• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/surgery
• Carcinoma, Hepatocellular/genetics
• Humans
• Liver Neoplasms/immunology
• Liver Neoplasms/pathology
• Liver Neoplasms/diagnosis
• Liver Neoplasms/surgery
• Liver Neoplasms/genetics
• Killer Cells, Natural/immunology
• Killer Cells, Natural/cytology
• Neoplasm Recurrence, Local/immunology
• Neoplasm Recurrence, Local/diagnosis
• Neoplasm Recurrence, Local/pathology
• Animals
• Mice
• Male
• Tumor Microenvironment/immunology
• Female
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Biomarkers, Tumor/analysis
• Interferon-gamma/metabolism
• Mice, Knockout
• Middle Aged
• Cohort Studies
• Extracellular Matrix Proteins/genetics
• Extracellular Matrix Proteins/deficiency
• Extracellular Matrix Proteins/metabolism
• Reproducibility of Results

• Humans
• Carcinoma, Hepatocellular/therapy
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/drug therapy
• Sorafenib/therapeutic use
• Sorafenib/administration & dosage
• Liver Neoplasms/therapy
• Liver Neoplasms/pathology
• Liver Neoplasms/mortality
• Liver Neoplasms/drug therapy
• Chemoembolization, Therapeutic/methods
• Male
• Female
• Middle Aged
• Neoplasm Recurrence, Local
• Aged
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/administration & dosage
• Neoplasm Staging
• Treatment Outcome
• Adult
• Combined Modality Therapy

• adverse events
• donafenib
• efficacy
• hepatocellular carcinoma
• postoperative adjuvant therapy
• safety

• Ablation
• Hepatocellular carcinoma (HCC)
• Liver resection
• Liver transplantation
• Recurrence

• HCC recurrence
• mechanism
• postoperative recurrence
• surgical stress
• tumor microenvironment

• Humans
• Carcinoma, Hepatocellular/drug therapy
• Liver Neoplasms/drug therapy
• Tumor Microenvironment
• Neoplasm Recurrence, Local

• Body composition
• Computed tomography
• Hepatocellular carcinoma
• Radiomics
• Recurrence

• Hepatocellular carcinoma
• Metastasis
• Molecular mechanisms
• Portal vein tumor thrombosis
• Therapy

Hepatocellular carcinoma (HCC) is one of the most lethal tumors in the world. Liver resection (LR) and liver transplantation (LT) are widely considered as radical treatments for early HCC. However, the recurrence rates after curative treatment are still high and overall survival is unsatisfactory. Microvascular invasion (MVI) is considered to be one of the important prognostic factors affecting postoperative recurrence and long-term survival. Unfortunately, whether HCC patients with MVI should receive postoperative adjuvant therapy remains unknown. In this review, we summarize the therapeutic effects of transcatheter arterial chemoembolization, hepatic arterial infusion chemotherapy, tyrosine protein kinase inhibitor-based targeted therapy, and immune checkpoint inhibitors in patients with MVI after LR or LT, aiming to provide a reference for the best adjuvant treatment strategy for HCC patients with MVI after LT or LR.

• Microvascular invasion
• Hepatocellular carcinoma
• Liver resection
• Liver transplantation
• Postoperative
• Adjuvant treatment

• TOMM34
• hepatocellular carcinoma
• metastasis
• metformin adaptation
• oxidative phosphorylation

Obesity is an established risk factor for several human cancers. Given the association between excess body weight and cancer, the increasing rates of obesity worldwide are worrisome. A variety of obesity-related factors has been implicated in cancer initiation, progression, and response to therapy. These factors include circulating nutritional factors, hormones, and cytokines, causing hyperinsulinemia, inflammation, and adipose tissue dysfunction. The impact of these conditions on cancer development and progression has been the focus of extensive literature. In this review, we concentrate on processes that can link obesity and cancer, and which provide a novel perspective: extracellular matrix remodeling, angiogenesis, and adrenergic signaling. We describe molecular mechanisms involved in these processes, which represent putative targets for intervention. Liver, pancreas, and breast cancers were chosen as exemplary disease models. In view of the expanding epidemic of obesity, a better understanding of the tumorigenic process in obese individuals might lead to more effective treatments and preventive measures.

