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Frontiers in Immunology 2023
Topics: Humans; Liver Transplantation; Liver Neoplasms; Transplants
PubMed: 37781357
DOI: 10.3389/fimmu.2023.1276566 -
Cancer Letters Feb 2024Growing evidence has suggested that increased matrix stiffness can significantly strengthen the malignant characteristics of hepatocellular carcinoma (HCC) cells....
Growing evidence has suggested that increased matrix stiffness can significantly strengthen the malignant characteristics of hepatocellular carcinoma (HCC) cells. However, whether and how increased matrix stiffness regulates the formation of invadopodia in HCC cells remain largely unknown. In the study, we developed different experimental systems in vitro and in vivo to explore the effects of matrix stiffness on the formation of invadopodia and its relevant molecular mechanism. Our results demonstrated that increased matrix stiffness remarkably augmented the migration and invasion abilities of HCC cells, upregulated the expressions of invadopodia-associated genes and enhanced the number of invadopodia. Two regulatory pathways contribute to matrix stiffness-driven invadopodia formation together in HCC cells, including direct triggering invadopodia formation through activating integrin β1 or Piezo1/ FAK/Src/Arg/cortactin pathway, and indirect stimulating invadopodia formation through improving EGF production to activate EGFR/Src/Arg/cortactin pathway. Src was identified as the common hub molecule of two synergistic regulatory pathways. Simultaneously, activation of integrin β1/RhoA/ROCK1/MLC2 and Piezo1/Ca/MLCK/MLC2 pathways mediate matrix stiffness-reinforced cell migration. This study uncovers a new mechanism by which mechanosensory pathway and biochemical signal pathway synergistically regulate the formation of invadopodia in HCC cells.
Topics: Humans; Carcinoma, Hepatocellular; Cortactin; Podosomes; Liver Neoplasms; Integrin beta1; Extracellular Matrix; Cell Line, Tumor; Neoplasm Invasiveness; rho-Associated Kinases
PubMed: 38145655
DOI: 10.1016/j.canlet.2023.216597 -
Annals of Hepatology 2024Hepatocellular carcinoma (HCC) is one of the most common cancers with a high mortality rate. HCC development is associated with its underlying etiologies, mostly caused... (Review)
Review
Hepatocellular carcinoma (HCC) is one of the most common cancers with a high mortality rate. HCC development is associated with its underlying etiologies, mostly caused by infection of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV), alcohol, non-alcoholic fatty liver disease, and exposure to aflatoxins. These variables, together with human genetic susceptibility, contribute to HCC molecular heterogeneity, including at the cellular level. HCC initiation, tumor recurrence, and drug resistance rates have been attributed to the presence of liver cancer stem cells (CSC). This review summarizes available data regarding whether various HCC etiologies may be associated to the appearance of CSC biomarkers. It also described the genetic variations of tumoral tissues obtained from Western and Eastern populations, in particular to the oncogenic effect of HBV in the human genome.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Hepatitis B, Chronic; Neoplasm Recurrence, Local; Hepatitis C; Hepatitis B virus; Hepatitis B
PubMed: 37734662
DOI: 10.1016/j.aohep.2023.101153 -
Cancer Medicine Feb 2024Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Hepatectomy remains the first-line treatment for patients with resectable... (Review)
Review
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Hepatectomy remains the first-line treatment for patients with resectable HCC. However, the reported recurrence rate of HCC at 5 years after surgery is between 50% and 70%. Tumor-related factors, including tumor size, number and differentiation, and underlying liver disease are well-known risk factors for recurrence after treatment. In addition to tumor-related factors, ever-increasing amounts of studies are finding that the tumor microenvironment also plays an important role in the recurrence of HCC, including systemic inflammatory response and immune regulation. Based on this, some inflammatory and immune markers were used in predicting postoperative cancer recurrence. These include neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, cytotoxic T cells, and regulatory T cells, among others. In this review, we summarized the inflammatory and immune markers that affect recurrence after HCC resection in order to provide direction for adjuvant therapy after HCC resection and ultimately achieve the goal of reducing recurrence.
Topics: Humans; Carcinoma, Hepatocellular; Hepatectomy; Liver Neoplasms; Neoplasm Recurrence, Local; Inflammation; Lymphocytes; Biomarkers; Retrospective Studies; Prognosis; Tumor Microenvironment
PubMed: 38457189
DOI: 10.1002/cam4.7018 -
International Journal of Biological... 2023Long non-coding RNAs have been reported to play a crucial role in tumor progression in hepatocellular carcinoma (HCC). Lnc-ZEB2-19 has been validated to be deficiently...
