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Cancers
Special Issues
Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment
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Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Clinical Research of Cancer".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 94097

Special Issue Editors

Prof. Dr. Matias A. Avila

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Guest Editor
1. Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain
2. Hepatology Program, CIMA, University of Navarra, Pamplona, Spain
Interests: hepatocarcinogenesis; cell signaling; differentiation; epigenetics
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Shelly Chi-Loo Lu

E-Mail Website
Guest Editor
Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Medicine, Los Angeles, CA 90048, USA
Interests: role of S-adenosylmethionine and glutathione in liver health and injury; regulation and functions of methionine adenosyltransferase genes; role of prohibitin 1 in liver health and cancer
Dr. Maria Luz Martinez-Chantar

E-Mail Website
Guest Editor
Liver Disease Lab, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Bizkaia, Spain
Interests: hepatocarcinogenesis; cell signaling; metabolism; liver injury Photograph is also in the attachment

Special Issue Information

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, has an overall 5-year survival rate of 18%, making it the second most lethal cancer after pancreatic cancer. While the mortality of many cancers such as lung, prostate, colorectal, and breast has decreased, the mortality of liver cancer has increased. Indeed, liver cancer incidence is rising faster than that of any other cancer in both men and women. Well-recognized risk factors for HCC include chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, chronic alcohol use, and fatty liver disease. The majority of HCC patients present late, and only 30% are candidates for surgical resection but, unfortunately, still face a recurrence rate of about 50% at 3 years. Tremendous progress has been made in understanding the pathogenesis of HCC with diverse etiologies. In addition, we now have more than multikinase inhibitors in the armamentarium for treating advanced HCC. However, we still need to improve the early detection of HCC. This Special Edition of Cancers is intended to update the readers on the pathogenesis regarding different etiologies, methods of detection, and available and emerging treatments.

Prof. Dr. Matias A. Avila
Prof. Dr. Shelly Chi-Loo Lu
Prof. Dr. Maria Luz Martinez-Chantar
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • hepatocellular carcinoma
  • risk factors
  • liquid biopsy
  • early diagnosis
  • multikinase inhibitors
  • immune checkpoint inhibitors

Published Papers (28 papers)

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Editorial

Jump to: Research, Review, Other

4 pages, 199 KiB  
Editorial
Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment
by Maria L. Martínez-Chantar, Matias A. Avila and Shelly C. Lu
Cancers 2020, 12(10), 2729; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102729 - 23 Sep 2020
Cited by 13 | Viewed by 2145
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and the second most common cause of cancer mortality worldwide [...] Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)

