Molecular Biology of Liver Cancer Stem Cells

Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. The concept of cancer stem cells (CSCs) is based primarily on the clinical and experimental observations that indicate the existence of a subpopulation of cells with the capacity to self-renew and differentiate as well as show increased resistance to radiation and chemotherapy. They are considered as the factors responsible for the cases of tumor relapse. Hepatic progenitor cells (HPCs) could form the basis of some hepatocellular carcinomas (HCC) and cholangiocarcinomas. Liver CSCs have been reported in multiple subtypes of HCC and are considered as the master regulators of HCC initiation, tumor metastasis, and progression. HPCs activators such as epithelial cell adhesion molecule (EpCAM), Wnt/β-catenin, transforming growth factor-beta (TGF-β), Notch and Hedgehog signaling systems expedite tumorigenesis or conversely, serve as a powerful cancer-prevention tool. Recent work has also identified Sal-like protein 4 (SALL4) and some epigenetic regulations as important molecules, while several therapeutic drugs that directly control HPCs have been tested both in vivo and in vitro. However, liver CSCs clearly have a complex pathogenesis, with the potential for considerable crosstalk and redundancy in signaling pathways. Hence, the targeting of single molecules or pathways may have limited benefit for treatment. In addition to the direct control of liver CSCs, many other factors are needed for CSC maintenance including angiogenesis, vasculogenesis, invasion and migration, hypoxia, immune evasion, multiple drug resistance, and radioresistance. Here, we provide a brief review of molecular signaling in liver CSCs and present insights into new therapeutic strategies for their targeting.

• Publication year

  2014

• Venue

  Liver Cancer

• Publication date

  2014-05-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1159/000343863PMID 24944998PMCID 4057789
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The transcription factor SALL4 regulates stemness of EpCAM-positive hepatocellular carcinoma.

  2014cited by this paper
• Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.

  2013cited by this paper
• Discrete nature of EpCAM+ and CD90+ cancer stem cells in human hepatocellular carcinoma

  2013cited by this paper
• Characteristics of hepatic stem/progenitor cells in the fetal and adult liver

  2012cited by this paper
• Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells

  2012cited by this paper
• Chromatin “Prepattern” and Histone Modifiers in a Fate Choice for Liver and Pancreas

  2011cited by this paper
• Stem and progenitor cells in liver regeneration and repair.

  2011cited by this paper
• Humoral response to catumaxomab correlates with clinical outcome: Results of the pivotal phase II/III study in patients with malignant ascites

  2011cited by this paper
• Novel therapeutic Strategies for Targeting Liver Cancer Stem Cells

  2011cited by this paper
• MiR-222 Overexpression Confers Cell Migratory Advantages in Hepatocellular Carcinoma through Enhancing AKT Signaling

  2010cited by this paper
• Highly Efficient Elimination of Colorectal Tumor-Initiating Cells by an EpCAM/CD3-Bispecific Antibody Engaging Human T Cells

  2010cited by this paper
• miR-130b Promotes CD133(+) liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1.

  2010cited by this paper
• Dkk1 Stabilizes Wnt Co-Receptor LRP6: Implication for Wnt Ligand-Induced LRP6 Down-Regulation

  2010cited by this paper
• Novel roles for Notch, Wnt and Hedgehog in hematopoesis derived from human pluripotent stem cells.

  2010cited by this paper
• Oncostatin m renders epithelial cell adhesion molecule-positive liver cancer stem cells sensitive to 5-Fluorouracil by inducing hepatocytic differentiation.

  2010cited by this paper
• Epithelial Cell Adhesion Molecule Regulation Is Associated with the Maintenance of the Undifferentiated Phenotype of Human Embryonic Stem Cells*

  2010cited by this paper
• Small-molecule modulators of the Sonic Hedgehog signaling pathway.