Long non-coding RNAs have been reported to play a crucial role in tumor progression in hepatocellular carcinoma (HCC). Lnc-ZEB2-19 has been validated to be deficiently expressed in HCC. However, the capabilities and underlying mechanisms of lnc-ZEB2-19 remain uncertain. In this study, we verified that the downregulation of lnc-ZEB2-19 was prevalent in HCC and significantly correlated with the unfavorable prognosis. Further in vitro and in vivo verified that lnc-ZEB2-19 notably inhibited the proliferation, metastasis, stemness, and lenvatinib resistance (LR) of HCC cells. Mechanistically, lnc-ZEB2-19 inhibited HCC progression and LR by specifically binding to transformer 2α (TRA2A) and promoting its degradation, which resulted in the instability of RSPH14 mRNA, leading to the downregulation of Rela(p65) and p-Rela(p-p65). Furthermore, rescue assays showed that silencing RSPH14 partially restrained the effect of knockdown expression of lnc-ZEB2-19 on HCC cell metastatic ability and stemness. The findings describe a novel regulatory axis, lnc-ZEB2-19/TRA2A/RSPH14, downregulating the nuclear factor kappa B to inhibit HCC progression and LR.
Topics: Humans; Carcinoma, Hepatocellular; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Liver Neoplasms; NF-kappa B; Signal Transduction; Zinc Finger E-box Binding Homeobox 2; Drug Resistance, Neoplasm; RNA, Long Noncoding
PubMed: 37564197
DOI: 10.7150/ijbs.85270 -
Journal of Gastroenterology Oct 2023Hepatocellular carcinoma has a substantial global mortality burden which is rising despite advancements in tackling the traditional viral risk factors. Metabolic... (Review)
Review
Hepatocellular carcinoma has a substantial global mortality burden which is rising despite advancements in tackling the traditional viral risk factors. Metabolic (dysfunction) associated fatty liver disease (MAFLD) is the most prevalent liver disease, increasing in parallel with the epidemics of obesity, diabetes and systemic metabolic dysregulation. MAFLD is a major factor behind this sustained rise in HCC incidence, both as a single disease entity and often via synergistic interactions with other liver diseases. Mechanisms behind MAFLD-related HCC are complex but is crucially underpinned by systemic metabolic dysregulation with variable contributions from interacting disease modifiers related to environment, genetics, dysbiosis and immune dysregulation. MAFLD-related HCC has a distinct clinical presentation, most notably its common occurrence in non-cirrhotic liver disease. This is just one of several major challenges to effective surveillance programmes. The response of MAFLD-related HCC to immune-checkpoint therapy is currently controversial, and is further complicated by the high prevalence of MAFLD in individuals with HCC from viral aetiologies. In this review, we highlight the current data on epidemiology, clinical characteristics, outcomes and screening controversies. In addition, concepts that have arisen because of the MAFLD paradigm such as HCC in MAFLD/NAFLD non-overlapping groups, dual aetiology tumours and MAFLD sub-phenotypes is reviewed.
Topics: Humans; Liver Neoplasms; Carcinoma, Hepatocellular; Dysbiosis; Non-alcoholic Fatty Liver Disease; Phenotype
PubMed: 37470858
DOI: 10.1007/s00535-023-02021-7 -
International Journal of Surgery... Oct 2023The presence of microvascular invasion (MVI) significantly impairs postoperative long-term survival of patients with hepatocellular carcinoma (HCC). The role of... (Randomized Controlled Trial)
Randomized Controlled Trial
Neoadjuvant intensity modulated radiotherapy for a single and small (≤5 cm) hepatitis B virus-related hepatocellular carcinoma predicted to have high risks of microvascular invasion: a randomized clinical trial.
BACKGROUND
The presence of microvascular invasion (MVI) significantly impairs postoperative long-term survival of patients with hepatocellular carcinoma (HCC). The role of neoadjuvant radiotherapy (RT) in treating patients with an early-stage HCC predicted to have high risks of MVI remains to be explored.
MATERIALS AND METHODS
Consecutive patients with a resectable single and small (≤5 cm) hepatitis B virus-related HCC predicted to have high risks of MVI were randomized 1:1 to receive either neoadjuvant intensity modulated radiation therapy (18 Gy with fractionated doses of 3 Gy) followed by surgery 4 weeks later or upfront surgery. The primary endpoint was disease-free survival (DFS). The secondary outcomes included overall survival (OS), objective response rate, RT-related toxicity and surgical complications.
RESULTS
There were 30 patients randomized to each of the two groups. In the neoadjuvant RT group, three patients violated the study protocol, with two having upfront hepatectomy and one radiofrequency ablation after RT. The objective response rate after RT was 25.0% (7/28), but 2 patients suffered from grade 3 liver toxicity. The median follow-up was 68 months (interquartile range, 58-70 months) in the neoadjuvant RT group, and 68 months (interquartile range, 62-75 months) in the upfront surgery group. On intention-to-treat analysis, the median DFS and median OS were not reached in both the 2 arms. The 1-year, 2-year, 3-year and 5-year DFS rates for the neoadjuvant RT group were 86.7%, 76.7%, 60.0% and 56.3%, versus 90.0%, 66.7%, 52.8% and 45.7% in the upfront surgery group ( P =0.448), respectively. The corresponding OS rates were 96.7%, 86.7%, 83.3% and 72.7%, versus 100.0%, 93.3%, 79.6% and 60.7% ( P = 0.399).