Research

Jump to: Editorial, Review, Other

17 pages, 4389 KiB  
Article
Novel Molecular Targets for Hepatocellular Carcinoma
by Beatrice Cavalluzzo, Angela Mauriello, Concetta Ragone, Carmen Manolio, Maria Lina Tornesello, Franco M. Buonaguro, Siri Amanda Tvingsholm, Sine Reker Hadrup, Maria Tagliamonte and Luigi Buonaguro
Cancers 2022, 14(1), 140; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010140 - 28 Dec 2021
Cited by 8 | Viewed by 1770
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer globally. Indeed, only a few treatments are available, most of which are effective only for the early stages of the disease. Therefore, there is an urgent needing for potential markers for [...] Read more.
Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer globally. Indeed, only a few treatments are available, most of which are effective only for the early stages of the disease. Therefore, there is an urgent needing for potential markers for a specifically targeted therapy. Candidate proteins were selected from datasets of The Human Protein Atlas, in order to identify specific tumor-associated proteins overexpressed in HCC samples associated with poor prognosis. Potential epitopes were predicted from such proteins, and homology with peptides derived from viral proteins was assessed. A multiparametric validation was performed, including recognition by PBMCs from HCC-patients and healthy donors, showing a T-cell cross-reactivity with paired epitopes. These results provide novel HCC-specific tumor-associated antigens (TAAs) for immunotherapeutic anti-HCC strategies potentially able to expand pre-existing virus-specific CD8+ T cells with superior anticancer efficacy. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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12 pages, 1004 KiB  
Article
Hepatic Arterial Infusion Chemotherapy with Cisplatin versus Sorafenib for Intrahepatic Advanced Hepatocellular Carcinoma: A Propensity Score-Matched Analysis
by Yuki Zaizen, Masahito Nakano, Kazuta Fukumori, Yoichi Yano, Kota Takaki, Takashi Niizeki, Kotaro Kuwaki, Masaru Fukahori, Takahiko Sakaue, Sohei Yoshimura, Mika Nakazaki, Ryoko Kuromatsu, Shusuke Okamura, Hideki Iwamoto, Shigeo Shimose, Tomotake Shirono, Yu Noda, Naoki Kamachi, Hironori Koga and Takuji Torimura
Cancers 2021, 13(21), 5282; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215282 - 21 Oct 2021
Cited by 8 | Viewed by 1818
Abstract
Given that the outcome of hepatic arterial infusion chemotherapy (HAIC) with cisplatin for intrahepatic advanced hepatocellular carcinoma (HCC) is unclear, we aimed to compare prognostic factors for overall survival (OS) following HAIC with cisplatin versus sorafenib for intrahepatic advanced HCC using propensity score-matched [...] Read more.
Given that the outcome of hepatic arterial infusion chemotherapy (HAIC) with cisplatin for intrahepatic advanced hepatocellular carcinoma (HCC) is unclear, we aimed to compare prognostic factors for overall survival (OS) following HAIC with cisplatin versus sorafenib for intrahepatic advanced HCC using propensity score-matched analysis. We enrolled 331 patients with intrahepatic advanced HCC who received HAIC with cisplatin (n = 88) or sorafenib (n = 243) between June 2006 and March 2020. No significant difference was observed in OS between HAIC with cisplatin and sorafenib cohorts (median survival time [MST]: 14.0 vs. 12.3 months; p = 0.0721). To reduce confounding effects, 166 patients were selected using propensity score-matched analysis (n = 83 for each treatment). HAIC with cisplatin significantly prolonged OS compared with sorafenib (MST: 15.6 vs. 11.0 months; p = 0.0157). Following stratification according to the Child-Pugh classification, for patients with class A (MST: 24.0 vs. 15.0 months; p = 0.0145), HAIC with cisplatin rather than sorafenib significantly prolonged OS. Our findings suggest that HAIC with cisplatin demonstrates longer prognostic effects than sorafenib in intrahepatic advanced HCC. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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30 pages, 9612 KiB  
Article
Mir-21 Suppression Promotes Mouse Hepatocarcinogenesis
by Marta Correia de Sousa, Nicolas Calo, Cyril Sobolewski, Monika Gjorgjieva, Sophie Clément, Christine Maeder, Dobrochna Dolicka, Margot Fournier, Laurent Vinet, Xavier Montet, Jean-François Dufour, Bostjan Humar, Francesco Negro, Christine Sempoux and Michelangelo Foti
Cancers 2021, 13(19), 4983; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13194983 - 04 Oct 2021
Cited by 17 | Viewed by 3344
Abstract
The microRNA 21 (miR-21) is upregulated in almost all known human cancers and is considered a highly potent oncogene and potential therapeutic target for cancer treatment. In the liver, miR-21 was reported to promote hepatic steatosis and inflammation, but whether miR-21 also drives [...] Read more.
The microRNA 21 (miR-21) is upregulated in almost all known human cancers and is considered a highly potent oncogene and potential therapeutic target for cancer treatment. In the liver, miR-21 was reported to promote hepatic steatosis and inflammation, but whether miR-21 also drives hepatocarcinogenesis remains poorly investigated in vivo. Here we show using both carcinogen (Diethylnitrosamine, DEN) or genetically (PTEN deficiency)-induced mouse models of hepatocellular carcinoma (HCC), total or hepatocyte-specific genetic deletion of this microRNA fosters HCC development—contrasting the expected oncogenic role of miR-21. Gene and protein expression analyses of mouse liver tissues further indicate that total or hepatocyte-specific miR-21 deficiency is associated with an increased expression of oncogenes such as Cdc25a, subtle deregulations of the MAPK, HiPPO, and STAT3 signaling pathways, as well as alterations of the inflammatory/immune anti-tumoral responses in the liver. Together, our data show that miR-21 deficiency promotes a pro-tumoral microenvironment, which over time fosters HCC development via pleiotropic and complex mechanisms. These results question the current dogma of miR-21 being a potent oncomiR in the liver and call for cautiousness when considering miR-21 inhibition for therapeutic purposes in HCC. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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11 pages, 3843 KiB  
Article
Etiology and Outcomes of Hepatocellular Carcinoma in an Ethnically Diverse Population: The Multiethnic Cohort
by Afsaneh Barzi, Kali Zhou, Songren Wang, Jennifer L. Dodge, Anthony El-Khoueiry and Veronica Wendy Setiawan
Cancers 2021, 13(14), 3476; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143476 - 12 Jul 2021
Cited by 13 | Viewed by 2466
Abstract
Backgrounds: HCC incidence varies by race/ethnicity. We characterized racial differences in underlying etiology, presentation, and survival in the linkage of Multiethnic Cohort Study with SEER and Medicare claims. Methods: HCC characteristics, treatment, and underlying etiology in participants were obtained. Deaths were ascertained using [...] Read more.
Backgrounds: HCC incidence varies by race/ethnicity. We characterized racial differences in underlying etiology, presentation, and survival in the linkage of Multiethnic Cohort Study with SEER and Medicare claims. Methods: HCC characteristics, treatment, and underlying etiology in participants were obtained. Deaths were ascertained using state death certificates and the National Death Index. Risk factors were collected via questionnaires. Cox models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for death. Results: Among 359 cases, the average age at diagnosis was 75.1. The most common etiology was hepatitis C (HCV) (33%), followed by nonalcoholic fatty liver disease (NAFLD) (31%), and different by ethnicity (p < 0.0001). African Americans (AA) (59.5%) and Latinos (40.6%) were more likely to be diagnosed with HCV-related HCC. In Japanese Americans (33.1%), Native Hawaiians (39.1%), and whites (34.8%), NAFLD was the most common etiology. Receipt of treatment varied across ethnic groups (p = 0.0005); AA had the highest proportion of no treatment (50.0%), followed by Latinos (45.3%), vs. whites (15.2%). HCC (72.2%) was the most common cause of death. In a multivariate analysis, AA (HR = 1.87; 95% CI: 1.06–3.28) had significantly higher mortality compared to whites. Conclusions: We found significant ethnic differences in HCC underlying etiology, receipt of treatment, and outcome. The findings are important for reducing disparities. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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14 pages, 4844 KiB  