  2010cited by this paper
• Expression of Oct4 in HCC and modulation to wnt/β-catenin and TGF-β signal pathways

  2010cited by this paper
• An open-label, randomized phase II study of adecatumumab, a fully human anti-EpCAM antibody, as monotherapy in patients with metastatic breast cancer.

  2010cited by this paper
• miR-130b is preferentially upregulated in CD133+ liver cancer stem cells and regulates tumor growth and self-renewal via tumor protein 53-induced nuclear protein 1

  2009cited by this paper
• EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features.

  2009cited by this paper
• Sall4 Is Essential for Stabilization, But Not for Pluripotency, of Embryonic Stem Cells by Repressing Aberrant Trophectoderm Gene Expression

  2009cited by this paper
• Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties

  2009cited by this paper
• Cancer stem cells: never Wnt away from the niche

  2009cited by this paper
• Blocking the hedgehog pathway inhibits hepatoblastoma growth

  2009cited by this paper
• miR-221 overexpression contributes to liver tumorigenesis

  2009cited by this paper
• The emerging role of EpCAM in cancer and stem cell signaling.

  2009cited by this paper
• Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling

  2009cited by this paper
• Nuclear signalling by tumour-associated antigen EpCAM

  2009cited by this paper
• Cancer stem cell markers in common cancers - therapeutic implications.

  2008cited by this paper
• MicroRNA-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of Stathmin1.

  2008cited by this paper
• Module map of stem cell genes guides creation of epithelial cancer stem cells.

  2008cited by this paper
• Down-regulation of Sonic hedgehog signaling pathway activity is involved in 5-fluorouracil-induced apoptosis and motility inhibition in Hep3B cells.

  2008cited by this paper
• Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor‐4α gene

  2008cited by this paper
• Progenitor/stem cells give rise to liver cancer due to aberrant TGF-β and IL-6 signaling

  2008cited by this paper
• Liver stem cells

  2007cited by this paper
• Ring1-mediated ubiquitination of H2A restrains poised RNA polymerase II at bivalent genes in mouse ES cells

  2007cited by this paper
• WNT Signaling Pathway and Stem Cell Signaling Network

  2007cited by this paper
• Liver regeneration

  2007cited by this paper
• Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma.

  2007cited by this paper
• siRNA-Mediated β-Catenin Knockdown in Human Hepatoma Cells Results in Decreased Growth and Survival*

  2007cited by this paper
• Pharmacokinetic and safety study of subcutaneously administered weekly ING-1, a human engineere monoclonal antibody targeting human EpCAM, in patients with advanced solid tumors.

  2007cited by this paper
• SiRNA‐Mediated β‐catenin Knockdown in Human Hepatoma Cells Results in Their Decreased Growth and Survival

  2007cited by this paper
• Epithelial cell adhesion molecule: more than a carcinoma marker and adhesion molecule.

  2007cited by this paper
• Hepatocellular stem cells

  2007cited by this paper
• The JNK signal transduction pathway.

  2007cited by this paper
• Signal transduction cascades and hepatitis B and C related hepatocellular carcinoma

  2006cited by this paper
• Notch signalling regulates stem cell numbers in vitro and in vivo

  2006cited by this paper
• Antiproliferative effects of interferon alpha on hepatic progenitor cells in vitro and in vivo

  2006cited by this paper
• Successful Therapy Must Eradicate Cancer Stem Cells

  2006cited by this paper
• Wnt signalling in stem cells and cancer

  2005cited by this paper
• The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation

  2004cited by this paper
• The Hedgehog Response Network: Sensors, Switches, and Routers

  2004cited by this paper
• Immunohistochemical analysis and mutational analyses of beta-catenin, Axin family and APC genes in hepatocellular carcinomas.

  2004cited by this paper
• Multiple niches for Notch in cancer: context is everything.

  2004cited by this paper
• Non-canonical Wnt signaling in Xenopus: regulation of axis formation and gastrulation.

