Extracellular vesicles as a new hope for diagnosis and therapeutic intervention for hepatocellular carcinoma

Nimitrungtawee, Natthaphong; Inmutto, Nakarin; Chattipakorn, Nipon

doi:10.1002/cam4.4370

Cited by 11 publications

(11 citation statements)

References 90 publications

(233 reference statements)

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“…Moreover, the obtained data revealed that HCC cell-derived EVs could deliver LOXL4 into macrophages to promote immunosuppression in HCC cells. It has been reported that EVs serve as a potential source of biomarkers for HCC by delivering biomolecular cargo, including nucleic acid, lipids, and proteins 7 . Tumor cells–derived exosomes induce HCC immune escape by carrying cancer‐derived molecules 9,35 .…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that extracellular vesicles (EVs) are implicated in the progression of HCC 6 . EVs significantly affect cell‐to‐cell communication by delivering molecules such as protein, mRNA, microRNA (miRNA), and long noncoding RNA 7 . It is interesting to note that HCC-derived exosomes can regulate immune cells during the progression of tumors 8,9 .…”

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confidence: 99%

“…6 EVs significantly affect cell-to-cell communication by delivering molecules such as protein, mRNA, microRNA (miRNA), and long noncoding RNA. 7 It is interesting to note that HCC-derived exosomes can regulate immune cells during the progression of tumors. 8,9 Another study has verified that HCC cellssecreted EVs produce direct immune effects to stimulate target cells, contributing to the invasion of HCC.…”

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confidence: 99%

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LOXL4 Shuttled by Tumor Cells–derived Extracellular Vesicles Promotes Immune Escape in Hepatocellular Carcinoma by Activating the STAT1/PD-L1 Axis

Zhao,

Pei,

Ding

et al. 2023

Journal of Immunotherapy

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Emerging evidence has validated that extracellular vesicles (EVs) regulate hepatocellular carcinoma (HCC) progression, while its role in HCC immune escape remains to be elucidated. This study investigates the role of EVs-encapsulated lysyl oxidase like-4 (LOXL4) derived from tumor cells in HCC immune escape. HCC-related microarray data sets GSE36376 and GSE87630 were obtained for differential analysis, followed by identifying the essential genes related to the prognosis of HCC patients. Bone marrow–derived macrophages were treated with EVs derived from mouse Hepa 1–6 cells and cocultured with CD8+T cells to observe the CD8+T-cell activity. At last, a mouse HCC orthotopic xenograft model was constructed to verify the effects of HCC cell-derived EVs on the immune escape of HCC cells and tumorigenicity in vivo by delivering LOXL4. It was found that ACAT1, C4BPA, EHHADH, and LOXL4 may be the essential genes related to the prognosis of HCC patients. On the basis of the TIMER database, there was a close correlation between LOXL4 and macrophage infiltration in HCC. Besides, STAT1 was closely related to LOXL4. In vitro experiments demonstrated that LOXL4 could induce programmed death-ligand 1 expression in macrophages and immunosuppression by activating STAT1. In vivo experiments also verified that HCC cell-derived EVs promoted the immune escape of HCC cells and tumorigenicity by delivering LOXL4. LOXL4 was delivered into macrophages via EVs to induce programmed death-ligand 1 by activating STAT1 and inhibiting the killing ability of CD8+T cells to HCC cells, thus promoting immune escape in HCC.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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LOXL4 Shuttled by Tumor Cells–derived Extracellular Vesicles Promotes Immune Escape in Hepatocellular Carcinoma by Activating the STAT1/PD-L1 Axis

Zhao,

Pei,

Ding

et al. 2023

Journal of Immunotherapy

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“…HCC is a lethal abdominal malignancy with few effective intervention strategies in its late stages [ 37 , 38 ]. The advent of immunotherapy, represented by ICB therapy, created novel opportunities for advanced HCC patients [ 39 , 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

A cohesin‐associated gene score may predict immune checkpoint blockade in hepatocellular carcinoma