Article
2-[18F]FDG PET/CT as a Predictor of Microvascular Invasion and High Histological Grade in Patients with Hepatocellular Carcinoma
by Aida Sabaté-Llobera, Judit Mestres-Martí, Gabriel Reynés-Llompart, Laura Lladó, Kristel Mils, Teresa Serrano, Montserrat Cortés-Romera, Esther Bertran, Isabel Fabregat and Emilio Ramos
Cancers 2021, 13(11), 2554; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112554 - 23 May 2021
Cited by 13 | Viewed by 2415
Abstract
Hepatocellular carcinoma (HCC) generally presents a low avidity for 2-deoxy-2-[18F]fluoro-d-glucose (FDG) in PET/CT although an increased FDG uptake seems to relate to more aggressive biological factors. To define the prognostic value of PET/CT with FDG in patients with an [...] Read more.
Hepatocellular carcinoma (HCC) generally presents a low avidity for 2-deoxy-2-[18F]fluoro-d-glucose (FDG) in PET/CT although an increased FDG uptake seems to relate to more aggressive biological factors. To define the prognostic value of PET/CT with FDG in patients with an HCC scheduled for a tumor resection, forty-one patients were prospectively studied. The histological factors of a poor prognosis were determined and FDG uptake in the HCC lesions was analyzed semi-quantitatively (lean body mass-corrected standardized uptake value (SUL) and tumor-to-liver ratio (TLR) at different time points). The PET metabolic parameters were related to the histological characteristics of the resected tumors and to the evolution of patients. Microvascular invasion (MVI) and a poor grade of differentiation were significantly related to a worse prognosis. The SULpeak of the lesion 60 min post-FDG injection was the best parameter to predict MVI while the SULpeak of the TLR at 60 min was better for a poor differentiation. Moreover, the latter parameter was also the best preoperative variable available to predict any of these two histological factors. Patients with an increased TLRpeak60 presented a significantly higher incidence of poor prognostic factors than the rest (75% vs. 28.6%, p = 0.005) and a significantly higher incidence of recurrence at 12 months (38% vs. 0%, p = 0.014). Therefore, a semi-quantitative analysis of certain metabolic parameters on PET/CT can help identify, preoperatively, patients with histological factors of a poor prognosis, allowing an adjustment of the therapeutic strategy for those patients with a higher risk of an early recurrence. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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16 pages, 1391 KiB  
Article
Liver Transplantation for Hepatocellular Carcinoma: A Real-Life Comparison of Milan Criteria and AFP Model
by Bleuenn Brusset, Jerome Dumortier, Daniel Cherqui, Georges-Philippe Pageaux, Emmanuel Boleslawski, Ludivine Chapron, Jean-Louis Quesada, Sylvie Radenne, Didier Samuel, Francis Navarro, Sebastien Dharancy and Thomas Decaens
Cancers 2021, 13(10), 2480; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13102480 - 19 May 2021
Cited by 5 | Viewed by 1943
Abstract
Purpose: To compare the agreement for the criteria on the explant and the results of liver transplantation (LT) before and after adoption of the AFP (α-fetoprotein) model. Methods: 523 patients consecutively listed in five French centers were reviewed to compare results of the [...] Read more.
Purpose: To compare the agreement for the criteria on the explant and the results of liver transplantation (LT) before and after adoption of the AFP (α-fetoprotein) model. Methods: 523 patients consecutively listed in five French centers were reviewed to compare results of the Milan criteria period (MilanCP, n = 199) (before 2013) and the AFP score period (AFPscP, n = 324) (after 2013). (NCT03156582). Results: During AFPscP, there was a significantly longer waiting time on the list (12.3 vs. 7.7 months, p < 0.001) and higher rate of bridging therapies (84 vs. 75%, p = 0.012) compared to the MilanCP. Dropout rate was slightly higher in the AFPscP (31 vs. 24%, p = 0.073). No difference was found in the histological AFP score between groups (p = 0.838) with a global agreement in 88% of patients. Post-LT recurrence was 9.2% in MilanCP vs. 13.2% in AFPscP (p = 0.239) and predictive factors were AFP > 2 on the last imaging, downstaging policy and salvage transplantation. Post-LT survival was similar (83 vs. 87% after 2 years, p = 0.100), but after propensity score analysis, the post-listing overall survival (OS) was worse in the AFPscP (HR 1.45, p = 0.045). Conclusions: Agreement for the AFP model on explant analysis (≤2) did not significantly change. AFP score > 2 was the major prognostic factor for recurrence. Graft allocation policy has a major impact on prognosis, with a post-listing OS significantly decreased, probably due to the increase in waiting time, increase in bridging therapies, downstaging policy and salvage transplantation. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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13 pages, 992 KiB  
Article
Clearance of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma Undergoing Surgical Resection or Liver Transplantation
by Víctor Amado, Sandra González-Rubio, Javier Zamora, Rafael Alejandre, María Lola Espejo-Cruz, Clara Linares, Marina Sánchez-Frías, Gema García-Jurado, José Luis Montero, Rubén Ciria, Manuel Rodríguez-Perálvarez, Gustavo Ferrín and Manuel De la Mata
Cancers 2021, 13(10), 2476; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13102476 - 19 May 2021
Cited by 16 | Viewed by 3301
Abstract
Background: In patients with hepatocellular carcinoma (HCC), a complete clearance of circulating tumor cells (CTCs) early after liver transplantation (LT) or surgical resection (LR) could prevent tumor recurrence. Methods: prospective pilot study including patients with HCC who underwent LR or LT from September [...] Read more.
Background: In patients with hepatocellular carcinoma (HCC), a complete clearance of circulating tumor cells (CTCs) early after liver transplantation (LT) or surgical resection (LR) could prevent tumor recurrence. Methods: prospective pilot study including patients with HCC who underwent LR or LT from September 2017 to May 2020. Enumeration of CTCs was performed in peripheral blood samples (7 mL) using the Isoflux® system (Fluxion Biosciences) immediately before surgery, at post-operative day 5 and at day 30. A clinically relevant number of CTCs was defined as >30 CTCs/sample. Results: 41 HCC patients were included (mean age 58.7 ± 6.3; 82.9% male). LR was performed in 10 patients (24.4%) and 31 patients (75.6%) underwent LT. The main etiology of liver disease was chronic hepatitis C (31.7%). Patients undergoing LR and LT were similar in terms of preoperative CTC count (p = 0.99), but clearance of CTCs within the first month was more pronounced in the LT group. Clusters of CTCs at baseline were associated with incomplete clearance of CTCs at day 30 (54.2% vs. 11.8%, p = 0.005), which in turn impacted negatively on survival (p = 0.038). Conclusion: Incomplete clearance of CTCs after surgery could be a surrogate marker of HCC aggressiveness. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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10 pages, 2469 KiB  
Article
The Hepatic Innovation Team Collaborative: A Successful Population-Based Approach to Hepatocellular Carcinoma Surveillance
by Shari S. Rogal, Vera Yakovchenko, Rachel Gonzalez, Angela Park, Lauren A. Beste, Karine Rozenberg-Ben-Dror, Jasmohan S. Bajaj, Dawn Scott, Heather McCurdy, Emily Comstock, Michael Sidorovic, Sandra Gibson, Carolyn Lamorte, Anna Nobbe, Maggie Chartier, David Ross, Jason A. Dominitz and Timothy R. Morgan
Cancers 2021, 13(9), 2251; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092251 - 07 May 2021
Cited by 13 | Viewed by 2494
Abstract
After implementing a successful hepatitis C elimination program, the Veterans Health Administration’s (VHA) Hepatic Innovation Team (HIT) Collaborative pivoted to focus on improving cirrhosis care. This national program developed teams of providers across the country and engaged them in using systems redesign methods [...] Read more.
