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Cancer Letters Jun 2024Liver metastasis is common in patients with gallbladder cancer (GBC), imposing a significant challenge in clinical management and serving as a poor prognostic indicator....
Liver metastasis is common in patients with gallbladder cancer (GBC), imposing a significant challenge in clinical management and serving as a poor prognostic indicator. However, the mechanisms underlying liver metastasis remain largely unknown. Here, we report a crucial role of tyrosine aminotransferase (TAT) in liver metastasis of GBC. TAT is frequently up-regulated in GBC tissues. Increased TAT expression is associated with frequent liver metastasis and poor prognosis of GBC patients. Overexpression of TAT promotes GBC cell migration and invasion in vitro, as well as liver metastasis in vivo. TAT knockdown has the opposite effects. Intriguingly, TAT promotes liver metastasis of GBC by potentiating cardiolipin-dependent mitophagy. Mechanistically, TAT directly binds to cardiolipin and leads to cardiolipin externalization and subsequent mitophagy. Moreover, TRIM21 (Tripartite Motif Containing 21), an E3 ubiquitin ligase, interacts with TAT. The histine residues 336 and 338 at TRIM21 are essential for this binding. TRIM21 preferentially adds the lysine 63 (K63)-linked ubiquitin chains on TAT principally at K136. TRIM21-mediated TAT ubiquitination impairs its dimerization and mitochondrial location, subsequently inhibiting tumor invasion and migration of GBC cells. Therefore, our study identifies TAT as a novel driver of GBC liver metastasis, emphasizing its potential as a therapeutic target.
Topics: Animals; Humans; Mice; Cell Line, Tumor; Cell Movement; Gallbladder Neoplasms; Gene Expression Regulation, Neoplastic; Liver Neoplasms; Mice, Inbred BALB C; Mice, Nude; Mitophagy; Neoplasm Invasiveness; Ribonucleoproteins; Ubiquitination; Tyrosine Transaminase
PubMed: 38697462
DOI: 10.1016/j.canlet.2024.216923 -
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 -
Korean Journal of Radiology Jun 2024Hepatocellular carcinoma (HCC) is a biologically heterogeneous tumor characterized by varying degrees of aggressiveness. The current treatment strategy for HCC is... (Review)
Review
Hepatocellular carcinoma (HCC) is a biologically heterogeneous tumor characterized by varying degrees of aggressiveness. The current treatment strategy for HCC is predominantly determined by the overall tumor burden, and does not address the diverse prognoses of patients with HCC owing to its heterogeneity. Therefore, the prognostication of HCC using imaging data is crucial for optimizing patient management. Although some radiologic features have been demonstrated to be indicative of the biologic behavior of HCC, traditional radiologic methods for HCC prognostication are based on visually-assessed prognostic findings, and are limited by subjectivity and inter-observer variability. Consequently, artificial intelligence has emerged as a promising method for image-based prognostication of HCC. Unlike traditional radiologic image analysis, artificial intelligence based on radiomics or deep learning utilizes numerous image-derived quantitative features, potentially offering an objective, detailed, and comprehensive analysis of the tumor phenotypes. Artificial intelligence, particularly radiomics has displayed potential in a variety of applications, including the prediction of microvascular invasion, recurrence risk after locoregional treatment, and response to systemic therapy. This review highlights the potential value of artificial intelligence in the prognostication of HCC as well as its limitations and future prospects.
Topics: Humans; Liver Neoplasms; Carcinoma, Hepatocellular; Artificial Intelligence; Prognosis; Image Interpretation, Computer-Assisted
PubMed: 38807336
DOI: 10.3348/kjr.2024.0070 -
Hepatology International Dec 2023Relapse of hepatocellular carcinoma (HCC) due to vascular invasion is common, but the genomic mechanisms remain unclear, and molecular determinants of high-risk relapse...
BACKGROUND
Relapse of hepatocellular carcinoma (HCC) due to vascular invasion is common, but the genomic mechanisms remain unclear, and molecular determinants of high-risk relapse cases are lacking. We aimed to reveal the evolutionary trajectory of microvascular invasion (MVI) and develop a predictive signature for relapse in HCC.