• Adrenergic signaling
• Angiogenesis
• Cancer
• Fibrosis
• Obesity

Hepatocellular carcinoma (HCC) is the most frequent primitive cancer of the liver, accounting for 90% of all recorded cases. HCC is the third most common cause of cancer-related death, with a 5-year survival rate of just 3%. In terms of the advanced stages, systemic treatments have allowed patients to achieve clinical benefits, although the prognosis remains very poor. In the past few decades, new molecular targeted therapies have been developed and clinically evaluated with interesting results. However, on the basis of the poor prognoses and the meager benefits deriving from the available systemic therapies, research into new treatments is extremely necessary. In this review, we focus on the available systemic therapies for advanced HCC, with a look toward the future.

Hepatocellular carcinoma (HCC) is the most frequent primitive cancer of the liver, accounting for 90% of all recorded cases. HCC is the third most common cause of cancer-related death, with a 5-year survival rate of just 3%. In the advanced stages, systemic treatments allow doctors to obtain clinical benefits, although the prognosis remains very poor. In the past few decades, new molecular targeted therapies against receptor tyrosine kinases have been developed and clinically evaluated. Sorafenib was the first oral tyrosine kinase inhibitor (TKI) approved for the treatment of advanced HCC in 2007. Subsequently, other TKIs, including Cabozantinib, Regorafenib, Lenvatinib, and vascular endothelial growth factor receptor (VEGFR) inhibitors such as Ramucirumab and VEGF inhibitors such as Bevacizumab have been approved as first- or second-line treatments. More recently, the combination of immune checkpoint inhibitors and VEGF inhibitors (Atezolizumab plus Bevacizumab) have been analyzed and approved for the treatment of advanced HCC. On the basis of the poor prognoses and the meager benefits deriving from the available systemic therapies, research into new treatments is extremely necessary. In this review, we focus on the available systemic therapies for advanced HCC, with a look toward the future.

• cancer therapy
• hepatocellular carcinoma
• immune checkpoint inhibitors
• immunotherapy
• targeted therapy
• tyrosine kinase inhibitors

Hepatoblastoma (HB) is the most common pediatric primary liver malignancy, and survival for high-risk disease approaches 50%. Mouse models of HB fail to recapitulate hallmarks of high-risk disease. The aim of this work was to generate murine models that show high-risk features including multifocal tumors, vascular invasion, metastasis, and circulating tumor cells (CTCs). HepT1 cells were injected into the livers or tail veins of mice, and tumor growth was monitored with magnetic resonance and bioluminescent imaging. Blood was analyzed with fluorescence-activated cell sorting to identify CTCs. Intra- and extra-hepatic tumor samples were harvested for immunohistochemistry and RNA and DNA sequencing. Cell lines were grown from tumor samples and profiled with RNA sequencing. With intrahepatic injection of HepT1 cells, 100% of animals grew liver tumors and showed vascular invasion, metastasis, and CTCs. Mutation profiling revealed genetic alterations in seven cancer-related genes, while transcriptomic analyses showed changes in gene expression with cells that invade vessels. Tail vein injection of HepT1 cells resulted in multifocal, metastatic disease. These unique models will facilitate further meaningful studies of high-risk HB.

This article has an associated First Person interview with the first author of the paper.

Summary: In this work, we developed and thoroughly characterized several unique models of hepatoblastoma derived from the HepT1 cell line that show high-risk features.

• Circulating tumor cell
• Hepatoblastoma
• Invasion
• Metastasis
• Mouse models
• Pediatric liver cancer

• Hepatocellular carcinoma
• Injectable hydrogel
• NK cell Adoptive therapy
• Neutrophil extracellular traps
• Tumor acidity

• Adhesives
• Carcinoma, Hepatocellular/metabolism
• Cell- and Tissue-Based Therapy
• Deoxyribonuclease I
• Extracellular Traps
• Hemostasis
• Hemostatics
• Humans
• Hydrogels/metabolism
• Liver Neoplasms/pathology
• Lyases/metabolism
• Tumor Microenvironment

• immune checkpoint inhibitors
• liver cancer
• molecular therapies
• tumor microenvironment
• tyrosine kinase inhibitors

The predicting values of programmed cell death protein 1 (PD-1) and programmed death-ligand 1(PD-L1) were unclear in Hepatocellular carcinoma (HCC) patients who receive sorafenib treatment after curative hepatic resection.