After implementing a successful hepatitis C elimination program, the Veterans Health Administration’s (VHA) Hepatic Innovation Team (HIT) Collaborative pivoted to focus on improving cirrhosis care. This national program developed teams of providers across the country and engaged them in using systems redesign methods and population health approaches to improve care. The HIT Collaborative developed an Advanced Liver Disease (ALD) Dashboard to identify Veterans with cirrhosis who were due for surveillance for hepatocellular carcinoma (HCC) and other liver care, promoted the use of an HCC Clinical Reminder in the electronic health record, and provided training and networking opportunities. This evaluation aimed to describe the VHA’s approach to improving cirrhosis care and identify the facility factors and HIT activities associated with HCC surveillance rates, using a quasi-experimental design. Across all VHA facilities, as the HIT focused on cirrhosis between 2018–2019, HCC surveillance rates increased from 46% (IQR 37–53%) to 51% (IQR 42–60%, p < 0.001). The median HCC surveillance rate was 57% in facilities with high ALD Dashboard utilization compared with 45% in facilities with lower utilization (p < 0.001) and 58% in facilities using the HCC Clinical Reminder compared with 47% in facilities not using this tool (p < 0.001) in FY19. Increased use of the ALD Dashboard and adoption of the HCC Clinical Reminder were independently, significantly associated with HCC surveillance rates in multivariate models, controlling for other facility characteristics. In conclusion, the VHA’s HIT Collaborative is a national healthcare initiative associated with significant improvement in HCC surveillance rates. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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18 pages, 6701 KiB  
Article
Growing Human Hepatocellular Tumors Undergo a Global Metabolic Reprogramming
by Fangrong Zhang, Yingchao Wang, Geng Chen, Zhenli Li, Xiaohua Xing, Csilla Putz-Bankuti, Rudolf E. Stauber, Xiaolong Liu and Tobias Madl
Cancers 2021, 13(8), 1980; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081980 - 20 Apr 2021
Cited by 10 | Viewed by 2680
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy with poor prognosis, high morbidity and mortality concerning with lack of effective diagnosis and high postoperative recurrence. Similar with other cancers, HCC cancer cells have to alter their metabolism to adapt to the changing requirements imposed [...] Read more.
Hepatocellular carcinoma (HCC) is a common malignancy with poor prognosis, high morbidity and mortality concerning with lack of effective diagnosis and high postoperative recurrence. Similar with other cancers, HCC cancer cells have to alter their metabolism to adapt to the changing requirements imposed by the environment of the growing tumor. In less vascularized regions of tumor, cancer cells experience hypoxia and nutrient starvation. Here, we show that HCC undergoes a global metabolic reprogramming during tumor growth. A combined proteomics and metabolomics analysis of paired peritumoral and tumor tissues from 200 HCC patients revealed liver-specific metabolic reprogramming and metabolic alterations with increasing tumor sizes. Several proteins and metabolites associated with glycolysis, the tricarboxylic acid cycle and pyrimidine synthesis were found to be differentially regulated in serum, tumor and peritumoral tissue with increased tumor sizes. Several prognostic metabolite biomarkers involved in HCC metabolic reprogramming were identified and integrated with clinical and pathological data. We built and validated this combined model to discriminate against patients with different recurrence risks. An integrated and comprehensive metabolomic analysis of HCC is provided by our present work. Metabolomic alterations associated with the advanced stage of the disease and poor clinical outcomes, were revealed. Targeting cancer metabolism may deliver effective therapies for HCC. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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22 pages, 6184 KiB  
Article
ARMCX3 Mediates Susceptibility to Hepatic Tumorigenesis Promoted by Dietary Lipotoxicity
by Serena Mirra, Aleix Gavaldà-Navarro, Yasmina Manso, Mónica Higuera, Román Serrat, María Teresa Salcedo, Ferran Burgaya, José Maria Balibrea, Eva Santamaría, Iker Uriarte, Carmen Berasain, Matias A. Avila, Beatriz Mínguez, Eduardo Soriano and Francesc Villarroya
Cancers 2021, 13(5), 1110; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13051110 - 05 Mar 2021
Cited by 5 | Viewed by 2777
Abstract
ARMCX3 is encoded by a member of the Armcx gene family and is known to be involved in nervous system development and function. We found that ARMCX3 is markedly upregulated in mouse liver in response to high lipid availability, and that hepatic ARMCX3 [...] Read more.
ARMCX3 is encoded by a member of the Armcx gene family and is known to be involved in nervous system development and function. We found that ARMCX3 is markedly upregulated in mouse liver in response to high lipid availability, and that hepatic ARMCX3 is upregulated in patients with NAFLD and hepatocellular carcinoma (HCC). Mice were subjected to ARMCX3 invalidation (inducible ARMCX3 knockout) and then exposed to a high-fat diet and diethylnitrosamine-induced hepatocarcinogenesis. The effects of experimental ARMCX3 knockdown or overexpression in HCC cell lines were also analyzed. ARMCX3 invalidation protected mice against high-fat-diet-induced NAFLD and chemically induced hepatocarcinogenesis. ARMCX3 invalidation promoted apoptotic cell death and macrophage infiltration in livers of diethylnitrosamine-treated mice maintained on a high-fat diet. ARMCX3 downregulation reduced the viability, clonality and migration of HCC cell lines, whereas ARMCX3 overexpression caused the reciprocal effects. SOX9 was found to mediate the effects of ARMCX3 in hepatic cells, with the SOX9 interaction required for the effects of ARMCX3 on hepatic cell proliferation. In conclusion, ARMCX3 is identified as a novel molecular actor in liver physiopathology and carcinogenesis. ARMCX3 downregulation appears to protect against hepatocarcinogenesis, especially under conditions of high dietary lipid-mediated hepatic insult. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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13 pages, 1764 KiB  
Article
Robotic Liver Resection Versus Percutaneous Ablation for Early HCC: Short- and Long-Term Results
by Paolo Magistri, Barbara Catellani, Samuele Frassoni, Cristiano Guidetti, Tiziana Olivieri, Giacomo Assirati, Cristian Caporali, Annarita Pecchi, Valentina Serra, Roberto Ballarin, Gian Piero Guerrini, Vincenzo Bagnardi, Stefano Di Sandro and Fabrizio Di Benedetto
Cancers 2020, 12(12), 3578; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123578 - 30 Nov 2020
Cited by 4 | Viewed by 1720
Abstract
Background: The correct approach for early hepatocellular carcinoma (HCC) is debatable, since multiple options are currently available. Percutaneous ablation (PA) is associated in some series to reduced morbidity compared to liver resection (LR); therefore, minimally invasive surgery may play a significant role in [...] Read more.
Background: The correct approach for early hepatocellular carcinoma (HCC) is debatable, since multiple options are currently available. Percutaneous ablation (PA) is associated in some series to reduced morbidity compared to liver resection (LR); therefore, minimally invasive surgery may play a significant role in this setting. Methods: All consecutive patients treated by robotic liver resection (RLR) or PA between January 2014 and October 2019 for a newly diagnosed single HCC, less than 3 cm in size (very early/early stages according to the Barcelona Clinic Liver Cancer (BCLC)) on chronic liver disease or liver cirrhosis, were enrolled in this retrospective study. The aim of this study was to compare short- and long-term outcomes to define the best approach in this specific cohort. Results: 60 patients fulfilled the inclusion criteria: 24 RLR and 36 PA. The two populations were homogeneous in terms of baseline characteristics. There were no statistically significant differences regarding the incidence of postoperative morbidity (RLR 38% vs. PA 19%, p = 0.15). The cumulative incidence of recurrence (CIR) was significantly higher in patients who underwent PA, with the one, two, and three years of CIR being 42%, 69%, and 73% in the PA group and 17%, 27%, and 27% in the RLR group, respectively. Conclusions: RLR provides a significantly higher potential of cure and tumor-related free survival in cases of newly diagnosed single HCCs smaller than 3 cm. Therefore, it can be considered as a first-line approach for the treatment of patients with those characteristics in high-volume centers with extensive experience in the field of hepatobiliary surgery and minimally invasive approaches. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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Review