  2002cited by this paper
• Epidemiology of hepatocellular carcinoma.

  2001cited by this paper
• The language of covalent histone modifications

  2000cited by this paper
• The sonic hedgehog-patched-gli pathway in human development and disease.

  2000cited by this paper
• Expression of Ep‐CAM in normal, regenerating, metaplastic, and neoplastic liver

  1999cited by this paper
• Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway.

  1999cited by this paper
• Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells.

  1999cited by this paper
• Identification of c-MYC as a target of the APC pathway.

  1998cited by this paper
• Epidemiology of hepatocellular carcinoma.

  1995cited by this paper

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  2025cites this paper
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  2025cites this paper
• The Multifaceted Roles of MicroRNA-181 in Stem Cell Differentiation and Cancer Stem Cell Plasticity

  2025cites this paper
• State-of-the-Art Liver Cancer Organoids: Modeling Cancer Stem Cell Heterogeneity for Personalized Treatment

  2025cites this paper
• The HHEX-ABI2/SLC17A9 axis induces cancer stem cell-like properties and tumorigenesis in HCC

  2024cites this paper
• The potential of cancer stem cells for personalized risk assessment and therapeutic intervention in individuals with intrahepatic cholangiocarcinoma

  2024cites this paper
• Cancer stem cell-immune cell crosstalk in the tumor microenvironment for liver cancer progression

  2024cites this paper
• Heterogeneity of Cholangiocarcinoma Immune Biology

  2023cites this paper
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  2023cites this paper
• PCK1 attenuates tumor stemness via activating the Hippo signaling pathway in hepatocellular carcinoma

  2023cites this paper
• Targeted therapy of breast tumor by PLGA-based nanostructures: The versatile function in doxorubicin delivery.

  2023cites this paper
• Clinicopathological progress of dual-phenotype hepatocellular carcinoma

  2023cites this paper
• FXR agonists for colorectal and liver cancers, as a stand-alone or in combination therapy.

  2023cites this paper
• Fc fragment of IgG binding protein is correlated with immune infiltration levels in hepatocellular carcinoma

  2023cites this paper
• Synthesis of doxorubicin-loaded peptosomes hybridized with gold nanorod for targeted drug delivery and CT imaging of metastatic breast cancer

  2022cites this paper
• The long noncoding RNA TINCR promotes self-renewal of human liver cancer stem cells through autophagy activation

  2022cites this paper
• Trimethylglycine betaine effects on NFκB, HIF1A and NFE2L2/AP-1 pathways, mitochondrial activity, glucose import, and levels of ROS, thiols and lipids in HeLa cells

  2022cites this paper
• Scalable Formation of Highly Viable and Functional Hepatocellular Carcinoma Spheroids in an Oxygen‐Permeable Microwell Device for Anti‐Tumor Drug Evaluation

  2022cites this paper
• Alcoholic hepatitis accelerates early hepatobiliary cancer by Alcoholic hepatitis accelerates early hepatobiliary cancer by increasing stemness and miR-122-mediated HIF-1alpha activation increasing stemness and miR-122-mediated HIF-1alpha activation

  2022cites this paper
• Nanog, as a key cancer stem cell marker in tumor progression.

  2022cites this paper
• SALL4 Oncogenic Function in Cancers: Mechanisms and Therapeutic Relevance

  2022cites this paper
• Chronic alcohol exposure induces hepatocyte damage by inducing oxidative stress, SATB2 and stem cell‐like characteristics, and activating lipogenesis

  2022cites this paper
• Advances in Liver Cancer Stem Cell Isolation and their Characterization

  2021cites this paper
• Hepatoprotective Effect of Trehalose: Insight into Its Mechanisms of Action.

