Cholangiocarcinoma 2020: the next horizon in mechanisms and management

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2020, Volume and Issue: 17(9), P. 557 - 588

Published: June 30, 2020

Abstract Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point the tree. Their incidence is increasing globally, currently accounting for ~15% all primary liver cancers and ~3% gastrointestinal malignancies. The silent presentation these combined with their aggressive nature refractoriness to chemotherapy contribute alarming mortality, representing ~2% cancer-related deaths worldwide yearly. current diagnosis CCA by non-invasive approaches not accurate enough, histological confirmation necessary. Furthermore, high heterogeneity CCAs genomic, epigenetic molecular levels severely compromises efficacy available therapies. In past decade, efforts have been made understand complexity develop new diagnostic tools therapies might help improve patient outcomes. this expert Consensus Statement, which endorsed European Network Study Cholangiocarcinoma, we aim summarize critically discuss latest advances in CCA, mostly focusing on classification, cells origin, genetic abnormalities, alterations, biomarker discovery treatments. horizon next decade from 2020 onwards highlighted.

Language: Английский

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Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Jan. 3, 2022

Abstract The Wnt/β-catenin pathway comprises a family of proteins that play critical roles in embryonic development and adult tissue homeostasis. deregulation signalling often leads to various serious diseases, including cancer non-cancer diseases. Although many articles have reviewed from aspects, systematic review encompassing the origin, composition, function, clinical trials tumour diseases is lacking. In this article, we comprehensively above five aspects combination with latest research. Finally, propose challenges opportunities for small-molecular compounds targeting Wnt disease treatment.

Language: Английский

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Integrated Proteogenomic Characterization of HBV-Related Hepatocellular Carcinoma

Cell, Journal Year: 2019, Volume and Issue: 179(2), P. 561 - 577.e22

Published: Oct. 1, 2019

We performed the first proteogenomic characterization of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) using paired tumor and adjacent liver tissues from 159 patients. Integrated analyses revealed consistency discordance among multi-omics, activation status key signaling pathways, liver-specific metabolic reprogramming in HBV-related HCC. Proteomic profiling identified three subgroups associated with clinical molecular attributes including patient survival, thrombus, genetic profile, proteome. These proteomic have distinct features reprogramming, microenvironment dysregulation, cell proliferation, potential therapeutics. Two prognostic biomarkers, PYCR2 ADH1A, related to subgrouping involved HCC were identified. CTNNB1 TP53 mutation-associated profiles revealed, which mutated CTNNB1-associated ALDOA phosphorylation was validated promote glycolysis proliferation. Our study provides a valuable resource that significantly expands knowledge may eventually benefit practice.

Language: Английский

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The Curious Case of the HepG2 Cell Line: 40 Years of Expertise

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(23), P. 13135 - 13135

Published: Dec. 4, 2021

Liver cancer is the third leading cause of death worldwide. Representing such a dramatic impact on our lives, liver significant public health concern. Sustainable and reliable methods for preventing treating require fundamental research its molecular mechanisms. Cell lines are treated as in vitro equivalents tumor tissues, making them must-have basic nature cancer. According to recent discoveries, certified cell retain most genetic properties original mimic microenvironment. On other hand, modern technologies allowing deepest level detail omics landscapes have shown differences even between samples same line due cross- mycoplasma infection. This observations suggest that, some cases, cultures not suitable models, with limited predictive value effectiveness new treatments. HepG2 popular hepatic line. It used wide range studies, from oncogenesis cytotoxicity substances liver. In this regard, we set out collect up-to-date information assess whether heterogeneity allows biomedical studies model guaranteed production quality.

Language: Английский

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β-Catenin signaling in hepatocellular carcinoma

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(4)

Published: Feb. 14, 2022

Deregulated Wnt/β-catenin signaling is one of the main genetic alterations in human hepatocellular carcinoma (HCC). Comprehensive genomic analyses have revealed that gain-of-function mutation CTNNB1, which encodes β-catenin, and loss-of-function AXIN1 occur approximately 35% HCC samples. Human HCCs with activation pathway demonstrate unique gene expression patterns pathological features. Activated synergizes multiple cascades to drive formation, it functions through its downstream effectors. Therefore, strategies targeting been pursued as possible therapeutics against HCC. Here, we review oncogenic roles aberrant during hepatocarcinogenesis. In addition, discuss implication this diagnosis, classification, personalized treatment.

