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Nature Reviews. Clinical Oncology Apr 2024Liver cancer, specifically hepatocellular carcinoma (HCC), is the sixth most common cancer and the third leading cause of cancer mortality worldwide. The development of... (Review)
Review
Liver cancer, specifically hepatocellular carcinoma (HCC), is the sixth most common cancer and the third leading cause of cancer mortality worldwide. The development of effective systemic therapies, particularly those involving immune-checkpoint inhibitors (ICIs), has substantially improved the outcomes of patients with advanced-stage HCC. Approximately 30% of patients are diagnosed with early stage disease and currently receive potentially curative therapies, such as resection, liver transplantation or local ablation, which result in median overall survival durations beyond 60 months. Nonetheless, up to 70% of these patients will have disease recurrence within 5 years of resection or local ablation. To date, the results of randomized clinical trials testing adjuvant therapy in patients with HCC have been negative. This major unmet need has been addressed with the IMbrave 050 trial, demonstrating a recurrence-free survival benefit in patients with a high risk of relapse after resection or local ablation who received adjuvant atezolizumab plus bevacizumab. In parallel, studies testing neoadjuvant ICIs alone or in combination in patients with early stage disease have also reported efficacy. In this Review, we provide a comprehensive overview of the current approaches to manage patients with early stage HCC. We also describe the tumour immune microenvironment and the mechanisms of action of ICIs and cancer vaccines in this setting. Finally, we summarize the available evidence from phase II/III trials of neoadjuvant and adjuvant approaches and discuss emerging clinical trials, identification of biomarkers and clinical trial design considerations for future studies.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Immunotherapy; Tumor Microenvironment
PubMed: 38424197
DOI: 10.1038/s41571-024-00868-0 -
European Journal of Clinical... Aug 2023Primary liver cancer (PLC) is the sixth most frequently occurring cancer, representing one of the top 5 leading causes of cancer-related mortality worldwide. Recently,...
BACKGROUND
Primary liver cancer (PLC) is the sixth most frequently occurring cancer, representing one of the top 5 leading causes of cancer-related mortality worldwide. Recently, researchers have focused more on the impact of living habits on the incidence and development of tumours. This study reports a relationship between sleep traits and PLC.
METHODS
In this study, we used published genome-wide association studies to obtain exposure factors of 6 sleep traits. Mendelian randomization (MR) analysis was used to assess the causal relationship between sleep traits and PLC via inverse-variance weighted (IVW), MR Egger and weighted median. Sensitivity analysis was used to reduce the bias.
RESULTS
Our investigation revealed that there was a negative correlation between sleep duration and the group of liver and bile duct cancer by IVW (p-value = .042), and this result was similarly observed in the liver cell carcinoma group by Weighted Median (p-value = .026). In contrast, there was a positive correlation found between napping during the day and primary liver cancer in the cohorts of liver and bile duct cancer (p-value = .030), liver cell carcinoma (p-value = .043) and malignant neoplasm of other and unspecified parts of the biliary tract (p-value = .016) by IVW. Furthermore, our study also revealed a positive correlation between insomnia and malignant neoplasm of the liver and intrahepatic bile ducts by IVW (p-value = .022).