  2021cites this paper
• Zajdela Ascitic Hepatoma As a Continuum for Tumor Cells in a Transitional State

  2021influential citation
• The Expression of Pro-Platelet Basic Protein and Transcription Factor Activating Enhancer Binding Protein 4 Genes in Non-Small Cell Lung Cancer and Prognostic Value

  2021cites this paper
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  2021cites this paper
• 간세포암종의 병리진단에 대한 최신 지견

  2021cites this paper
• Identification of a 9-gene signature related to stemness for prognosis in hepatocellular carcinoma basing on weighted gene coexpression network analysis

  2021cites this paper
• Application of propofol combined with sevoflurane anesthesia in staged hepatectomy liver detachment and portal vein ligation.

  2021cites this paper
• Paradoxical functions of long noncoding RNAs in modulating STAT3 signaling pathway in hepatocellular carcinoma.

  2021cites this paper
• Molecular pathology underlying the robustness of cancer stem cells

  2021cites this paper
• The apoptosis mechanisms of HepG2 cells induced by bitter melon seed.

  2021cites this paper
• Liver cancer stem cells: Recent progress in basic and clinical research

  2021cites this paper
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  2021cites this paper
• Immunotherapy for targeting cancer stem cells in hepatocellular carcinoma

  2021cites this paper
• S100A4 promotes hepatocellular carcinogenesis by intensifying fibrosis-associated cancer cell stemness

  2020cites this paper
• Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3 and Reducing STAT3

  2020cites this paper
• Upregulation of C-Reactive Protein by Placenta-Derived Mesenchymal Stem Cells Promotes Angiogenesis in A Rat Model with Cirrhotic Liver

  2020cites this paper
• Diagnostic significance and carcinogenic mechanism of pan‐cancer gene POU5F1 in liver hepatocellular carcinoma

  2020cites this paper
• Gross type of hepatocellular carcinoma reflects the tumor hypoxia, fibrosis, and stemness-related marker expression

  2020cites this paper
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  2020cites this paper
• miR-515-5p suppresses HCC migration and invasion via targeting IL6/JAK/STAT3 pathway.

  2020cites this paper
• Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer

  2020cites this paper
• Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3/DAT and Reducing STAT3

  2020cites this paper
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  2019cites this paper
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  2019cites this paper
• Androgen receptor (AR)/miR-520f-3p/SOX9 signaling is involved in altering hepatocellular carcinoma (HCC) cell sensitivity to the Sorafenib therapy under hypoxia via increasing cancer stem cells phenotype.

  2019cites this paper
• 4-Acetylantroquinonol B from antrodia cinnamomea enhances immune function of dendritic cells against liver cancer stem cells.

  2019cites this paper
• MiR-6875-3p promotes the proliferation, invasion and metastasis of hepatocellular carcinoma via BTG2/FAK/Akt pathway

  2019cites this paper
• Effect of propofol and sevoflurane anesthesia on postoperative cognitive function and levels of Aβ-42 and Tau in patients undergoing hepatectomy.

  2019cites this paper
• Hepatoprotective effects of rosmarinic acid: Insight into its mechanisms of action.

  2019cites this paper
• Retrodifferentiation of Human Tumor Hepatocytes to Stem Cells Leads to Metabolic Reprogramming and Chemoresistance.

  2019cites this paper
• MKP-4 suppresses hepatocarcinogenesis by targeting ERK1/2 pathway

  2019cites this paper
• Analysis on Effects of Comprehensive Nursing Care Applied in Interventional Therapy for Patients with Liver Cirrhosis and Liver Cancer

  2019cites this paper
• Role of Cancer Stem Cells in Cholangiocarcinoma and Therapeutic Implications

  2019cites this paper
• Tumorsphere Derivation and Treatment from Primary Tumor Cells Isolated from Mouse Rhabdomyosarcomas.

  2019cites this paper
• Role of stereotactic body radiation therapy in the treatment of liver metastases: clinical results and prognostic factors

  2019cites this paper
• Wnt-β-catenin signaling pathway, the Achilles' heels of cancer multidrug resistance.