Language: Английский

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Molecular Bases of Drug Resistance in Hepatocellular Carcinoma

Cancers, Journal Year: 2020, Volume and Issue: 12(6), P. 1663 - 1663

Published: June 23, 2020

The poor outcome of patients with non-surgically removable advanced hepatocellular carcinoma (HCC), the most frequent type primary liver cancer, is mainly due to high refractoriness this aggressive tumor classical chemotherapy. Novel pharmacological approaches based on use inhibitors tyrosine kinases (TKIs), sorafenib and regorafenib, have provided only a modest prolongation overall survival in these HCC patients. present review an update available information regarding our understanding molecular bases mechanisms chemoresistance (MOC) significant impact response existing tools, which include chemotherapeutic agents, TKIs novel immune-sensitizing strategies. Many more than one hundred genes involved seven MOC been identified as potential biomarkers predict failure treatment, well druggable targets develop strategies aimed at increasing sensitivity treatments.

Language: Английский

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Fibrosis Regression After Eradication of Hepatitis C Virus: From Bench to Bedside

Gastroenterology, Journal Year: 2021, Volume and Issue: 160(5), P. 1502 - 1520.e1

Published: Jan. 30, 2021

Language: Английский

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Pathogenesis and Current Treatment Strategies of Hepatocellular Carcinoma

Biomedicines, Journal Year: 2022, Volume and Issue: 10(12), P. 3202 - 3202

Published: Dec. 9, 2022

Hepatocellular carcinoma (HCC) is the most frequent liver cancer with high lethality and low five-year survival rates leading to a substantial worldwide burden for healthcare systems. HCC initiation progression are favored by different etiological risk factors including hepatitis B virus (HBV) C (HCV) infection, non-/and alcoholic fatty disease (N/AFLD), tobacco smoking. In molecular pathogenesis, endogenous alteration in genetics (TP53, TERT, CTNNB1, etc.), epigenetics (DNA-methylation, miRNA, lncRNA, dysregulation of key signaling pathways (Wnt/β-catenin, JAK/STAT, etc.) strongly contribute development HCC. The multitude complexity pathomechanisms also reflect difficulties tailored medical therapy Treatment options strictly dependent on tumor staging function, which structured updated Barcelona Clinic Liver Cancer classification system. Surgical resection, local ablative techniques, transplantation valid curative therapeutic early stages. For multifocal metastatic diseases, systemic recommended. While Sorafenib had been standalone first-line decades, recent developments led approval new treatment as well second-line treatment. Anti-PD-L1 directed combination therapies either anti-VEGF agents or anti-CTLA-4 active substances have implemented standard setting. However, data from clinical trials indicate responses specific regimens depending underlying pathogenesis hepatocellular cancer. Therefore, histopathological examinations re-emphasized current international guidelines addition standardized radiological diagnosis using contrast-enhanced cross-sectional imaging. this review, we emphasize knowledge carcinoma. On occasion, sequences advanced stages according recently system algorithm (first-, second-, third-line treatment) summarized. Furthermore, discuss novel precautional pre-therapeutic approaches vaccination, adoptive cell transfer, locoregional enhancement, non-coding RNA-based promising options. These treatments may prolong overall regard quality life function mainstay therapy.

Language: Английский

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Targeting strategies for bone diseases: signaling pathways and clinical studies

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 17, 2023

Abstract Since the proposal of Paul Ehrlich’s magic bullet concept over 100 years ago, tremendous advances have occurred in targeted therapy. From initial selective antibody, antitoxin to drug delivery that emerged past decades, more precise therapeutic efficacy is realized specific pathological sites clinical diseases. As a highly pyknotic mineralized tissue with lessened blood flow, bone characterized by complex remodeling and homeostatic regulation mechanism, which makes therapy for skeletal diseases challenging than other tissues. Bone-targeted has been considered promising approach handling such drawbacks. With deepening understanding biology, improvements some established bone-targeted drugs novel targets deliveries on horizon. In this review, we provide panoramic summary recent strategies based targeting. We highlight targeting structure biology. For agents, addition classic denosumab, romosozumab, PTH1R ligands, potential process key membrane expressions, cellular crosstalk, gene expression, all cells exploited. delivery, different matrix, marrow, are summarized comparison between ligands. Ultimately, review will summarize translation therapies perspective challenges application clinic future trends area.

Language: Английский

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PRMT3-mediated arginine methylation of IGF2BP1 promotes oxaliplatin resistance in liver cancer

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: April 6, 2023

Abstract Although oxaliplatin-based chemotherapy has been effective in the treatment of hepatocellular carcinoma (HCC), primary or acquired resistance to oxaliplatin remains a major challenge clinic. Through functional screening using CRISPR/Cas9 activation library, transcriptomic profiling clinical samples, and validation vitro vivo, we identify PRMT3 as key driver resistance. Mechanistically, PRMT3-mediated oxaliplatin-resistance is part dependent on methylation IGF2BP1 at R452, which critical for function stabilizing mRNA HEG1, an effector PRMT3-IGF2BP1 axis. Also, overexpression may serve biomarker HCC patients. Collectively, our study defines PRTM3-IGF2BP1-HEG1 axis important regulators therapeutic targets suggests potential use expression level pretreatment biopsy

Language: Английский

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