Jump to: Editorial, Research, Other

21 pages, 2112 KiB  
Review
Immunotherapy and Microbiota for Targeting of Liver Tumor-Initiating Stem-like Cells
by Keigo Machida and Stanley M. Tahara
Cancers 2022, 14(10), 2381; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14102381 - 12 May 2022
Cited by 4 | Viewed by 2175
Abstract
Cancer contains tumor-initiating stem-like cells (TICs) that are resistant to therapies. Hepatocellular carcinoma (HCC) incidence has increased twice over the past few decades, while the incidence of other cancer types has trended downward globally. Therefore, an understanding of HCC development and therapy resistance [...] Read more.
Cancer contains tumor-initiating stem-like cells (TICs) that are resistant to therapies. Hepatocellular carcinoma (HCC) incidence has increased twice over the past few decades, while the incidence of other cancer types has trended downward globally. Therefore, an understanding of HCC development and therapy resistance mechanisms is needed for this incurable malignancy. This review article describes links between immunotherapies and microbiota in tumor-initiating stem-like cells (TICs), which have stem cell characteristics with self-renewal ability and express pluripotency transcription factors such as NANOG, SOX2, and OCT4. This review discusses (1) how immunotherapies fail and (2) how gut dysbiosis inhibits immunotherapy efficacy. Gut dysbiosis promotes resistance to immunotherapies by breaking gut immune tolerance and activating suppressor immune cells. Unfortunately, this leads to incurable recurrence/metastasis development. Personalized medicine approaches targeting these mechanisms of TIC/metastasis-initiating cells are emerging targets for HCC immunotherapy and microbiota modulation therapy. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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22 pages, 642 KiB  
Review
Upper Limits of Downstaging for Hepatocellular Carcinoma in Liver Transplantation
by Marco Biolato, Tiziano Galasso, Giuseppe Marrone, Luca Miele and Antonio Grieco
Cancers 2021, 13(24), 6337; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13246337 - 17 Dec 2021
Cited by 3 | Viewed by 2587
Abstract
In Europe and the United States, approximately 1100 and 1800 liver transplantations, respectively, are performed every year for hepatocellular carcinoma (HCC), compared with an annual incidence of 65,000 and 39,000 new cases, respectively. Because of organ shortages, proper patient selection is crucial, especially [...] Read more.
In Europe and the United States, approximately 1100 and 1800 liver transplantations, respectively, are performed every year for hepatocellular carcinoma (HCC), compared with an annual incidence of 65,000 and 39,000 new cases, respectively. Because of organ shortages, proper patient selection is crucial, especially for those exceeding the Milan criteria. Downstaging is the reduction of the HCC burden to meet the eligibility criteria for liver transplantation. Many techniques can be used in downstaging, including ablation, chemoembolisation, radioembolisation and systemic treatments, with a reported success rate of 60–70%. In recent years, an increasing number of patient responders to downstaging procedures has been included in the waitlist, generally with a comparable five-year post-transplant survival but with a higher probability of dropout than HCC patients within the Milan criteria. While the Milan criteria are generally accepted as the endpoint of downstaging, the upper limits of tumour burden for downstaging HCC for liver transplantation are controversial. Very challenging situations involve HCC patients with large nodules, macrovascular invasion or even extrahepatic metastasis at baseline who respond to increasingly more effective downstaging procedures and who aspire to be placed on the waitlist for transplantation. This narrative review analyses the most important evidence available on cohorts subjected to “extended” downstaging, including HCC patients over the up-to-seven criteria and over the University of California San Francisco downstaging criteria. We also address surrogate markers of biological aggressiveness, such as alpha-fetoprotein and the response stability to locoregional treatments, which are very useful in selecting responders to downstaging procedures for waitlisting inclusion. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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14 pages, 940 KiB  
Review
Review: Challenges of In Vitro CAF Modelling in Liver Cancers
by Alba Herrero, Elisabeth Knetemann and Inge Mannaerts
Cancers 2021, 13(23), 5914; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13235914 - 24 Nov 2021
Cited by 3 | Viewed by 2640
Abstract
Primary and secondary liver cancer are the third cause of death in the world, and as the incidence is increasing, liver cancer represents a global health burden. Current treatment strategies are insufficient to permanently cure patients from this devastating disease, and therefore other [...] Read more.
Primary and secondary liver cancer are the third cause of death in the world, and as the incidence is increasing, liver cancer represents a global health burden. Current treatment strategies are insufficient to permanently cure patients from this devastating disease, and therefore other approaches are under investigation. The importance of cancer-associated fibroblasts (CAFs) in the tumour microenvironment is evident, and many pre-clinical studies have shown increased tumour aggressiveness in the presence of CAFs. However, it remains unclear how hepatic stellate cells are triggered by the tumour to become CAFs and how the recently described CAF subtypes originate and orchestrate pro-tumoural effects. Specialized in vitro systems will be needed to address these questions. In this review, we present the currently used in vitro models to study CAFs in primary and secondary liver cancer and highlight the trend from using oversimplified 2D culture systems to more complex 3D models. Relatively few studies report on the impact of cancer (sub)types on CAFs and the tumour microenvironment, and most studies investigated the impact of secreted factors due to the nature of the models. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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37 pages, 3163 KiB  
Review
The Hepatic Sinusoid in Chronic Liver Disease: The Optimal Milieu for Cancer
by Albert Gibert-Ramos, David Sanfeliu-Redondo, Peio Aristu-Zabalza, Ana Martínez-Alcocer, Jordi Gracia-Sancho, Sergi Guixé-Muntet and Anabel Fernández-Iglesias
Cancers 2021, 13(22), 5719; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225719 - 15 Nov 2021
Cited by 14 | Viewed by 10424
Abstract
The liver sinusoids are a unique type of microvascular beds. The specialized phenotype of sinusoidal cells is essential for their communication, and for the function of all hepatic cell types, including hepatocytes. Liver sinusoidal endothelial cells (LSECs) conform the inner layer of the [...] Read more.
The liver sinusoids are a unique type of microvascular beds. The specialized phenotype of sinusoidal cells is essential for their communication, and for the function of all hepatic cell types, including hepatocytes. Liver sinusoidal endothelial cells (LSECs) conform the inner layer of the sinusoids, which is permeable due to the fenestrae across the cytoplasm; hepatic stellate cells (HSCs) surround LSECs, regulate the vascular tone, and synthetize the extracellular matrix, and Kupffer cells (KCs) are the liver-resident macrophages. Upon injury, the harmonic equilibrium in sinusoidal communication is disrupted, leading to phenotypic alterations that may affect the function of the whole liver if the damage persists. Understanding how the specialized sinusoidal cells work in coordination with each other in healthy livers and chronic liver disease is of the utmost importance for the discovery of new therapeutic targets and the design of novel pharmacological strategies. In this manuscript, we summarize the current knowledge on the role of sinusoidal cells and their communication both in health and chronic liver diseases, and their potential pharmacologic modulation. Finally, we discuss how alterations occurring during chronic injury may contribute to the development of hepatocellular carcinoma, which is usually developed in the background of chronic liver disease. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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19 pages, 2550 KiB  