CONCLUSIONS
Overall, our study indicates that insomnia and nap during the day may be risk factors of PLC and adequate night sleep might keep us away from PLC.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Mendelian Randomization Analysis; Carcinoma, Hepatocellular; Genome-Wide Association Study; Sleep; Cholangiocarcinoma; Bile Duct Neoplasms; Liver Neoplasms; Polymorphism, Single Nucleotide
PubMed: 37029746
DOI: 10.1111/eci.14002 -
Current Treatment Options in Oncology Jul 2023Hepatocellular carcinoma is the fourth leading cause of cancer-related deaths worldwide and its associated mortality rate is expected to rise within the next decade. The... (Review)
Review
Hepatocellular carcinoma is the fourth leading cause of cancer-related deaths worldwide and its associated mortality rate is expected to rise within the next decade. The incidence rate of hepatocellular carcinoma varies significantly across countries and the latter can be attributed to the differences in risk factors that are prevalent across different countries. Some of the risk factors associated with hepatocellular carcinoma include hepatitis B and C infections, non-alcoholic fatty liver disease, and alcoholic liver disease. Regardless of the underlying aetiology, the end result is liver fibrosis and cirrhosis that ultimately progress into carcinoma. The treatment and management of hepatocellular carcinoma is complicated by treatment resistance and high tumor recurrence rates. Early stages of hepatocellular carcinoma are treated with liver resection and other forms of surgical therapy. Advanced stages of hepatocellular carcinoma can be treated with chemotherapy, immunotherapy, and the use of oncolytic viruses and these treatment options can be combined with nanotechnology to improve efficacy and reduce side effects. Moreover, chemotherapy and immunotherapy can be combined to further improve treatment efficacy and overcome resistance. Despite the treatment options available, the high mortality rates provide evidence that current treatment options for advanced-stage hepatocellular carcinoma are not achieving the desired therapeutic goals. Various clinical trials are ongoing to improve treatment efficacy, reduce recurrence rates, and ultimately prolong survival. This narrative review aims to provide an update on our current knowledge and future direction of research on hepatocellular carcinoma.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Chemoembolization, Therapeutic; Neoplasm Recurrence, Local; Risk Factors
PubMed: 37103744
DOI: 10.1007/s11864-023-01098-9 -
Surgical Pathology Clinics Sep 2023Mesenchymal neoplasms of the liver can be diagnostically challenging, particularly on core needle biopsies. Here, I discuss recent updates in neoplasms that are specific... (Review)
Review
Mesenchymal neoplasms of the liver can be diagnostically challenging, particularly on core needle biopsies. Here, I discuss recent updates in neoplasms that are specific to the liver (mesenchymal hamartoma, undifferentiated embryonal sarcoma, calcifying nested stromal-epithelial tumor), vascular tumors of the liver (anastomosing hemangioma, hepatic small vessel neoplasm, epithelioid hemangioendothelioma, angiosarcoma), and other tumor types that can occur primarily in the liver (PEComa/angiomyolipoma, inflammatory pseudotumor-like follicular dendritic cell sarcoma, EBV-associated smooth muscle tumor, inflammatory myofibroblastic tumor, malignant rhabdoid tumor). Lastly, I discuss metastatic sarcomas to the liver, as well as pitfalls presented by metastatic melanoma and sarcomatoid carcinoma.
Topics: Humans; Liver Neoplasms; Hemangiosarcoma; Hemangioma; Sarcoma; Soft Tissue Neoplasms; Hamartoma
PubMed: 37536892
DOI: 10.1016/j.path.2023.04.013 -
Hepatology (Baltimore, Md.) Jun 2024Microvascular invasion (MVI) is a crucial pathological hallmark of HCC that is closely associated with poor outcomes, early recurrence, and intrahepatic metastasis...
BACKGROUND AND AIMS
Microvascular invasion (MVI) is a crucial pathological hallmark of HCC that is closely associated with poor outcomes, early recurrence, and intrahepatic metastasis following surgical resection and transplantation. However, the intricate tumor microenvironment and transcriptional programs underlying MVI in HCC remain poorly understood.
APPROACH AND RESULTS
We performed single-cell RNA sequencing of 46,789 individual cells from 10 samples of MVI+ (MVI present) and MVI- (MVI absent) patients with HCC. We conducted comprehensive and comparative analyses to characterize cellular and molecular features associated with MVI and validated key findings using external bulk, single-cell, and spatial transcriptomic datasets coupled with multiplex immunofluorescence assays. The comparison identified specific subtypes of immune and stromal cells critical to the formation of the immunosuppressive and pro-metastatic microenvironment in MVI+ tumors, including cycling T cells, lysosomal associated membrane protein 3+ dendritic cells, triggering receptor expressed on myeloid cells 2+ macrophages, myofibroblasts, and arterial i endothelial cells. MVI+ malignant cells are characterized by high proliferation rates, whereas MVI- malignant cells exhibit an inflammatory milieu. Additionally, we identified the midkine-dominated interaction between triggering receptor expressed on myeloid cells 2+ macrophages and malignant cells as a contributor to MVI formation and tumor progression. Notably, we unveiled a spatially co-located multicellular community exerting a dominant role in shaping the immunosuppressive microenvironment of MVI and correlating with unfavorable prognosis.