CONCLUSION AND RELEVANCE
For patients with a resectable single and small hepatitis B virus-related HCC predicted to have high risks of MVI, neoadjuvant RT gave a promising response rate with a mild toxicity. Nevertheless, the neoadjuvant RT yielded similar long-term DFS and OS rates compared with patients who underwent upfront surgery.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Neoadjuvant Therapy; Hepatitis B virus; Radiotherapy, Intensity-Modulated; Treatment Outcome; Hepatectomy; Retrospective Studies
PubMed: 37352528
DOI: 10.1097/JS9.0000000000000574 -
International Journal of Molecular... Jun 2024The autonomic nervous system plays an integral role in motion and sensation as well as the physiologic function of visceral organs. The nervous system additionally plays... (Review)
Review
The autonomic nervous system plays an integral role in motion and sensation as well as the physiologic function of visceral organs. The nervous system additionally plays a key role in primary liver diseases. Until recently, however, the impact of nerves on cancer development, progression, and metastasis has been unappreciated. This review highlights recent advances in understanding neuroanatomical networks within solid organs and their mechanistic influence on organ function, specifically in the liver and liver cancer. We discuss the interaction between the autonomic nervous system, including sympathetic and parasympathetic nerves, and the liver. We also examine how sympathetic innervation affects metabolic functions and diseases like nonalcoholic fatty liver disease (NAFLD). We also delve into the neurobiology of the liver, the interplay between cancer and nerves, and the neural regulation of the immune response. We emphasize the influence of the neuroimmune axis in cancer progression and the potential of targeted interventions like neurolysis to improve cancer treatment outcomes, especially for hepatocellular carcinoma (HCC).
Topics: Humans; Liver Neoplasms; Neuroimmunomodulation; Animals; Carcinoma, Hepatocellular; Liver; Non-alcoholic Fatty Liver Disease; Autonomic Nervous System
PubMed: 38892423
DOI: 10.3390/ijms25116237 -
Cell Reports. Medicine Feb 2024A tumor ecosystem constantly evolves over time in the face of immune predation or therapeutic intervention, resulting in treatment failure and tumor progression. Here,...
A tumor ecosystem constantly evolves over time in the face of immune predation or therapeutic intervention, resulting in treatment failure and tumor progression. Here, we present a single-cell transcriptome-based strategy to determine the evolution of longitudinal tumor biopsies from liver cancer patients by measuring cellular lineage and ecology. We construct a lineage and ecological score as joint dynamics of tumor cells and their microenvironments. Tumors may be classified into four main states in the lineage-ecological space, which are associated with clinical outcomes. Analysis of longitudinal samples reveals the evolutionary trajectory of tumors in response to treatment. We validate the lineage-ecology-based scoring system in predicting clinical outcomes using bulk transcriptomic data of additional cohorts of 716 liver cancer patients. Our study provides a framework for monitoring tumor evolution in response to therapeutic intervention.
Topics: Humans; Cell Lineage; Gene Expression Profiling; Liver Neoplasms; Transcriptome; Tumor Microenvironment
PubMed: 38280378
DOI: 10.1016/j.xcrm.2024.101394 -
Annals of Surgery Oct 2023We report here the results of a prospective study of circulating tumor DNA (ctDNA) detection in patients undergoing uveal melanoma (UM) liver metastases resection...
OBJECTIVE
We report here the results of a prospective study of circulating tumor DNA (ctDNA) detection in patients undergoing uveal melanoma (UM) liver metastases resection (NCT02849145).
BACKGROUND
In UM patients, the liver is the most common and often only site of metastases. Local treatments of liver metastases, such as surgical resection, have a likely benefit in selected patients.
METHODS
Upon enrollment, metastatic UM patients eligible for curative liver surgery had plasma samples collected before and after surgery. GNAQ / GNA11 mutations were identified in archived tumor tissue and used to quantify ctDNA by droplet digital polymerase chain reaction which was then associated with the patient's surgical outcomes.
RESULTS
Forty-seven patients were included. Liver surgery was associated with a major increase of cell-free circulating DNA levels, with a peak 2 days after surgery (∼20-fold). Among 40 evaluable patients, 14 (35%) had detectable ctDNA before surgery, with a median allelic frequency of 1.1%. These patients experienced statistically shorter relapse-free survival (RFS) versus patients with no detectable ctDNA before surgery (median RFS: 5.5 vs 12.2 months; hazard ratio=2.23, 95% CI: 1.06-4.69, P =0.04), and had a numerically shorter overall survival (OS) (median OS: 27.0 vs 42.3 months). ctDNA positivity at postsurgery time points was also associated with RFS and OS.
CONCLUSIONS
This study is the first to report ctDNA detection rate and prognostic impact in UM patients eligible for surgical resection of their liver metastases. If confirmed by further studies in this setting, this noninvasive biomarker could inform treatment decisions in UM patients with liver metastases.
Topics: Humans; Circulating Tumor DNA; Prognosis; Prospective Studies; Neoplasm Recurrence, Local; Liver Neoplasms; Biomarkers, Tumor; Mutation
PubMed: 36847256
DOI: 10.1097/SLA.0000000000005822