Malignant Transformation of Liver Progenitor Cells into Liver Cancer Stem Cells: Mechanistic Insights and Research Advances
WANG Jie, LIANG Yu, YANG Xinmao, YANG Yaqian, SHI Danning, PAN Yanfang*
Primary hepatocellular carcinoma is a globally prevalent malignant tumor of the digestive system, whose high heterogeneity, recurrence rate, and therapy resistance severely limit clinical efficacy. In recent years, LCSCs (liver cancer stem cells), as key drivers of tumorigenesis and progression, have attracted significant attention, with the malignant transformation of LPCs (liver progenitor cells) being recognized as a crucial mechanism for LCSC origin. This review systematically deciphers the molecular regulatory network underlying LPCs-to-LCSCs transformation: aberrant activation of Wnt/β-catenin, Notch, and other signaling pathways promotes malignant transformation by modulating target gene expression; epigenetics and non-coding RNA remodels the malignant phenotype of LPCs through silencing tumor suppressor genes or activating oncogenes; the tumor microenvironment, including TWEAK secretion by macrophages, hypoxia-induced PI3K/Akt signaling, and immune suppression mediated by hepatic stellate cells, collaboratively fosters a pro-tumor niche; abnormal expression/activation of stemness-related transcription factors (Oct3/4, Sox2, Nanog) further drives malignancy. Elucidating these mechanisms not only provides novel strategies for targeted therapy but also highlights therapeutic potentials in LPCs transplantation, gene editing, and drug delivery. In summary, this review delineates the mechanisms of LPCs malignant transformation into LCSCs, aiming to offer fresh perspectives and strategies for early diagnosis and treatment of hepatocellular carcinoma.
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