Review
Hepatocyte Polyploidy: Driver or Gatekeeper of Chronic Liver Diseases
by Romain Donne, Flora Sangouard, Séverine Celton-Morizur and Chantal Desdouets
Cancers 2021, 13(20), 5151; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205151 - 14 Oct 2021
Cited by 11 | Viewed by 2887
Abstract
Polyploidy, also known as whole-genome amplification, is a condition in which the organism has more than two basic sets of chromosomes. Polyploidy frequently arises during tissue development and repair, and in age-associated diseases, such as cancer. Its consequences are diverse and clearly different [...] Read more.
Polyploidy, also known as whole-genome amplification, is a condition in which the organism has more than two basic sets of chromosomes. Polyploidy frequently arises during tissue development and repair, and in age-associated diseases, such as cancer. Its consequences are diverse and clearly different between systems. The liver is a particularly fascinating organ in that it can adapt its ploidy to the physiological and pathological context. Polyploid hepatocytes are characterized in terms of the number of nuclei per cell (cellular ploidy; mononucleate/binucleate hepatocytes) and the number of chromosome sets in each nucleus (nuclear ploidy; diploid, tetraploid, octoploid). The advantages and disadvantages of polyploidy in mammals are not fully understood. About 30% of the hepatocytes in the human liver are polyploid. In this review, we explore the mechanisms underlying the development of polyploid cells, our current understanding of the regulation of polyploidization during development and pathophysiology and its consequences for liver function. We will also provide data shedding light on the ways in which polyploid hepatocytes cope with centrosome amplification. Finally, we discuss recent discoveries highlighting the possible roles of liver polyploidy in protecting against tumor formation, or, conversely, contributing to liver tumorigenesis. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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14 pages, 882 KiB  
Review
Circadian Clock and Liver Cancer
by María Crespo, Magdalena Leiva and Guadalupe Sabio
Cancers 2021, 13(14), 3631; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143631 - 20 Jul 2021
Cited by 20 | Viewed by 4418
Abstract
Circadian clocks control several homeostatic processes in mammals through internal molecular mechanisms. Chronic perturbation of circadian rhythms is associated with metabolic diseases and increased cancer risk, including liver cancer. The hepatic physiology follows a daily rhythm, driven by clock genes that control the [...] Read more.
Circadian clocks control several homeostatic processes in mammals through internal molecular mechanisms. Chronic perturbation of circadian rhythms is associated with metabolic diseases and increased cancer risk, including liver cancer. The hepatic physiology follows a daily rhythm, driven by clock genes that control the expression of several proteins involved in distinct metabolic pathways. Alteration of the liver clock results in metabolic disorders, such as non-alcoholic fatty liver diseases (NAFLD) and impaired glucose metabolism, that can trigger the activation of oncogenic pathways, inducing spontaneous hepatocarcinoma (HCC). In this review, we provide an overview of the role of the liver clock in the metabolic and oncogenic changes that lead to HCC and discuss new potentially useful targets for prevention and management of HCC. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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24 pages, 2017 KiB  
Review
The TGF-β Pathway: A Pharmacological Target in Hepatocellular Carcinoma?
by Ester Gonzalez-Sanchez, Javier Vaquero, Maite G. Férnandez-Barrena, Juan José Lasarte, Matías A. Avila, Pablo Sarobe, María Reig, Mariona Calvo and Isabel Fabregat
Cancers 2021, 13(13), 3248; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13133248 - 29 Jun 2021
Cited by 39 | Viewed by 4797
Abstract
Transforming Growth Factor-beta (TGF-β) superfamily members are essential for tissue homeostasis and consequently, dysregulation of their signaling pathways contributes to the development of human diseases. In the liver, TGF-β signaling participates in all the stages of disease progression from initial liver injury to [...] Read more.
Transforming Growth Factor-beta (TGF-β) superfamily members are essential for tissue homeostasis and consequently, dysregulation of their signaling pathways contributes to the development of human diseases. In the liver, TGF-β signaling participates in all the stages of disease progression from initial liver injury to hepatocellular carcinoma (HCC). During liver carcinogenesis, TGF-β plays a dual role on the malignant cell, behaving as a suppressor factor at early stages, but contributing to later tumor progression once cells escape from its cytostatic effects. Moreover, TGF-β can modulate the response of the cells forming the tumor microenvironment that may also contribute to HCC progression, and drive immune evasion of cancer cells. Thus, targeting the TGF-β pathway may constitute an effective therapeutic option for HCC treatment. However, it is crucial to identify biomarkers that allow to predict the response of the tumors and appropriately select the patients that could benefit from TGF-β inhibitory therapies. Here we review the functions of TGF-β on HCC malignant and tumor microenvironment cells, and the current strategies targeting TGF-β signaling for cancer therapy. We also summarize the clinical impact of TGF-β inhibitors in HCC patients and provide a perspective on its future use alone or in combinatorial strategies for HCC treatment. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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22 pages, 1507 KiB  
Review
The Role of Extracellular Vesicles in Disease Progression and Detection of Hepatocellular Carcinoma
by Yi-Te Lee, Benjamin V. Tran, Jasmine J. Wang, Icy Y. Liang, Sungyong You, Yazhen Zhu, Vatche G. Agopian, Hsian-Rong Tseng and Ju Dong Yang
Cancers 2021, 13(12), 3076; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13123076 - 20 Jun 2021
Cited by 28 | Viewed by 4298
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and one of the leading causes of cancer-related death worldwide. Despite the improvements in surveillance and treatment, the prognosis of HCC remains poor. Extracellular vesicles (EVs) are a heterogeneous group of phospholipid bilayer-enclosed [...] Read more.
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and one of the leading causes of cancer-related death worldwide. Despite the improvements in surveillance and treatment, the prognosis of HCC remains poor. Extracellular vesicles (EVs) are a heterogeneous group of phospholipid bilayer-enclosed particles circulating in the bloodstream and mediating intercellular communication. Emerging studies have shown that EVs play a crucial role in regulating the proliferation, immune escape, and metastasis of HCC. In addition, because EVs are present in the circulation at relatively early stages of disease, they are getting attention as an attractive biomarker for HCC detection. Over the past decade, dedicated efforts have been made to isolate EVs more efficiently and make them useful tools in different clinical settings. In this review article, we provide an overview of the EVs isolation methods and highlight the role of EVs as mediators in the pathogenesis and progression of HCC. Lastly, we summarize the potential applications of EVs in early-stage HCC detection. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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16 pages, 428 KiB  