Liu

Chen

et al. 2022

FEBS Open Bio

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Stromal antigen 1 (STAG1), a component of cohesion, is overexpressed in various cancers, but it is unclear whether it has a role in the transcriptional regulation of hepatocellular carcinoma (HCC). To test this hypothesis, here, we screened global HCC datasets and performed multiscale embedded gene co-expression network analysis to identify the potential functional modules of differentially expressed STAG1 co-expressed genes. The putative transcriptional targets of STAG1 were identified using chromatin immunoprecipitation followed by high-throughput DNA sequencing. The cohesin-associated gene score (CAGS) was quantified using the The Cancer Genome Atlas HCC cohort and single-sample gene set enrichment analysis. Distinct cohesin-associated gene patterns were identified by calculating the euclidean distance of each patient. We assessed the potential ability of the CAGS in predicting immune checkpoint blockade (ICB) treatment response using IMvigor210 and GSE78220 cohorts. STAG1 was upregulated in 3313 HCC tissue samples compared with 2692 normal liver tissue samples (standard mean difference = 0.54). A total of three cohesinassociated gene patterns were identified, where cluster 2 had a high TP53 mutated rate and a poor survival outcome. Low CAGS predicted a significant survival advantage but presaged poor immunotherapy response. Differentially expressed STAG1 co-expression genes were enriched in the mitotic cell cycle, lymphocyte activation, and blood vessel development. PDS5A and PDGFRA were predicted as the downstream transcriptional targets of STAG1. In summary, STAG1 is significantly upregulated in global HCC tissue samples and may participate in blood vessel development and the mitotic cell cycle. A cohesin-associated gene scoring system may have potential to predict the ICB response.Abbreviations CAG, cohesin-associated gene; CAGS, cohesin-associated genes scores; ChIP-seq, chromatin immunoprecipitation sequencing; CIBERSORT, cell type identification by estimating relative subsets of RNA transcripts; CR, complete remission; ESTIMATE, estimation of STromal and immune cells in MAlignant tumor tissue using expression data; HCC, hepatocellular carcinoma; ICB, immune checkpoint blockade; MEGENA, multiscale embedded gene co-expression network analysis; PD, progressive disease; PR, partial remission; SD, stable disease; SMD, standard mean difference; ssGSEA, single-sample gene set enrichment analysis; STAG1, stromal antigen 1; WGCNA, weighted gene co-expression network analysis.

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“…60 EVs are promising biomarkers for early HCC detection evidenced by the increasing number of studies published. [61][62][63][64][65] As key mediators of intercellular communication EVs are present in the circulation at early stages of disease. 66,67 One study in 158 patients with HCC that a 10-gene molecular signature had 94% sensitivity and 89% specificity in detecting early HCC.…”

Section: Data On Clinical Applications Of Liquid Biopsy For Hcc Early...mentioning

confidence: 99%

Biomarker Development Using Liquid Biopsy in Hepatocellular Carcinoma

Grinspan

Villanueva

2022

Semin Liver Dis

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Liver cancer incidence rate continues to increase and currently ranks third in the total number of annual deaths, behind only lung and colorectal cancer. Most patients with hepatocellular carcinoma (HCC) are diagnosed at advanced stages, and they live for less than 2 years after diagnosis on average. This contrasts with those diagnosed at an early stage, who can be cured with surgery. However, even after curative resection, there remains a risk of up to 70% of postoperative HCC recurrence. There have been major changes in the management of HCC in the past 5 years, particularly for patients at advanced stages. Despite this multitude of new therapies, there is a lack of clear biomarkers to guide providers on the best approach to sequence therapies, which would maximize efficacy while minimizing toxicity. There are several areas in clinical management of HCC that are particularly challenging, and would benefit from development and implementation of new biomarkers to improve patient overall survival. Here, we review the major advances in liquid biopsy biomarkers for early detection of HCC, minimum residual disease, and predicting response to treatment.

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Extracellular vesicles as a new hope for diagnosis and therapeutic intervention for hepatocellular carcinoma

Cited by 11 publications

References 90 publications

LOXL4 Shuttled by Tumor Cells–derived Extracellular Vesicles Promotes Immune Escape in Hepatocellular Carcinoma by Activating the STAT1/PD-L1 Axis

LOXL4 Shuttled by Tumor Cells–derived Extracellular Vesicles Promotes Immune Escape in Hepatocellular Carcinoma by Activating the STAT1/PD-L1 Axis

A cohesin‐associated gene score may predict immune checkpoint blockade in hepatocellular carcinoma

Biomarker Development Using Liquid Biopsy in Hepatocellular Carcinoma

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