CONCLUSIONS
This study provides a comprehensive single-cell atlas of MVI in HCC, shedding light on the complex multicellular ecosystem and molecular features associated with MVI. These findings deepen our understanding of the underlying mechanisms driving MVI and provide valuable insights for improving clinical diagnosis and developing more effective treatment strategies.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Tumor Microenvironment; Single-Cell Analysis; Neoplasm Invasiveness; Microvessels; Male; Female; Macrophages
PubMed: 37972953
DOI: 10.1097/HEP.0000000000000673 -
Revista Espanola de Medicina Nuclear E... 2023Surgical resection is considered the curative treatment par excellence for patients with primary or metastatic liver tumors. However, less than 40% of them are... (Review)
Review
Surgical resection is considered the curative treatment par excellence for patients with primary or metastatic liver tumors. However, less than 40% of them are candidates for surgery, either due to non-modifiable factors (comorbidities, age, liver dysfunction…), or to the invasion or proximity of the tumor to the main vascular requirements, the lack of a future liver remnant (FLR) adequate to maintain postoperative liver function, or criteria of tumor size and number. In these last factors, hepatic radioembolization has been shown to play a role as a presurgical tool, either by hypertrophy of the FLR or by reducing tumor size that manages to reduce tumor staging (term known as "downstaging"). To these is added a third factor, which is its ability to apply the test of time, which makes it possible to identify those patients who present progression of the disease in a short period of time (both locally and at distance), avoiding a unnecessary surgery. This paper aims to review RE as a tool to facilitate liver surgery, both through the experience of our center and the available scientific evidence.
Topics: Humans; Embolization, Therapeutic; Hepatectomy; Liver Neoplasms; Neoplasm Staging
PubMed: 37321348
DOI: 10.1016/j.remnie.2023.06.002 -
Theranostics 2023As a key endogenous negative regulator of ferroptosis, glutathione peroxidase 4 (GPX4) can regulate its antioxidant function through multiple post-translational...
Protein phosphatase 2A-B55β mediated mitochondrial p-GPX4 dephosphorylation promoted sorafenib-induced ferroptosis in hepatocellular carcinoma via regulating p53 retrograde signaling.
As a key endogenous negative regulator of ferroptosis, glutathione peroxidase 4 (GPX4) can regulate its antioxidant function through multiple post-translational modification pathways. However, the effects of the phosphorylation/dephosphorylation status of GPX4 on the regulation of inducible ferroptosis in hepatocellular carcinoma (HCC) remain unclear. To investigate the effects and molecular mechanism of GPX4 phosphorylation/dephosphorylation modification on ferroptosis in HCC cells. Sorafenib (Sora) was used to establish the ferroptosis model in HCC cells . Using the site-directed mutagenesis method, we generated the mimic GPX4 phosphorylation or dephosphorylation HCC cell lines at specific serine sites of GPX4. The effects of GPX4 phosphorylation/dephosphorylation modification on ferroptosis in HCC cells were examined. The interrelationships among GPX4, p53, and protein phosphatase 2A-B55β subunit (PP2A-B55β) were also explored. To explore the synergistic anti-tumor effects of PP2A activation on Sora-administered HCC, we established PP2A-B55β overexpression xenograft tumors in a nude mice model . In the Sora-induced ferroptosis model of HCC , decreased levels of cytoplasmic and mitochondrial GPX4, mitochondrial dysfunction, and enhanced p53 retrograde signaling occurred under Sora treatment. Further, we found that mitochondrial p53 retrograded remarkably into the nucleus and aggravated Sora-induced ferroptosis. The phosphorylation status of GPX4 at the serine 2 site (GPX4) revealed that mitochondrial p-GPX4 dephosphorylation was positively associated with ferroptosis, and the mechanism might be related to mitochondrial p53 retrograding into the nucleus. In HCC cells overexpressing PP2A-B55β, it was found that PP2A-B55β directly interacted with mitochondrial GPX4 and promoted Sora-induced ferroptosis in HCC. Further, PP2A-B55β reduced the interaction between mitochondrial GPX4 and p53, leading to mitochondrial p53 retrograding into the nucleus. Moreover, it was confirmed that PP2A-B55β enhanced the ferroptosis-mediated tumor growth inhibition and mitochondrial p53 retrograde signaling in the Sora-treated HCC xenograft tumors. Our data uncovered that the PP2A-B55β/p-GPX4/p53 axis was a novel regulatory pathway of Sora-induced ferroptosis. Mitochondrial p-GPX4 dephosphorylation triggered ferroptosis via inducing mitochondrial p53 retrograding into the nucleus, and PP2A-B55β was an upstream signal modulator responsible for mitochondrial p-GPX4 dephosphorylation. Our findings might serve as a potential theranostic strategy to enhance the efficacy of Sora in HCC treatment through the targeted intervention of p-GPX4 dephosphorylation via PP2A-B55β activation.