Review
Evolving Treatment of Advanced Hepatocellular Carcinoma in the Asia–Pacific Region: A Review and Multidisciplinary Expert Opinion
by Sadahisa Ogasawara, Su-Pin Choo, Jiang-Tao Li, Changhoon Yoo, Bruce Wang, Dee Lee and Pierce K. H. Chow
Cancers 2021, 13(11), 2626; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112626 - 27 May 2021
Cited by 8 | Viewed by 3655
Abstract
Hepatocellular carcinoma (HCC) is the fourth most common driver of cancer-related death globally, with an estimated 72% of cases in Asia. For more than a decade, first-line systemic treatments for advanced or unresectable HCC were limited to the multi-targeted kinase inhibitors sorafenib and, [...] Read more.
Hepatocellular carcinoma (HCC) is the fourth most common driver of cancer-related death globally, with an estimated 72% of cases in Asia. For more than a decade, first-line systemic treatments for advanced or unresectable HCC were limited to the multi-targeted kinase inhibitors sorafenib and, more recently, lenvatinib. Now, treatment options have expanded to include immunotherapy, as exemplified by the immune checkpoint inhibitor (ICI) atezolizumab combined with the antiangiogenic agent bevacizumab. Additional combinations of ICIs with kinase inhibitors, other ICIs, or antiangiogenic agents are under investigation, further supporting the new era of immunotherapy for first-line treatment of advanced or unresectable HCC. We describe this evolving landscape and provide expert opinion on therapeutic best practices in the Asia–Pacific region, where different costs of, and patient access to, treatment are a challenge. With the combination of atezolizumab plus bevacizumab likely to become the clinical standard of care, optimising treatment sequence and ensuring patient access to newer therapies remain priorities. Cost containment and treatment sequencing may be facilitated by characterisation of predictive positive and negative biomarkers. With these considerations in mind, this review and expert opinion focused on advanced HCC in the Asia–Pacific region offers perspectives of multiple stakeholders, including physicians, payer systems, and patients. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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15 pages, 855 KiB  
Review
The Endless Sources of Hepatocellular Carcinoma Heterogeneity
by Marina Barcena-Varela and Amaia Lujambio
Cancers 2021, 13(11), 2621; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112621 - 26 May 2021
Cited by 16 | Viewed by 3369
Abstract
Hepatocellular carcinoma (HCC) represents a global health problem. The incidence keeps increasing and current therapeutic options confer limited benefits to the patients. Tumor heterogeneity plays a central role in this context, limiting the availability of predictive biomarkers and complicating the criteria used to [...] Read more.
Hepatocellular carcinoma (HCC) represents a global health problem. The incidence keeps increasing and current therapeutic options confer limited benefits to the patients. Tumor heterogeneity plays a central role in this context, limiting the availability of predictive biomarkers and complicating the criteria used to choose the most suitable therapeutic option. HCC heterogeneity occurs at different levels: within the population (inter-patient heterogeneity) and within tumors from the same patient (intra-patient and intra-tumor heterogeneity). Experts in the field have made many efforts to classify the patients based on clinicopathological characteristics and molecular signatures; however, there is still much work ahead to be able to integrate the extra-tumor heterogeneity that emerges from the complexity of the tumor microenvironment, which plays a critical role in the pathogenesis of the disease and therapy responses. In this review, we summarize tumor intrinsic and extrinsic sources of heterogeneity of the most common etiologies of HCC and summarize the most recent discoveries regarding the evolutionary trajectory of liver cancer cells and the influence of tumor-extrinsic factors such as the microbiome and the host immune system. We further highlight the potential of novel high-throughput methodologies to contribute to a better understanding of this devastating disease and to the improvement of the clinical management of patients. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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13 pages, 1741 KiB  
Review
Mitochondrial Dynamics and Liver Cancer
by María Isabel Hernández-Alvarez and Antonio Zorzano
Cancers 2021, 13(11), 2571; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112571 - 24 May 2021
Cited by 22 | Viewed by 4041
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer. Due to its rising incidence and limited therapeutic options, HCC has become a leading cause of cancer-related death worldwide, accounting for 85% of all deaths due to primary liver cancers. Standard therapy for [...] Read more.
Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer. Due to its rising incidence and limited therapeutic options, HCC has become a leading cause of cancer-related death worldwide, accounting for 85% of all deaths due to primary liver cancers. Standard therapy for advanced-stage HCC is based on anti-angiogenic drugs such as sorafenib and, more recently, lenvatinib and regorafenib as a second line of treatment. The identification of novel therapeutic strategies is urgently required. Mitochondrial dynamics describes a group of processes that includes the movement of mitochondria along the cytoskeleton, the regulation of mitochondrial morphology and distribution, and connectivity mediated by tethering and fusion/fission events. In recent years, mitochondrial dynamic processes have emerged as key processes in the maintenance of liver mitochondrial homeostasis. In addition, some data are accumulating on the role played by mitochondrial dynamics during cancer development, and specifically on how such dynamics act directly on tumor cells or indirectly on cells responsible for tumor aggression and defense. Here, we review the data that suggest mitochondrial dynamics to be involved in the development of liver tumors. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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19 pages, 924 KiB  
Review
Unique Features of Hepatitis B Virus-Related Hepatocellular Carcinoma in Pathogenesis and Clinical Significance
by Sheng-Han Wang, Shiou-Hwei Yeh and Pei-Jer Chen
Cancers 2021, 13(10), 2454; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13102454 - 18 May 2021
Cited by 16 | Viewed by 5306
Abstract
Hepatitis B virus (HBV) infection is one of the important risk factors for hepatocellular carcinoma (HCC) worldwide, accounting for around 50% of cases. Chronic hepatitis B infection generates an inflammatory microenvironment, in which hepatocytes undergoing repeated cycles of damage and regeneration accumulate genetic [...] Read more.
Hepatitis B virus (HBV) infection is one of the important risk factors for hepatocellular carcinoma (HCC) worldwide, accounting for around 50% of cases. Chronic hepatitis B infection generates an inflammatory microenvironment, in which hepatocytes undergoing repeated cycles of damage and regeneration accumulate genetic mutations predisposing them to cancer. A striking male dominance in HBV-related HCC highlights the influence of sex hormones which interact with viral factors to influence carcinogenesis. HBV is also considered an oncogenic virus since its X and surface mutant proteins showed tumorigenic activity in mouse models. The other unique mechanism is the insertional mutagenesis by integration of HBV genome into hepatocyte chromosomes to activate oncogenes. HCC survival largely depends on tumor stages at diagnosis and effective treatment. However, early diagnosis by the conventional protein biomarkers achieves limited success. A new biomarker, the circulating virus–host chimera DNA from HBV integration sites in HCC, provides a liquid biopsy approach for monitoring the tumor load in the majority of HBV–HCC patients. To maximize the efficacy of new immunotherapies or molecular target therapies, it requires better classification of HCC based on the tumor microenvironment and specific carcinogenic pathways. An in-depth study may benefit both the diagnosis and treatment of HBV-related HCC. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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24 pages, 294 KiB  
