Editorial

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Open AccessEditorial

Human Hepatocellular Carcinoma (HCC)

by Luigi Buonaguro

Cancers 2020, 12(12), 3739; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123739 - 12 Dec 2020

Cited by 5 | Viewed by 1722

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer and accounts for 8 [...] Full article

(This article belongs to the Special Issue Human Hepatocellular Carcinoma (HCC))

Research

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13 pages, 1952 KiB

Open AccessArticle

Incidence of Hepatocellular Carcinoma after Treatment with Sofosbuvir-Based or Sofosbuvir-Free Regimens in Patients with Chronic Hepatitis C

by Eiichi Ogawa, Hideyuki Nomura, Makoto Nakamuta, Norihiro Furusyo, Eiji Kajiwara, Kazufumi Dohmen, Akira Kawano, Aritsune Ooho, Koichi Azuma, Kazuhiro Takahashi, Takeaki Satoh, Toshimasa Koyanagi, Yasunori Ichiki, Masami Kuniyoshi, Kimihiko Yanagita, Hiromasa Amagase, Chie Morita, Rie Sugimoto, Masaki Kato, Shinji Shimoda and Jun Hayashi Show full author list Hide full author list

Cancers 2020, 12(9), 2602; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092602 - 11 Sep 2020

Cited by 9 | Viewed by 2378

Abstract

Advanced fibrosis/cirrhosis and related biomarkers have been recognized as useful predictors of the development of hepatocellular carcinoma (HCC) by patients with chronic hepatitis C (CHC) following hepatitis C virus (HCV) cure by direct-acting antivirals (DAAs). However, it remains unclear if DAAs themselves have [...] Read more.

Advanced fibrosis/cirrhosis and related biomarkers have been recognized as useful predictors of the development of hepatocellular carcinoma (HCC) by patients with chronic hepatitis C (CHC) following hepatitis C virus (HCV) cure by direct-acting antivirals (DAAs). However, it remains unclear if DAAs themselves have an influence on or facilitate the development of HCC. This multicenter cohort study included CHC patients without a history of HCC who achieved HCV elimination by DAAs. Cohorts of 835 patients treated with a sofosbuvir (SOF)-based regimen and 835 treated with a SOF-free regimen were matched 1:1 by propensity scoring with nine variables to evaluate differences in HCC incidence. The median observation period was 3.5 years. Sixty-nine cases of HCC were found during 5483.9 person-years (PY) over the entire follow-up period. The annual incidence was similar for both groups (SOF-based 1.25 and SOF-free 1.27 per 100 PY, respectively: adjusted hazard ratio (HR) 1.26, 95% confidence interval (CI) 0.75–2.12, p = 0.39). However, the annual incidence within the first two years was higher for patients treated with SOF than for those without, but did not reach significance (1.50 and 0.97 per 100 PY incidence rates, respectively: adjusted HR 2.05, 95% CI 0.98–4.25, p = 0.06). In summary, DAA treatment with SOF was not associated with an increase in the development of de novo HCC. Full article

(This article belongs to the Special Issue Human Hepatocellular Carcinoma (HCC))

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17 pages, 8220 KiB

Open AccessArticle

Radiosensitisation of Hepatocellular Carcinoma Cells by Vandetanib

by Sami Znati, Rebecca Carter, Marcos Vasquez, Adam Westhorpe, Hassan Shahbakhti, Jessica Prince, Petra Vlckova, Chiara De Vellis, Zainab Bascal, Marilena Loizidou and Ricky A. Sharma

Cancers 2020, 12(7), 1878; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071878 - 13 Jul 2020

Cited by 15 | Viewed by 3236

Abstract

Hepatocellular Carcinoma (HCC) is increasing in incidence worldwide and requires new approaches to therapy. The combination of anti-angiogenic drug therapy and radiotherapy is one promising new approach. The anti-angiogenic drug vandetanib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) [...] Read more.