Topics: Animals; Humans; Mice; Carcinoma, Hepatocellular; Cell Nucleus; Down-Regulation; Drug Resistance, Neoplasm; Ferroptosis; Heterografts; Liver Neoplasms; Mice, Inbred BALB C; Mice, Nude; Mitochondria; Neoplasm Transplantation; Phospholipid Hydroperoxide Glutathione Peroxidase; Phosphorylation; Signal Transduction; Sorafenib; Protein Phosphatase 2
PubMed: 37554285
DOI: 10.7150/thno.82132 -
Journal of Hepatology Jul 2024The effectiveness of immune checkpoint inhibitor (ICI) therapy for hepatocellular carcinoma (HCC) is limited by treatment resistance. However, the mechanisms underlying...
BACKGROUND & AIMS
The effectiveness of immune checkpoint inhibitor (ICI) therapy for hepatocellular carcinoma (HCC) is limited by treatment resistance. However, the mechanisms underlying immunotherapy resistance remain elusive. We aimed to identify the role of CT10 regulator of kinase-like (CRKL) in resistance to anti-PD-1 therapy in HCC.
METHODS
Gene expression in HCC specimens from 10 patients receiving anti-PD-1 therapy was identified by RNA-sequencing. A total of 404 HCC samples from tissue microarrays were analyzed by immunohistochemistry. Transgenic mice (Alb-Cre/Trp53) received hydrodynamic tail vein injections of a CRKL-overexpressing vector. Mass cytometry by time of flight was used to profile the proportion and status of different immune cell lineages in the mouse tumor tissues.
RESULTS
CRKL was identified as a candidate anti-PD-1-resistance gene using a pooled genetic screen. CRKL overexpression nullifies anti-PD-1 treatment efficacy by mobilizing tumor-associated neutrophils (TANs), which block the infiltration and function of CD8 T cells. PD-L1 TANs were found to be an essential subset of TANs that were regulated by CRKL expression and display an immunosuppressive phenotype. Mechanistically, CRKL inhibits APC (adenomatous polyposis coli)-mediated proteasomal degradation of β-catenin by competitively decreasing Axin1 binding, and thus promotes VEGFα and CXCL1 expression. Using human HCC samples, we verified the positive correlations of CRKL/β-catenin/VEGFα and CXCL1. Targeting CRKL using CRISPR-Cas9 gene editing (CRKL knockout) or its downstream regulators effectively restored the efficacy of anti-PD-1 therapy in an orthotopic mouse model and a patient-derived organotypic tumor spheroid model.
CONCLUSIONS
Activation of the CRKL/β-catenin/VEGFα and CXCL1 axis is a critical obstacle to successful anti-PD-1 therapy. Therefore, CRKL inhibitors combined with anti-PD-1 could be useful for the treatment of HCC.
IMPACT AND IMPLICATIONS
Here, we found that CRKL was overexpressed in anti-PD-1-resistant hepatocellular carcinoma (HCC) and that CRKL upregulation promotes anti-PD-1 resistance in HCC. We identified that upregulation of the CRKL/β-catenin/VEGFα and CXCL1 axis contributes to anti-PD-1 tolerance by promoting infiltration of tumor-associated neutrophils. These findings support the strategy of bevacizumab-based immune checkpoint inhibitor combination therapy, and CRKL inhibitors combined with anti-PD-1 therapy may be developed for the treatment of HCC.