METHODS
Whole-exome sequencing was performed on tumor and peritumor tissues, portal vein tumor thrombus (PVTT), and circulating tumor DNA (ctDNA) to compare the genomic profiles between 5 HCC patients with MVI and 5 patients without MVI. We conducted an integrated analysis of exome and transcriptome to develop and validate a prognostic signature in two public cohorts and one cohort from Zhongshan Hospital, Fudan University.
RESULTS
Shared genomic landscapes and identical clonal origins among tumor, PVTT, and ctDNA were observed in MVI ( +) HCC, suggesting that genomic changes favoring metastasis occur at the primary tumor stage and are inherited in metastatic lesions and ctDNA. There was no clonal relatedness between the primary tumor and ctDNA in MVI ( - ) HCC. HCC had dynamic mutation alterations during MVI and exhibited genetic heterogeneity between primary and metastatic tumors, which can be comprehensively reflected by ctDNA. A relapse-related gene signature named RGS was developed based on the significantly mutated genes associated with MVI and shown to be a robust classifier of HCC relapse.
CONCLUSIONS
We characterized the genomic alterations during HCC vascular invasion and revealed a previously undescribed evolution pattern of ctDNA in HCC. A novel multiomics-based signature was developed to identify high-risk relapse populations.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Circulating Tumor DNA; Exome Sequencing; Neoplasm Recurrence, Local; Neoplasm Invasiveness; Recurrence
PubMed: 37217808
DOI: 10.1007/s12072-023-10540-x -
Clinical & Translational Oncology :... Feb 2024Hepatocellular carcinoma (HCC) caused by HBV, HCV infection, and other factors is one of the most common malignancies in the world. Although, percutaneous treatments... (Review)
Review
Hepatocellular carcinoma (HCC) caused by HBV, HCV infection, and other factors is one of the most common malignancies in the world. Although, percutaneous treatments such as surgery, ethanol injection, radiofrequency ablation, and transcatheter treatments such as arterial chemoembolization are useful for local tumor control, they are not sufficient to improve the prognosis of patients with HCC. External interferon agents that induce interferon-related genes or type I interferon in combination with other drugs can reduce the recurrence rate and improve survival in HCC patients after surgery. Therefore, in this review, we focus on recent advances in the mechanism of action of type I interferons, emerging therapies, and potential therapeutic strategies for the treatment of HCC using IFNs.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Interferon Type I; Prognosis; Treatment Outcome; Neoplasm Recurrence, Local
PubMed: 37402970
DOI: 10.1007/s12094-023-03266-7 -
Hepatobiliary & Pancreatic Diseases... Dec 2023More than 50% of patients with colorectal cancer develop liver metastases. Hepatectomy is the preferred treatment for resectable liver metastases. This review provides a... (Review)
Review
BACKGROUND
More than 50% of patients with colorectal cancer develop liver metastases. Hepatectomy is the preferred treatment for resectable liver metastases. This review provides a perspective on the utility and relevant prognostic factors of repeat hepatectomy in recurrent colorectal liver metastasis (CRLM).
DATA SOURCES
The keywords "recurrent colorectal liver metastases", "recurrent hepatic metastases from colorectal cancer", "liver metastases of colorectal cancer", "repeat hepatectomy", "repeat hepatic resection", "second hepatic resection", and "prognostic factors" were used to retrieve articles published in the PubMed database up to August 2020. Additional articles were identified by a manual search of references from key articles.
RESULTS
Despite improvements in surgical methods and perioperative chemotherapy, recurrence remains common in 37%-68% of patients. Standards or guidelines for the treatment of recurrent liver metastases are lacking. Repeat hepatectomy appears to be the best option for patients with resectable metastases. The commonly reported prognostic factors after repeat hepatectomy were R0 resection, carcinoembryonic antigen level, the presence of extrahepatic disease, a short disease-free interval between initial and repeat hepatectomy, the number (> 1) and size (≥ 5 cm) of hepatic lesions, requiring blood transfusion, and no adjuvant chemotherapy after initial hepatectomy. The median overall survival after repeat hepatectomy ranged from 19.3 to 62 months, and the 5-year overall survival ranged from 21% to 73%. Chemotherapy can act as a test for the biological behavior of tumors with the goal of avoiding unnecessary surgery, and a multimodal approach involving aggressive chemotherapy and repeat hepatectomy might be the treatment of choice for patients with early recurrent CRLM.
