Cancer-Associated Fibroblasts in Hepatocellular Carcinoma and Cholangiocarcinoma

Fan, Ying; Chan, Mandy Sze Man; Lee, Terence

doi:10.1016/j.jcmgh.2023.01.006

Cited by 42 publications

(23 citation statements)

References 134 publications

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“…However, no statistical differences in survival were observed among mice orthotopically transplanted with the control, KO, and KO/Res PLC/PRF/5 cells (n=5/group) ( Figure 4H ). Given that CAFs are known to promote liver cancer progression (23), we tested co-injection of a human hepatic stellate cell (HSC) line LX2 with the KO or KO/Res PLC/PRF/5 cells as HSCs are the main source of liver cancer CAFs (24). Mice orthotopically injected with LX2 and KO/Res cells showed significantly shorter survival than those injected with LX2 and KO cells (n=5/group) ( Figure 4I ).…”

Section: Resultsmentioning

confidence: 99%

HKDC1 Promotes Liver Cancer Stemness Under Hypoxia via Stabilizing β-Catenin

Fan,

Tian,

Yang

et al. 2024

Preprint

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Background and AimsHexokinases (HKs), a group of enzymes catalyzing the first step of glycolysis, have been shown to play important roles in liver metabolism and tumorigenesis. Our recent studies identified HKDC1 as a top candidate associated with liver cancer metastasis. We aimed to compare its cell-type specificity with other HKs upregulated in liver cancer and investigate the molecular mechanisms underlying its involvement in liver cancer metastasis.Approach and ResultsWe found that, compared to HK1 and HK2, the other two commonly upregulated HKs in liver cancer, HKDC1 was most strongly associated with the metastasis potential of tumors and organoids derived from two liver cancer mouse models we previously established. RNA in situ hybridization and single-cell RNA-seq analysis revealed that HKDC1 was specifically upregulated in malignant cells in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) patient tumors, whereas HK1 and HK2 were widespread across various tumor microenvironment lineages. An unbiased metabolomic profiling demonstrated that HKDC1 overexpression in HCC cells led to metabolic alterations distinct from those from HK1 and HK2 overexpression, with HKDC1 particularly impacting the tricarboxylic acid (TCA) cycle. HKDC1 was prometastatic in HCC orthotopic and tail vein injection mouse models and, molecularly, HKDC1 was induced by hypoxia and bound to glycogen synthase kinase 3β to stabilize β-catenin, leading to enhanced stemness of HCC cells.ConclusionsOverall, our findings underscore HKDC1 as a prometastatic HK specifically expressed in the malignant compartment of primary liver tumors, thereby providing a mechanistic basis for targeting this enzyme in advanced liver cancer.

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Section: Resultsmentioning

confidence: 99%

HKDC1 Promotes Liver Cancer Stemness Under Hypoxia via Stabilizing β-Catenin

Fan,

Tian,

Yang

et al. 2024

Preprint

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“…CAFs can promote metastasis in HCC through chemokines such as CXCL11, and CAF-carried proteins, such as CCL2 and CCL7 have been shown to enhance HCC progression [ 13 , 36 – 38 ]. The clinical analysis found CAF abundance is often associated with poor clinical outcomes and is considered an attractive therapeutic target in primary HCC [ 39 ]. The bioinformatics method provides clues in predicting CAF-related genes and prognosis in HCC.…”

Section: Discussionmentioning

confidence: 99%

Prediction of CAF-related genes in immunotherapy and drug sensitivity in hepatocellular carcinoma: a multi-database analysis

Yao,

Yang,

Wang

et al. 2024

Genes Immun

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This study aims to identify the cancer-associated fibroblasts (CAF)-related genes that can affect immunotherapy and drug sensitivity in hepatocellular carcinoma (HCC). Expression data and survival data associated with HCC were obtained in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Weighted correlation network analysis (WGCNA) analysis was performed to obtain CAF-related genes. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used for regression analysis and risk models. Subsequently, Gene Set Enrichment Analysis (GSEA) analysis, Gene Set Enrichment Analysis (ssGSEA) analysis, Tumor Immune Dysfunction and Exclusion (TIDE) analysis and drug sensitivity analysis were performed on the risk models. Survival analysis of CAF scores showed that the survival rate was lower in samples with high CAF scores than those with low scores. However, this difference was not significant, suggesting CAF may not directly influence the prognosis of HCC patients. Further screening of CAF-related genes yielded 33 CAF-related genes. Seven risk models constructed based on CDR2L, SPRED1, PFKP, ENG, KLF2, FSCN1 and VCAN, showed significant differences in immunotherapy and partial drug sensitivity in HCC. Seven CAF-related genes may have important roles in immunotherapy, drug sensitivity and prognostic survival in HCC patients.

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“…Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population of fibroblasts and myofibroblast-like cells and constitute CCA stroma chiefly with typical phenotypic markers such as α-SMA, PDGFRβ, FAP, and so on ( 89 ). In CCA, CAFs likely derive from a variety of cell types including hepatic stellate cells, portal fibroblasts, fibrocytes, or epithelial mesenchymal transition (EMT) ( 90 ). CAFs can mediate crosstalk with CCA cells or TME which pave the road for tumorigenesis.…”

Section: Tumor Microenvironment Of Ecca No Cell Is Alonementioning

confidence: 99%

An overview of extrahepatic cholangiocarcinoma: from here to where?

Yang

Zhang

2023

Front. Oncol.

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Extrahepatic cholangiocarcinoma (eCCA) contains perihilar cholangiocarcinoma and distal cholangiocarcinoma both of which can arise at any point of the biliary tree and originate from disparate anatomical sites. Generally, the incidence of eCCA is increasing globally. Though surgical resection is the principal treatment of choice for the early stages of eCCA, optimal survival remains restricted by the high risk of recurrence when most patients are present with unresectable disease or distant metastasis. Furthermore, both intra- and intertumoral heterogeneity make it laborious to determine molecularly targeted therapies. In this review, we mainly focused on current findings in the field of eCCA, mostly including epidemiology, genomic abnormalities, molecular pathogenesis, tumor microenvironment, and other details while a summary of the biological mechanisms driving eCCA may shed light on intricate tumorigenesis and feasible treatment strategies.

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Cancer-Associated Fibroblasts in Hepatocellular Carcinoma and Cholangiocarcinoma

Cited by 42 publications

References 134 publications

HKDC1 Promotes Liver Cancer Stemness Under Hypoxia via Stabilizing β-Catenin

HKDC1 Promotes Liver Cancer Stemness Under Hypoxia via Stabilizing β-Catenin

Prediction of CAF-related genes in immunotherapy and drug sensitivity in hepatocellular carcinoma: a multi-database analysis

An overview of extrahepatic cholangiocarcinoma: from here to where?

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