  2019cites this paper
• Multidrug Resistance in Hepatocellular Carcinoma

  2019cites this paper
• Postoperative recurrent factors and therapeutic and preventive strategies for hepatocellular carcinoma

  2019cites this paper
• Rodent Hepatocellular Carcinoma Cells Found in Hepatic Veins Do Not Necessarily Colonize the Lung: Observations in Line with the “Seed and Soil” Hypothesis

  2019cites this paper
• AccessReview Stemness features in liver cancer

  2019cites this paper
• Microporous cellulosic scaffold as a spheroid culture system modulates chemotherapeutic responses and stemness in hepatocellular carcinoma

  2018cites this paper
• Effects of TACE combined with precise RT on p53 gene expression and prognosis of HCC patients

  2018cites this paper
• Stemness features in liver cancer

  2018influential citation
• [Recent progress in nanomedicine for hepatocellular carcinoma therapy].

  2018cites this paper
• A high-content screen for small-molecule regulators of epithelial cell-adhesion molecule (EpCAM) cleavage yields a robust inhibitor

  2018cites this paper
• Hepatitis B Virus-Associated Hepatocellular Carcinoma and Hepatic Cancer Stem Cells

  2018cites this paper
• Clinical implications of the Hippo-YAP pathway in multiple cancer contexts

  2018influential citation
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  2018cites this paper
• Title Cold-inducible RNA-binding protein promotes thedevelopment of liver cancer

  2018cites this paper
• C/EBPα‐dependent preneoplastic tumor foci are the origin of hepatocellular carcinoma and aggressive pediatric liver cancer

  2018cites this paper
• Phase II trial on SBRT for unresectable liver metastases: long-term outcome and prognostic factors of survival after 5 years of follow-up

  2018cites this paper
• Rapid phenotyping of cancer stem cells using multichannel nanosensor arrays.

  2018cites this paper
• Transcription factor AP-4 promotes tumorigenic capability and activates the Wnt/β-catenin pathway in hepatocellular carcinoma

  2018cites this paper
• Oxidative stress and hepatocarcinogenesis

  2018cites this paper
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  2018cites this paper
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  2017cites this paper
• Signaling Pathways as Potential Therapeutic Targets in Hepatocarcinogenesis

  2017cites this paper
• Upregulated microRNA-429 inhibits the migration of HCC cells by targeting TRAF6 through the NF-κB pathway.

  2017cites this paper
• Translational research for hepatocellular carcinoma: What’s new?

  2017cites this paper
• MicroRNA-98 Plays a Suppressive Role in Non-Small Cell Lung Cancer Through Inhibition of SALL4 Protein Expression

  2017cites this paper
• FXR-Gankyrin axis is involved in development of pediatric liver cancer

  2017cites this paper
• The Pathology and Molecular Pathology of Hepatocellular Carcinoma

  2017cites this paper
• Contribution of the Cancer Stem Cell Phenotype to Hepatocellular Carcinoma Resistance

  2017cites this paper
• Ablation therapy for hepatocellular carcinoma

  2017cites this paper
• Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups

  2017cites this paper
• The mechanism of CIRP in inhibition of keratinocytes growth arrest and apoptosis following low dose UVB radiation

  2017cites this paper
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  2017cites this paper
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  2017cites this paper
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  2017cites this paper
• Expression of Wnt3a in hepatocellular carcinoma and its effects on cell cycle and metastasis

  2017cites this paper
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  2017cites this paper
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• The miR‐200b–ZEB1 circuit regulates diverse stemness of human hepatocellular carcinoma

  2017cites this paper
• Musashi 2 contributes to the stemness and chemoresistance of liver cancer stem cells via LIN28A activation.

  2017cites this paper
• Road to stemness in hepatocellular carcinoma

  2017cites this paper
• Strategies to optimize siRNA delivery to hepatocellular carcinoma cells

  2017influential citation