CONCLUSIONS
Repeat hepatectomy is a relatively safe and effective treatment for resectable recurrent CRLM. The presence or absence of prognostic factors might facilitate patient selection to improve short- and long-term outcomes.
Topics: Humans; Hepatectomy; Prognosis; Colorectal Neoplasms; Reoperation; Liver Neoplasms; Neoplasm Recurrence, Local; Retrospective Studies
PubMed: 36858891
DOI: 10.1016/j.hbpd.2023.02.005 -
Experimental and Clinical... Jul 2023Patients with neuroendocrine tumors with unresec-table liver involvement can benefit from liver transplant. There is a specific set of guidelines for neuroendocrine... (Review)
Review
Patients with neuroendocrine tumors with unresec-table liver involvement can benefit from liver transplant. There is a specific set of guidelines for neuroendocrine tumors with liver metastasis that involve less than 50% of the liver. However, beyond those guidelines, there are reports of exceptional criteria patients who benefited from liver transplant. Here, we present 2 unusual cases of patients with exceptional circumstances and with neuroendocrine tumors who underwent liver transplant. The first case describes a patient with an extremely rare neuroen-docrine tumor of the proximal common bile duct that caused liver biliary cirrhosis. The patient underwent tumor resection and liver transplant concurrently. The second case describes a patient with a neuroendocrine tumor of unknown primary origin with more than 50% hepatic involvement who received a liver transplant after downstaging. In our center, patients with unresectable hepatic metastases from neuroendoc-rine tumors are currently selected for liver transplant based on well-established criteria. However, these 2 cases did not meet the criteria for consideration of liver transplant; thus, multidisciplinary team sessions were held to discuss these 2 cases. After a period of nonsurgical treatment and evaluation of the tumor behavior, we selected the patients as candidates for liver transplant based on the favorable tumor behavior and favorable response to treatment. For both patients, we did not observe any signs of tumor recurrence during follow-up. The outcomes were acceptable, and the patients tolerated treatment well. Considering the favorable tumor pathology (G1 phase and low Ki67 index), we suggest that more studies should be conducted to evaluate the outcomes of patients with low-grade tumors and that the criteria for patients with low-grade tumors could be extended based on such future data.
Topics: Humans; Neuroendocrine Tumors; Liver Transplantation; Neoplasm Recurrence, Local; Liver Neoplasms
PubMed: 37584538
DOI: 10.6002/ect.2023.0110 -
International Journal of Biological... 2023Sorafenib is a first-line chemotherapy drug for treating advanced hepatocellular carcinoma (HCC). However, its therapeutic effect has been seriously affected by the...
Sorafenib is a first-line chemotherapy drug for treating advanced hepatocellular carcinoma (HCC). However, its therapeutic effect has been seriously affected by the emergence of sorafenib resistance in HCC patients. The underlying mechanism of sorafenib resistance is unclear. Here, we report a circular RNA, cDCBLD2, which plays an important role in sorafenib resistance in HCC. We found that cDCBLD2 was upregulated in sorafenib-resistant (SR) HCC cells, and knocking down cDCBLD2 expression could significantly increase sorafenib-related cytotoxicity. Further evidence showed that cDCBLD2 can bind to microRNA (miR)-345-5p through a competing endogenous RNA mechanism, increase type IIA topoisomerase (TOP2A) mRNA stability through a miRNA sponge mechanism, and reduce the effects of sorafenib treatment on HCC by inhibiting apoptosis. Our findings also suggest that miR-345-5p can negatively regulate TOP2A levels by binding to the coding sequence region of its mRNA. Additionally, targeting cDCBLD2 by injecting a specific small interfering RNA (siRNA) could significantly overcome sorafenib resistance in a patient-derived xenograft (PDX) mouse model of HCC. Taken together, our study provides a proof-of-concept for a potential strategy to overcome sorafenib resistance in HCC patients by targeting cDCBLD2 or TOP2A.