Topics: Carcinoma, Hepatocellular; Liver Neoplasms; Animals; Humans; Mice; Drug Resistance, Neoplasm; Immune Checkpoint Inhibitors; Adaptor Proteins, Signal Transducing; Neutrophil Infiltration; Programmed Cell Death 1 Receptor; Mice, Transgenic; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Male; Chemokine CXCL1
PubMed: 38403027
DOI: 10.1016/j.jhep.2024.02.009 -
Cancer Research Mar 2024N6-methyladenosine (m6A) RNA modification is the most common and conserved epigenetic modification in mRNA and has been shown to play important roles in cancer biology....
UNLABELLED
N6-methyladenosine (m6A) RNA modification is the most common and conserved epigenetic modification in mRNA and has been shown to play important roles in cancer biology. As the m6A reader YTHDF1 has been reported to promote progression of hepatocellular carcinoma (HCC), it represents a potential therapeutic target. In this study, we evaluated the clinical significance of YTHDF1 using human HCC samples and found that YTHDF1 was significantly upregulated in HCCs with high stemness scores and was positively associated with recurrence and poor prognosis. Analysis of HCC spheroids revealed that YTHDF1 was highly expressed in liver cancer stem cells (CSC). Stem cell-specific conditional Ythdf1 knockin (CKI) mice treated with diethylnitrosamine showed elevated tumor burden as compared with wild-type mice. YTHDF1 promoted CSCs renewal and resistance to the multiple tyrosine kinase inhibitors lenvatinib and sorafenib in patient-derived organoids and HCC cell lines, which could be abolished by catalytically inactive mutant YTHDF1. Multiomic analysis, including RNA immunoprecipitation sequencing, m6A methylated RNA immunoprecipitation sequencing, ribosome profiling, and RNA sequencing identified NOTCH1 as a direct downstream of YTHDF1. YTHDF1 bound to m6A modified NOTCH1 mRNA to enhance its stability and translation, which led to increased NOTCH1 target genes expression. NOTCH1 overexpression rescued HCC stemness in YTHDF1-deficient cells in vitro and in vivo. Lipid nanoparticles targeting YTHDF1 significantly enhanced the efficacy of lenvatinib and sorafenib in HCC in vivo. Taken together, YTHDF1 drives HCC stemness and drug resistance through an YTHDF1-m6A-NOTCH1 epitranscriptomic axis, and YTHDF1 is a potential therapeutic target for treating HCC.
SIGNIFICANCE
Inhibition of YTHDF1 expression suppresses stemness of hepatocellular carcinoma cells and enhances sensitivity to targeted therapies, indicating that targeting YTHDF1 may be a promising therapeutic strategy for liver cancer.
Topics: Humans; Animals; Mice; Carcinoma, Hepatocellular; Sorafenib; Drug Resistance, Neoplasm; Liver Neoplasms; Adenosine; RNA, Messenger; RNA; Receptor, Notch1; RNA-Binding Proteins; Phenylurea Compounds; Quinolines
PubMed: 38241695
DOI: 10.1158/0008-5472.CAN-23-1916 -
International Journal of Molecular... Jul 2023According to the WHO's recently released worldwide cancer data for 2020, liver cancer ranks sixth in morbidity and third in mortality among all malignancies.... (Review)
Review
According to the WHO's recently released worldwide cancer data for 2020, liver cancer ranks sixth in morbidity and third in mortality among all malignancies. Hepatocellular carcinoma (HCC), the most common kind of liver cancer, accounts approximately for 80% of all primary liver malignancies and is one of the leading causes of death globally. The intractable tumor microenvironment plays an important role in the development and progression of HCC and is one of three major unresolved issues in clinical practice (cancer recurrence, fatal metastasis, and the refractory tumor microenvironment). Despite significant advances, improved molecular and cellular characterization of the tumor microenvironment is still required since it plays an important role in the genesis and progression of HCC. The purpose of this review is to present an overview of the HCC immune microenvironment, distinct cellular constituents, current therapies, and potential immunotherapy methods.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Neoplasm Recurrence, Local; Immunotherapy; Tumor Microenvironment; Immune System
PubMed: 37511228
DOI: 10.3390/ijms241411471