bcl-2, Bax, Bak, and XIAP proteins, ultimately affecting Caspase-3 activation and cell survival