We retrospectively enrolled HCC patients who received adjuvant sorafenib treatment after curative resection (N = 154), and patients had resection alone (N = 312). Immunohistochemistry was used to assess expression of PD-1 on tumor infiltration immune cells and PD-L1 on HCC cells. Cox proportional hazard models were used to explore association between clinicopathological factors and risk of tumor recurrence.

No significant difference was detected in RFS (p = 0.542), or OS (p = 0.542) between the resection and sorafenib group and resection alone group. In the 154 patients who received adjuvant sorafenib, expression of PD-1 or PD-L1 was not significantly associated with long-term outcomes. However, in the 122 patients at high risk of postoperative recurrence who had adjuvant sorafenib treatment, characterized by maxim tumor size ≥5 cm, or the presence of macro- or micro-vascular invasion, patients with PD-L1 overexpression (≥3.0) had significantly worse RFS (p = 0.021), and overexpression of PD-L1 (HR: 1.88, 95%CI: 1.18–2.99, p = 0.008) was identified as an independent risk factor associated with unfavorable RFS.

Overexpression of PD-L1 serves as an independent predictor of recurrence in HCC patients at high risk of relapse who received adjuvant sorafenib treatment after curative resection.

• National Natural Science Foundation of China

Sorafenib was reported as a useful adjuvant treatment in patients with hepatocellular carcinoma who underwent surgical resection. However, its therapeutic value remains controversial. This meta-analysis examined the available data regarding the efficacy and safety of sorafenib in patients with hepatocellular carcinoma after radical surgery.

The meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The protocol was registered in advance with PROSPERO (CRD42021233868). We searched PubMed, Embase, Cochrane Library, and Web of Science to identify eligible studies. Overall survival, recurrence-free survival, and recurrence rates were analyzed, and adverse events were reviewed. Hazard ratios or pooled risk ratios with 95% CIs were collected and analyzed using STATA version 12.0 in a fixed-effects or random-effects meta-analysis model.

In total, 2655 patients from 13 studies were ultimately included in this meta-analysis. The combined results illustrated that sorafenib was associated with better overall survival than the control (hazard ratio = 0.71, 95% CI = 0.59–0.86; P < 0.001). Similarly, the drug also improved recurrence-free survival (hazard ratio = 0.68, 95% CI = 0.54–0.86, P = 0.001). Combined data revealed that patients treated with sorafenib after resection had a lower recurrence rate (pooled risk ratio = 0.78, 95% CI = 0.68–0.90, P < 0.001). The primary adverse events were hand-foot skin reaction, fatigue, and diarrhea of mild-to-moderate severity, whereas grade 4 adverse events were rare (< 1%).

This meta-analysis demonstrated that adjuvant sorafenib therapy after resection in patients with hepatocellular carcinoma could prolong overall survival and recurrence-free survival and reduce recurrence rates without intolerable side effects. However, more evidence is needed before reaching a definitive conclusion.

