Hepatic Cancer Stem Cells: Molecular Mechanisms, Therapeutic Implications, and Circulating Biomarkers

Gramantieri, Laura; Giovannini, Catia; Suzzi, Fabrizia; Leoni, Ilaria; Fornari, Francesca

doi:10.3390/cancers13184550

Cited by 7 publications

(4 citation statements)

References 128 publications

(135 reference statements)

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“…Tumor heterogeneity is one of the main characteristics of HCC, which makes the progress of treatment slow [ 1 , 2 ]. At present, there is still a lack of biomarkers and effective prognostic models for diagnosis, prognosis, and prediction of therapeutic efficacy of HCC.…”

Section: Introductionmentioning

confidence: 99%

Development and Optimization of a Prognostic Model Associated with Stemness Genes in Hepatocellular Carcinoma

Zhang

Xie

Huo

et al. 2022

BioMed Research International

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Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, which is associated with a variety of risk factors. Cancer stem cells are self-renewal cells, which can promote the occurrence and metastasis of tumors and enhance the drug resistance of tumor treatment. This study aimed to develop a stemness score model to assess the prognosis of hepatocellular carcinoma (HCC) patients for the optimization of treatment. The single-cell sequencing data GSE149614 was downloaded from the GEO database. Then, we compared the gene expression of hepatic stem cells and other hepatocytes in tumor samples to screen differentially expressed genes related to stemness. R package “clusterProfiler” was used to explore the potential function of stemness-related genes. We then constructed a prognostic model using LASSO regression analysis based on the TCGA and GSE14520 cohorts. The associations of stemness score with clinical features, drug sensitivity, gene mutation, and tumor immune microenvironment were further explored. R package “rms” was used to construct the nomogram model. A total of 18 stemness-related genes were enrolled to construct the prognosis model. Kaplan-Meier analysis proved the good performance of the stemness score model at predicting overall survival (OS) of HCC patients. The stemness score was closely associated with clinical features, drug sensitivity, and tumor immune microenvironment of HCC. The infiltration level of CD8+ T cells was lower, and tumor-associated macrophages were higher in patients with high-stemness score, indicating an immunosuppressive microenvironment. Our study established an 18 stemness-related gene model that reliably predicts OS in HCC. The findings may help clarify the biological characteristics and progression of HCC and help the future diagnosis and therapy of HCC.

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Section: Introductionmentioning

confidence: 99%

Development and Optimization of a Prognostic Model Associated with Stemness Genes in Hepatocellular Carcinoma

Zhang

Xie

Huo

et al. 2022

BioMed Research International

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“…Of note, liver resident macrophages isolated from PTEN-deficient mice produced elevated levels of proinflammatory cytokines IL-6 and TNFα in response to lipopolysaccharide (LPS), activating cancer progenitor cells (eg, oval cells) that play an active role in liver cancer development as we previously reviewed. 38 Thus, immune cell populations create an inflammatory microenvironment that heavily contribute to liver injury and to the development of NASH-related HCC in this preclinical model. In agreement, Vidotto et al have recently focused on the emerging role of PTEN loss in the evasion of the immune response by sustaining immunosuppressive environments in different human tumors.…”

Section: Genetically Modified Mouse Models Of Nash-hccmentioning

confidence: 95%

Animal Models of Hepatocellular Carcinoma: Current Applications in Clinical Research

Fornari¹,

Giovannini²,

Piscaglia³

et al. 2022

JHC

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In the last decade, relevant advances have occurred in the treatment of hepatocellular carcinoma (HCC), with novel drugs entering the clinical practice, among which tyrosine kinase inhibitors (TKIs) such as lenvatinib, cabozantinib and regorafenib, and immune checkpoint inhibitors (ICPIs) either alone or in combination with VEGF inhibitors. Clinical trials have driven the introduction of such novel molecules into the clinics but, at present, no biomarker drives the choice of first-line options, which relies only upon clinical and imaging assessment. Remarkably, clinical and imaging-based evaluations do not consider the huge heterogeneity of HCC and do not allow to realize the potential of personalized treatments. Preclinical research still does not inform the design of clinical trials, even though many animal models mimicking specific subgroups of HCC are available and might provide relevant information. Although animal models directly informing the clinical practice, such as patients-derived xenografts, are not used to help the choice of treatment in advanced HCC, however, the preclinical research can count on a wide range of valuable models. Here we will review some HCC models which might turn informative for specific questions in defined patient subgroups, and we will describe recent preclinical studies for the mechanistic evaluation of immunotherapy-based treatment approaches. To this aim, we will mainly focus on two issues: (i) HCC models informative on NAFLD-NASH HCC and (ii) HCC models helping to elucidate mechanisms underneath immunotherapy. We have chosen these two settings since they represent, respectively, the most rapidly arising cause of chronic liver disease (CLD) and HCC in western countries and the most promising therapeutic option for advanced HCC.

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“…Furthermore, the heterogeneity of the CSCs of the same HCC remains [ 84 ]. Examinations of the circulating biomarkers of those with HCC may be a further issue [ 19 , 154 ]. The second challenge is that the treatment of the tumor microenvironment is relatively complex, with pre-tumor fibroblasts in the tumor microenvironment continuing to recruit CSCs in order to promote intrahepatic metastasis [ 104 ].…”

Section: Challenges Of Targeting Cancer Stem Cells Of Hcc and Future ...mentioning

confidence: 99%

Cellular and Molecular Biology of Cancer Stem Cells of Hepatocellular Carcinoma

Jeng

Chang

Sheen

et al. 2023

IJMS

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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death globally. The cancer stem cells (CSCs) of HCC are responsible for tumor growth, invasion, metastasis, recurrence, chemoresistance, target therapy resistance and radioresistance. The reported main surface markers used to identify liver CSCs include epithelial cell adhesion/activating molecule (EpCAM), cluster differentiation 90 (CD90), CD44 and CD133. The main molecular signaling pathways include the Wnt/β-catenin, transforming growth factors-β (TGF-β), sonic hedgehog (SHH), PI3K/Akt/mTOR and Notch. Patients with EpCAM-positive alpha-fetoprotein (AFP)-positive HCC are usually young but have advanced tumor-node-metastasis (TNM) stages. CD90-positive HCCs are usually poorly differentiated with worse prognosis. Those with CD44-positive HCC cells develop early metastases. Those with CD133 expression have a higher recurrence rate and a shorter overall survival. The Wnt/β-catenin signaling pathway triggers angiogenesis, tumor infiltration and metastasis through the enhancement of angiogenic factors. All CD133+ liver CSCs, CD133+/EpCAM+ liver CSCs and CD44+ liver CSCs contribute to sorafenib resistance. SHH signaling could protect HCC cells against ionizing radiation in an autocrine manner. Reducing the CSC population of HCC is crucial for the improvement of the therapy of advanced HCC. However, targeting CSCs of HCC is still challenging.

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Hepatic Cancer Stem Cells: Molecular Mechanisms, Therapeutic Implications, and Circulating Biomarkers

Cited by 7 publications

References 128 publications

Development and Optimization of a Prognostic Model Associated with Stemness Genes in Hepatocellular Carcinoma

Development and Optimization of a Prognostic Model Associated with Stemness Genes in Hepatocellular Carcinoma

Animal Models of Hepatocellular Carcinoma: Current Applications in Clinical Research

Cellular and Molecular Biology of Cancer Stem Cells of Hepatocellular Carcinoma

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