Review
The Role of the Microbiome in Liver Cancer
by Mar Moreno-Gonzalez and Naiara Beraza
Cancers 2021, 13(10), 2330; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13102330 - 12 May 2021
Cited by 15 | Viewed by 3329
Abstract
Hepatocellular carcinoma (HCC) is the most common malignancy occuring in the context of chronic liver disease and is one of the main causes of cancer-derived death worldwide. The lack of effective treatments, together with the poor prognosis, underlines the urge to develop novel [...] Read more.
Hepatocellular carcinoma (HCC) is the most common malignancy occuring in the context of chronic liver disease and is one of the main causes of cancer-derived death worldwide. The lack of effective treatments, together with the poor prognosis, underlines the urge to develop novel and multidisciplinary therapeutics. An increasing body of evidence shows that HCC associates with changes in intestinal microbiota abundance and composition as well as with impaired barrier function, leading to the release of bacteria and their metabolites to the liver. These factors trigger a cascade of inflammatory responses contributing to liver cirrhosis and constituting an ideal environment for the progression of HCC. Interestingly, the use of bacteriotherapy in human and preclinical studies of chronic liver disease and HCC has been shown to successfully modify the microbiota composition, reducing overall inflammation and fibrosis. In this review, we explore the existing knowledge on the characterisation of the intestinal microbial composition in humans and experimental murine chronic liver disease and HCC, as well as the use of antibiotics and bacteriotherapy as therapeutic options. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
17 pages, 634 KiB  
Review
Adoptive Cell Therapy in Hepatocellular Carcinoma: Biological Rationale and First Results in Early Phase Clinical Trials
by Philippe Rochigneux, Brice Chanez, Bernadette De Rauglaudre, Emmanuel Mitry, Christian Chabannon and Marine Gilabert
Cancers 2021, 13(2), 271; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13020271 - 13 Jan 2021
Cited by 37 | Viewed by 4606
Abstract
The mortality of hepatocellular carcinoma (HCC) is quickly increasing worldwide. In unresectable HCC, the cornerstone of systemic treatments is switching from tyrosine kinase inhibitors to immune checkpoints inhibitors (ICI). Next to ICI, adoptive cell transfer represents another promising field of immunotherapy. Targeting tumor [...] Read more.
The mortality of hepatocellular carcinoma (HCC) is quickly increasing worldwide. In unresectable HCC, the cornerstone of systemic treatments is switching from tyrosine kinase inhibitors to immune checkpoints inhibitors (ICI). Next to ICI, adoptive cell transfer represents another promising field of immunotherapy. Targeting tumor associated antigens such as alpha-fetoprotein (AFP), glypican-3 (GPC3), or New York esophageal squamous cell carcinoma-1 (NY-ESO-1), T cell receptor (TCR) engineered T cells and chimeric antigen receptors (CAR) engineered T cells are emerging as potentially effective therapies, with objective responses reported in early phase trials. In this review, we address the biological rationale of TCR/CAR engineered T cells in advanced HCC, their mechanisms of action, and results from recent clinical trials. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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27 pages, 2020 KiB  
Review
Animal Models: A Useful Tool to Unveil Metabolic Changes in Hepatocellular Carcinoma
by Marina Serra, Amedeo Columbano, Andrea Perra and Marta Anna Kowalik
Cancers 2020, 12(11), 3318; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113318 - 10 Nov 2020
Cited by 4 | Viewed by 2795
Abstract
Hepatocellular carcinoma (HCC) is one the most frequent and lethal human cancers. At present, no effective treatment for advanced HCC exist; therefore, the overall prognosis for HCC patients remains dismal. In recent years, a better knowledge of the signaling pathways involved in the [...] Read more.
Hepatocellular carcinoma (HCC) is one the most frequent and lethal human cancers. At present, no effective treatment for advanced HCC exist; therefore, the overall prognosis for HCC patients remains dismal. In recent years, a better knowledge of the signaling pathways involved in the regulation of HCC development and progression, has led to the identification of novel potential targets for therapeutic strategies. However, the obtained benefits from current therapeutic options are disappointing. Altered cancer metabolism has become a topic of renewed interest in the last decades, and it has been included among the core hallmarks of cancer. In the light of growing evidence for metabolic reprogramming in cancer, a wide number of experimental animal models have been exploited to study metabolic changes characterizing HCC development and progression and to further expand our knowledge of this tumor. In the present review, we discuss several rodent models of hepatocarcinogenesis, that contributed to elucidate the metabolic profile of HCC and the implications of these changes in modulating the aggressiveness of neoplastic cells. We also highlight the apparently contrasting results stemming from different animal models. Finally, we analyze whether these observations could be exploited to improve current therapeutic strategies for HCC. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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8 pages, 1371 KiB  
Perspective
Development and Implementation of Multidisciplinary Liver Tumor Boards in the Veterans Affairs Health Care System: A 10-Year Experience
by Atoosa Rabiee, Tamar Taddei, Ayse Aytaman, Shari S. Rogal, David E. Kaplan and Timothy R. Morgan
Cancers 2021, 13(19), 4849; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13194849 - 28 Sep 2021
Cited by 5 | Viewed by 1682
Abstract
In this perspective piece, we summarize the development and implementation of multidisciplinary liver tumor boards across the Veterans Affairs health care system dating back to 2010. Referral to multidisciplinary tumor boards (MDLTB) has been demonstrated to decrease the number of unnecessary invasive procedures, [...] Read more.
In this perspective piece, we summarize the development and implementation of multidisciplinary liver tumor boards across the Veterans Affairs health care system dating back to 2010. Referral to multidisciplinary tumor boards (MDLTB) has been demonstrated to decrease the number of unnecessary invasive procedures, reduce health care costs and maximize patient outcomes. Although the VA is the largest single care provider in the US, there is significant heterogeneity in healthcare delivery. We have shown that receiving care at VA centers with MDLTB is associated with higher odds of receiving active therapy and a 13% reduction in mortality. Access to expert hepatology care appears to be one of the critical benefits of MDLTB resulting in 30% reduction in mortality. Integrated health care systems such as the VA have the unique capability of implementing virtual tumor boards that can easily overcome geographic barriers and standardize care across multiple facilities regardless of their access to hepatology or other disciplines. Significant barriers remain requiring implementation plans. This document serves as a roadmap to establish multidisciplinary tumor boards, including standardization of imaging reports, identifying stake holders who need to be present at tumor board, institution buy-in, and specifics for local, regional and integrated service network tumor boards. Full article
(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)
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