Hepatocellular Carcinoma (HCC) is increasing in incidence worldwide and requires new approaches to therapy. The combination of anti-angiogenic drug therapy and radiotherapy is one promising new approach. The anti-angiogenic drug vandetanib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and RET proto-oncogene with radio-enhancement potential. To explore the benefit of combined vandetanib and radiotherapy treatment for HCC, we studied outcomes following combined treatment in pre-clinical models. Methods: Vandetanib and radiation treatment were combined in HCC cell lines grown in vitro and in vivo. In addition to 2D migration and clonogenic assays, the combination was studied in 3D spheroids and a syngeneic mouse model of HCC. Results: Vandetanib IC

_{50}

s were measured in 20 cell lines and the drug was found to significantly enhance radiation cell kill and to inhibit both cell migration and invasion in vitro. In vivo, combination therapy significantly reduced cancer growth and improved overall survival, an effect that persisted for the duration of vandetanib treatment. Conclusion: In 2D and 3D studies in vitro and in a syngeneic model in vivo, the combination of vandetanib plus radiotherapy was more efficacious than either treatment alone. This new combination therapy for HCC merits evaluation in clinical trials. Full article

(This article belongs to the Special Issue Human Hepatocellular Carcinoma (HCC))

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15 pages, 2376 KiB

Open AccessArticle

Immune Cytolytic Activity for Comprehensive Understanding of Immune Landscape in Hepatocellular Carcinoma

by Hideo Takahashi, Tsutomu Kawaguchi, Li Yan, Xuan Peng, Qianya Qi, Luc G.T. Morris, Timothy A. Chan, Allan Tsung, Eigo Otsuji and Kazuaki Takabe

Cancers 2020, 12(5), 1221; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12051221 - 13 May 2020

Cited by 49 | Viewed by 4289

Abstract

Cytolytic activity score (CYT), defined by granzyme A and perforin expression, is a useful marker for underlying immunity. We hypothesized that CYT-high hepatocellular carcinomas (HCCs) have stronger immunogenicity and favorable tumor microenvironments, which would result in better clinical outcomes, using the cancer genome [...] Read more.

Cytolytic activity score (CYT), defined by granzyme A and perforin expression, is a useful marker for underlying immunity. We hypothesized that CYT-high hepatocellular carcinomas (HCCs) have stronger immunogenicity and favorable tumor microenvironments, which would result in better clinical outcomes, using the cancer genome atlas (TCGA) cohort with 371 patients with HCC. We found CYT-high HCCs were associated with higher expressions of the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3), well-known mutagenic enzymes. Further, higher numbers of anti-cancer immune cells, such as CD8+ T cells and M1 macrophages, were infiltrated in CYT-high HCCs. Major T cell exhaustion markers were expressed significantly higher in CYT-high HCCs, likely as a negative feedback loop. Additionally, CYT-high HCCs strongly enriched gene sets related with enhanced immune activity. With strong immunity, patients with CYT-high HCCs had significantly longer disease-specific survival (DSS) and overall survival (OS) (p = 0.03 and <0.01). Furthermore, when the OS is stratified by exhaustion marker expressions, the CYT-high/exhaustion-low group had the best and CYT-low/exhaustion-high groups had the worst OS. Lastly, high CYT was an independent protective factor for prognosis. In conclusion, CYT-high HCCs were associated with enhanced immunity and better survival. Our findings suggest that proper identification of tumor-immune microenvironments could stratify the patients for appropriate treatments. Full article

(This article belongs to the Special Issue Human Hepatocellular Carcinoma (HCC))

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17 pages, 3930 KiB

Open AccessArticle

Haprolid Inhibits Tumor Growth of Hepatocellular Carcinoma through Rb/E2F and Akt/mTOR Inhibition

by Jun Xing, Vikas Bhuria, Khac Cuong Bui, Mai Ly Thi Nguyen, Zexi Hu, Chih-Jen Hsieh, Kathrin Wittstein, Marc Stadler, Ludwig Wilkens, Jun Li, Markus Kalesse, Przemyslaw Bozko and Ruben R. Plentz

Cancers 2020, 12(3), 615; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030615 - 06 Mar 2020

Cited by 10 | Viewed by 3570

Abstract

Background: Hepatocellular carcinoma (HCC) represents a major health burden with limited curative treatment options. There is a substantial unmet need to develop innovative approaches to impact the progression of advanced HCC. Haprolid is a novel natural component isolated from myxobacteria. Haprolid has been [...] Read more.