Topics: Animals; Humans; Mice; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Liver Neoplasms; MicroRNAs; RNA, Small Interfering; Sorafenib; RNA, Circular
PubMed: 37781045
DOI: 10.7150/ijbs.86227 -
Ageing Research Reviews Jun 2024Hepatocellular carcinoma is a common and highly lethal tumour. The tumour microenvironment (TME) plays an important role in the progression and metastasis of... (Review)
Review
BACKGROUND
Hepatocellular carcinoma is a common and highly lethal tumour. The tumour microenvironment (TME) plays an important role in the progression and metastasis of hepatocellular carcinoma (HCC). A cell death mechanism, termed NETosis, has been found to play an important role in the TME of HCC.
SUMMARY
This review article focuses on the role of NETosis in the TME of HCC, a novel form of cell death in which neutrophils capture and kill microorganisms by releasing a type of DNA meshwork fibres called "NETs". This process is associated with neutrophil activation, local inflammation and cytokines. The study suggests that NETs play a multifaceted role in the development and metastasis of HCC. The article also discusses the role of NETs in tumour proliferation and metastasis, epithelial-mesenchymal transition (EMT), and surgical stress. In addition, the article discusses the interaction of NETosis with other immune cells in the TME and related therapeutic strategies. A deeper understanding of NETosis can help us better understand the complexity of the immune system and provide a new therapeutic basis for the treatment and prevention of HCC.
KEY INFORMATION
In conclusion, NETosis is important in the TME of liver. NETs have been shown to contribute to the progression and metastasis of liver cancer. The interaction between NETosis and immune cells in the TME, as well as related therapies, are important areas of research.
Topics: Humans; Liver Neoplasms; Tumor Microenvironment; Carcinoma, Hepatocellular; Extracellular Traps; Animals; Neoplasm Metastasis; Epithelial-Mesenchymal Transition; Neutrophils
PubMed: 38599524
DOI: 10.1016/j.arr.2024.102297 -
International Journal of Molecular... Aug 2023Members of the tripartite motif (TRIM)-containing protein family have been found to be involved in the progression of hepatocellular carcinoma (HCC). TRIM14 exerts a...
Members of the tripartite motif (TRIM)-containing protein family have been found to be involved in the progression of hepatocellular carcinoma (HCC). TRIM14 exerts a promotive impact on several cancers. This study aimed to explore the function and mechanism of TRIM14 in HCC. TRIM14 expression in HCC tissues and HCC cell lines was detected. The overexpression or knockdown model of TRIM14 was established in HCC cell lines. Cell Counting Kit-8 (CCK-8) assay, flow cytometry, Transwell assay, RT-PCR, Western blot, and immunofluorescence were performed to verify the influence of TRIM14 on cell proliferation, sensitivity to chemotherapy drugs, apoptosis, migration, invasion, and autophagy. A xenograft tumor model was used to confirm the impact of TRIM14 on tumor cell growth. As shown by the data, TRIM14 level was notably higher in the tumor tissues of HCC patients than in the adjacent tissues. The overall survival rate of patients with a high TRIM14 expression was relatively lower than that of patients with a low TRIM14 expression. TRIM14 upregulation enhanced the proliferation, autophagy, migration, and invasion of HCC cells and chemoresistant HCC cells and decreased apoptosis. TRIM14 knockdown contributed to the opposite effects. In in vivo experiments, TRIM14 upregulation bolstered tumor growth. Western blot analysis revealed that TRIM14 upregulation boosted signal transducer and activator of transcription3 (STAT3) and hypoxia-inducible factor-1alpha (HIF-1α) expression, and TRIM14 knockdown suppressed their expression. Moreover, repressing STAT3 and HIF-1α could mitigate the tumor-promoting role of TRIM14 in HCC cells. Overall, TRIM14 facilitated malignant HCC development and induced chemoresistance in HCC cells by activating the STAT3/HIF-1α axis.
Topics: Humans; Animals; Carcinoma, Hepatocellular; Drug Resistance, Neoplasm; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Neoplasms; Cell Line; Disease Models, Animal; Tripartite Motif Proteins; Intracellular Signaling Peptides and Proteins; STAT3 Transcription Factor
PubMed: 37628777
DOI: 10.3390/ijms241612589