• HCC
• Hepatocellular carcinoma
• Meta-analysis
• Resection
• Sorafenib

Portal vein tumor thrombus (PVTT) is one of the most serious forms of hepatocellular carcinoma (HCC) vessel metastasis and has a poor survival rate. However, the molecular mechanism of PVTT has not yet been elucidated. In this study, the molecular mechanism of AXL expressed in tumor-derived endothelial cells (TECs) in vessel metastasis was investigated. High AXL expression was observed in TECs, but not in the tumor cells of HCC patients with PVTT and this was associated with poor overall survival (OS) and disease-free survival (DFS). AXL overexpression was positively associated with CD 31 expression both in vitro and in vivo. AXL promoted the cell proliferation, tube formation, and migration of both TECs and normal endothelial cells (NECs). High expression of AXL in TECs promoted the cell migration, but not the proliferation of HCC cells. Further studies demonstrated that AXL promoted cell migration and tube formation through activation of the PI3K/AKT/SOX2/DKK-1 axis. AXL overexpression in HUVECs promoted tumor growth and liver or vessel metastasis of HCC in xenograft nude mice, which could be counteracted by treatment with R428, an AXL inhibitor. R428 reduced tumor growth and CD 31 expression in HCC in PDX xenograft nude mice. Therefore, AXL over-expression in TECs promotes vessel metastasis of HCC, which indicates that AXL in TECs could be a potential therapeutic target in HCC patients with PVTT.

• AXL
• endothelial cells
• hepatocellular carcinoma
• portal vein tumor thrombus
• vessel metastasis

Plantamajoside (PMS), a major component of Plantago asiatica L, has several pharmacological properties, including anti-proliferative, anti-inflammatory and anti-tumor effects. However, the effects of PMS on hepatocellular carcinoma (HCC) have yet to be determined. The aim of the present study was to investigate the effects of PMS on HCC and elucidate the underlying mechanism. All assays were conducted using 5 groups, namely control, sorafenib, and PMS 100, 50, and 25 µg/ml groups. Cell proliferation was determined by the MTT assay. Cell migration was evaluated with the wound healing and Transwell assays, respectively. Cell apoptosis and cell cycle distribution were evaluated via flow cytometry. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis and western blotting were used to further investigate the mechanism of action of PMS. Sorafenib and PMS both significantly attenuated the proliferation and migration of HCC cells, and markedly promoted cell apoptosis. PMS induced cell cycle arrest in the G0/G1 phase. The efficacy of PMS increased in a dose-dependent manner. Further study evaluated the expression of peroxisome proliferator-activated receptor (PPARγ), nuclear factor (NF)-κB and cyclooxygenase (Cox-2) using RT-qPCR analysis and western blotting. The results demonstrated that PMS promoted the expression of PPARγ and suppressed the expression of NF-κB and Cox-2. In conclusion, PMS was shown to affect cell proliferation, migration, apoptosis and cell cycle distribution. Furthermore, PMS promoted the expression of PPARγ and inhibited the expression of NF-κB and Cox-2, which may be the mechanism underlying its biological effects. Based on the results of the present study, PMS appears to be a promising agent for HCC therapy.

• hepatocellular carcinoma
• herbal medicine
• peroxisome proliferator-activated receptor γ
• plantamajoside

Although long-term outcomes may be comparable between laparoscopic liver resection (LLR) and open liver resection (OLR) for hepatocellular carcinoma (HCC), there has been little discussion regarding the patterns of recurrence after LLR.

Patients with HCC who underwent hepatectomy between April 2015 and November 2018 were included in this study. The recurrence patterns were analyzed in detail. The recurrence outcomes following laparoscopic versus OLR for HCC were compared after 1:2 propensity score matching. Potential risk factors for recurrence were also assessed with Cox proportional risk models.

Among 425 patients after LLR, 144 (33.8%) experienced recurrence at the last follow-up, with a median recurrence-free survival (RFS) of 10.0 months (range 1–58 months). The most frequent recurrence site was the liver (n = 99, 68.8%), followed by the surgical margin (n = 15, 10.4%) and distant metastases (n = 12, 8.3%). Liver recurrence with distant metastasis (n = 10, 6.9%) tended to occur early (median 8.0 months), while peritoneal recurrence (n = 8, 5.6%) occurred later (median 14.0 months). A total of 120 (83.3%) patients had recurrence within 2 years after LLR. No trocar site recurrence was observed in this study. The recurrence patterns, timing, and treatment did not show significant differences between the LLR and OLR. The independent risk factors for recurrence included ALBI grade, postoperative α-fetoprotein > 8 ng/ml, tumor size > 5 cm, surgical margin ≤ 1 cm, and multiple tumors. Patients with recurrence had 1- and 5-year overall survival rates of 81.1% and 60.7%, respectively, compared with rates of 95.8% and 92.9% for patients without recurrence (P < 0.000).