Background: Hepatocellular carcinoma (HCC) represents a major health burden with limited curative treatment options. There is a substantial unmet need to develop innovative approaches to impact the progression of advanced HCC. Haprolid is a novel natural component isolated from myxobacteria. Haprolid has been reported as a potent selective cytotoxin against a panel of tumor cells in recent studies including HCC cells. The aims of this study are to evaluate the antitumor effect of haprolid in HCC and to understand its underlying molecular mechanisms. Methods: The efficacy of haprolid was evaluated in human HCC cell lines (Huh-7, Hep3B and HepG2) and xenograft tumors (NMRI-Foxn1^nu mice with injection of Hep3B cells). Cytotoxic activity of haprolid was determined by the WST-1 and crystal violet assay. Wound healing, transwell and tumorsphere assays were performed to investigate migration and invasion of HCC cells. Apoptosis and cell-cycle distribution were measured by flow cytometry. The effects of haprolid on the Rb/E2F and Akt/mTOR pathway were examined by immunoblotting and immunohistochemistry. Results: haprolid treatment significantly inhibited cell proliferation, migration and invasion in vitro. The epithelial–mesenchymal transition (EMT) was impaired by haprolid treatment and the expression level of N-cadherin, vimentin and Snail was downregulated. Moreover, growth of HCC cells in vitro was suppressed by inhibition of G1/S transition, and partially by induction of apoptosis. The drug induced downregulation of cell cycle regulatory proteins cyclin A, cyclin B and CDK2 and induced upregulation of p21 and p27. Further evidence showed that these effects of haprolid were associated with Rb/E2F downregulation and Akt/mTOR inhibition. Finally, in vivo nude mice experiments demonstrated significant inhibition of tumor growth upon haprolid treatment. Conclusion: Our results show that haprolid inhibits the growth of HCC through dual inhibition of Rb/E2F and Akt/mTOR pathways. Therefore, haprolid might be considered as a new and promising candidate for the palliative therapy of HCC. Full article

(This article belongs to the Special Issue Human Hepatocellular Carcinoma (HCC))

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14 pages, 2134 KiB

Open AccessArticle

Association of TIM-3 with BCLC Stage, Serum PD-L1 Detection, and Response to Transarterial Chemoembolization in Patients with Hepatocellular Carcinoma

by Maria Tampaki, Evangelos Ionas, Emilia Hadziyannis, Melanie Deutsch, Katerina Malagari and John Koskinas

Cancers 2020, 12(1), 212; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010212 - 15 Jan 2020

Cited by 20 | Viewed by 3362

Abstract

Considering the increasing importance of immune checkpoints in tumor immunity we investigated the clinical relevance of serum T-cell immunoglobulin and mucin domain-3 (TIM-3) in patients with hepatocellular carcinoma (HCC). Serum TIM-3 levels were measured and their association with HCC stage and the detection [...] Read more.

Considering the increasing importance of immune checkpoints in tumor immunity we investigated the clinical relevance of serum T-cell immunoglobulin and mucin domain-3 (TIM-3) in patients with hepatocellular carcinoma (HCC). Serum TIM-3 levels were measured and their association with HCC stage and the detection of serum programmed death ligand-1 (PD-L1) were assessed. In patients submitted to transarterial chemoembolization (TACE), pre- and 1-week post-treatment TIM-3 levels were also evaluated. We studied 53 HCC patients with BCLC stages: 0 (5.7%), A (34%), B (32.1%), C (22.6%), and D (5.7%). The patients with advanced HCC (BCLC C) had significantly higher TIM-3 levels than patients with BCLC A (p = 0.009) and BCLC B (p = 0.019). TIM-3 levels were not associated with HCC etiology (p = 0.183). PD-L1 detection (9/53 patients) correlated with TIM-3 levels (univariate analysis, p = 0.047). In 33 patients who underwent TACE, post-treatment TIM-3 levels (231 pg/mL, 132–452) were significantly higher than pre-TACE levels (176 pg/mL, 110–379), (p = 0.036). Complete responders had higher post-TACE TIM-3 levels (534 pg/mL, 370–677) than partial responders (222 pg/mL, 131–368), (p = 0.028). Collectively, TIM-3 may have a role in anti-tumor immunity following TACE, setting a basis for combining immunotherapy and chemoembolization. Full article

(This article belongs to the Special Issue Human Hepatocellular Carcinoma (HCC))

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13 pages, 1298 KiB

Open AccessEditor’s ChoiceArticle

Comprehensive Metabolomic Search for Biomarkers to Differentiate Early Stage Hepatocellular Carcinoma from Cirrhosis

by Da Jung Kim, Eun Ju Cho, Kyung-Sang Yu, In-Jin Jang, Jung-Hwan Yoon, Taesung Park and Joo-Youn Cho

Cancers 2019, 11(10), 1497; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101497 - 06 Oct 2019

Cited by 54 | Viewed by 4652

Abstract

The established biomarker for hepatocellular carcinoma (HCC), serum α-fetoprotein (AFP), has suboptimal performance in early disease stages. This study aimed to develop a metabolite panel to differentiate early-stage HCC from cirrhosis. Cross-sectional metabolomic analyses of serum samples were performed for 53 and 47 [...] Read more.

The established biomarker for hepatocellular carcinoma (HCC), serum α-fetoprotein (AFP), has suboptimal performance in early disease stages. This study aimed to develop a metabolite panel to differentiate early-stage HCC from cirrhosis. Cross-sectional metabolomic analyses of serum samples were performed for 53 and 47 patients with early HCC and cirrhosis, respectively, and 50 matched healthy controls. Results were validated in 82 and 80 patients with early HCC and cirrhosis, respectively. To retain a broad spectrum of metabolites, technically distinct analyses (global metabolomic profiling using gas chromatography time-of-flight mass spectrometry and targeted analyses using liquid chromatography with tandem mass spectrometry) were employed. Multivariate analyses classified distinct metabolites; logistic regression was employed to construct a prediction model for HCC diagnosis. Five metabolites (methionine, proline, ornithine, pimelylcarnitine, and octanoylcarnitine) were selected in a panel. The panel distinguished HCC from cirrhosis and normal controls, with an area under the receiver operating curve (AUC) of 0.82; this was significantly better than that of AFP (AUC: 0.75). During validation, the panel demonstrated significantly better predictability (AUC: 0.94) than did AFP (AUC: 0.78). Defects in ammonia recycling, the urea cycle, and amino acid metabolism, demonstrated on enrichment pathway analysis, may reliably distinguish HCC from cirrhosis. Compared with AFP alone, the metabolite panel substantially improved early-stage HCC detection. Full article

(This article belongs to the Special Issue Human Hepatocellular Carcinoma (HCC))

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15 pages, 1644 KiB

Open AccessArticle

Comparison of Models for Tumor Recurrence after Liver Transplantation for the Patients with Hepatocellular Carcinoma: A Multicenter Long-Term Follow-Up Study

by Young Chang, Yuri Cho, Jeong-Hoon Lee, Yun Bin Lee, Eun Ju Cho, Su Jong Yu, Dong Hyun Sinn, Bo Hyun Kim, Seoung Hoon Kim, Nam-Joon Yi, Kwang-Woong Lee, Jong Man Kim, Joong-Won Park, Yoon Jun Kim, Jung-Hwan Yoon, Jae-Won Joh and Kyung-Suk Suh

Cancers 2019, 11(9), 1295; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11091295 - 03 Sep 2019

Cited by 13 | Viewed by 2800

Abstract

Background and Aims: Several models have been developed to predict tumor the recurrence of hepatocellular carcinoma (HCC) after liver transplantation besides the conventional Milan criteria (MC), including the MoRAL score. This study aimed to compare the prognostication power of the MoRAL score to [...] Read more.

Background and Aims: Several models have been developed to predict tumor the recurrence of hepatocellular carcinoma (HCC) after liver transplantation besides the conventional Milan criteria (MC), including the MoRAL score. This study aimed to compare the prognostication power of the MoRAL score to most models designed so far in the Eastern and Western countries. Methods: This study included 564 patients who underwent living donor liver transplantation (LDLT) in three large-volume hospitals in Korea. The primary and secondary endpoints were time-to-recurrence, and overall survival (OS), respectively. The performance of the MoRAL score was compared with those of other various Liver transplantation (LT) criteria, including the Milan criteria, University of California San Francisco (UCSF) criteria, up-to-seven criteria, Kyoto criteria, AFP model, total tumor volume/AFP criteria, Metroticket 2.0 model, and Weill Cornell Medical College group model. Results: The median follow-up duration was 78.1 months. Among all models assessed, the MoRAL score showed the best discrimination function for predicting the risk of tumor recurrence after LT, with c-index of 0.78, compared to other models (all p < 0.001). The MoRAL score also represented the best calibration function by Hosmer-Lemeshow test (p = 0.15). Especially in the beyond-MC sub-cohort, the MoRAL score predicted tumor recurrence (c-index, 0.80) and overall survival (OS) (c-index, 0.70) significantly better than any other models (all p < 0.001). When the MoRAL score was low (<314.8), the five-year cumulative risks of tumor recurrence and death were excellent in beyond-MC (27.8%, and 20.5%, respectively) and within-MC (16.3%, and 21.1%, respectively) sub-cohorts. Conclusions: The MoRAL score provides the most refined prognostication for predicting HCC recurrence after LDLT. Full article

(This article belongs to the Special Issue Human Hepatocellular Carcinoma (HCC))

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Review

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20 pages, 20364 KiB

Open AccessReview

The Crosstalk between Tumor Cells and the Microenvironment in Hepatocellular Carcinoma: The Role of Exosomal microRNAs and Their Clinical Implications

by Devis Pascut, Muhammad Yogi Pratama, Niem V.T. Vo, Rina Masadah and Claudio Tiribelli

Cancers 2020, 12(4), 823; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12040823 - 29 Mar 2020

Cited by 40 | Viewed by 4900

Abstract

The communication between hepatocellular carcinoma (HCC) cells and their microenvironment is an essential mechanism supporting or preventing tumor development and progression. Recent evidence has identified extracellular vesicles (EVs) as one of the mechanisms mediating paracrine signaling between cells. Exosomes, the most described class [...] Read more.

The communication between hepatocellular carcinoma (HCC) cells and their microenvironment is an essential mechanism supporting or preventing tumor development and progression. Recent evidence has identified extracellular vesicles (EVs) as one of the mechanisms mediating paracrine signaling between cells. Exosomes, the most described class of EVs, deliver proteins, mRNAs, noncoding RNAs, DNA, and lipids to recipient cells, also at remote distances. MicroRNAs (miRNAs), as part of the non-coding RNA exosomal cargo, have an important role in regulating cellular pathways in targeted cells, regulating several processes related to tumor progression invasion and metastasis, such as angiogenesis, immune-escape, epithelial-to-mesenchymal transition, invasion, and multi-drug resistance. Accumulating evidence suggests exosomal miRNAs as relevant players in the dynamic crosstalk among cancerous, immune, and stromal cells in establishing the tumorigenic microenvironment. In addition, they sustain the metastasic niche formation at distant sites. In this review, we summarized the recent findings on the role of the exosome-derived miRNAs in the cross-communication between tumor cells and different hepatic resident cells, with a focus on the molecular mechanisms responsible for the cell re-programming. In addition, we describe the clinical implication derived from the exosomal miRNA-driven immunomodulation to the current immunotherapy strategies and the molecular aspects influencing the resistance to therapeutic agents. Full article

(This article belongs to the Special Issue Human Hepatocellular Carcinoma (HCC))

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