This study suggested that intrahepatic recurrence was still the most common recurrence pattern for HCC after LLR and that LLR did not increase the risk of trocar hole recurrence or implantation. Most cases of recurrence occurred within 2 years after LLR, suggesting that surveillance should be targeted to early recurrence.

The online version of this article (10.1007/s00464-021-08390-5) contains supplementary material, which is available to authorized users.

• Hepatocellular carcinoma
• Laparoscopic liver resection
• Recurrence patterns
• Recurrence-free survival

Hepatocellular carcinoma (HCC) is the most prevalent form of liver malignancy and carries poor prognoses due to late presentation of symptoms. Treatment of late-stage HCC relies heavily on chemotherapeutics, many of which target cellular energy metabolism. A key platform for testing candidate chemotherapeutic compounds is the intrahepatic orthotopic xenograft (IOX) model in rodents. Translational efficacy from the IOX model to clinical use is limited (in part) by variation in the metabolic phenotypes of the tumor-derived cells that can be induced by selective adaptation to subculture conditions.

In this study, a detailed multilevel systems approach combining microscopy, respirometry, potentiometry, and extracellular flux analysis (EFA) was utilized to examine metabolic adaptations that occur under aglycemic growth media conditions in HCC-derived (HEPG2) cells. We hypothesized that aglycemic growth would result in adaptive “aerobic poise” characterized by enhanced capacity for oxidative phosphorylation over a range of physiological energetic demand states.

Aglycemic growth did not invoke adaptive changes in mitochondrial content, network complexity, or intrinsic functional capacity/efficiency. In intact cells, aglycemic growth markedly enhanced fermentative glycolytic substrate-level phosphorylation during glucose refeeding and enhanced responsiveness of both fermentation and oxidative phosphorylation to stimulated energy demand. Additionally, aglycemic growth induced sensitivity of HEPG2 cells to the provitamin menadione at a 25-fold lower dose compared to control cells.

These findings indicate that growth media conditions have substantial effects on the energy metabolism of subcultured tumor-derived cells, which may have significant implications for chemotherapeutic sensitivity during incorporation in IOX testing panels. Additionally, the metabolic phenotyping approach used in this study provides a practical workflow that can be incorporated with IOX screening practices to aid in deciphering the metabolic underpinnings of chemotherapeutic drug sensitivity.

The online version contains supplementary material available at 10.1186/s40170-021-00241-0.

• Cancer
• Confocal microscopy
• Galactose
• Glycolysis
• HEPG2
• Mitochondria
• Oroboros
• Oxidative phosphorylation
• Seahorse xf24

• ERK
• HCC
• PLK1
• STK39
• proliferation

• Animals
• Apoptosis
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Cell Cycle Proteins/genetics
• Cell Cycle Proteins/metabolism
• Cell Proliferation
• Extracellular Signal-Regulated MAP Kinases/genetics
• Extracellular Signal-Regulated MAP Kinases/metabolism
• Gene Expression Regulation, Neoplastic
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Protein Serine-Threonine Kinases/genetics
• Protein Serine-Threonine Kinases/metabolism
• Proto-Oncogene Proteins/genetics
• Proto-Oncogene Proteins/metabolism
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• Polo-Like Kinase 1

• Sorafenib
• hepatocellular carcinoma (HCC)
• microvascular invasion (MVI)

• Antineoplastic Agents/therapeutic use
• Carcinoma, Hepatocellular/drug therapy
• Humans
• Liver Neoplasms/drug therapy
• Neoplasm Recurrence, Local
• Sorafenib/therapeutic use

The novel curcumin analog C086, previously identified as an oral novel heat shock protein 90 (Hsp90) inhibitor, was found to exhibit anti-hepatoma activity in vitro and in vivo. However, owing to its limited aqueous solubility, the usage of C086 in the clinical application was restricted. This research focused on the increase of the aqueous solubility and bioavailability of C086 via a solid dispersion preparation to improve its accumulation in the liver, which accordingly enhanced anti-hepatoma activity. C086-solid dispersion (C086-SD) was successfully prepared by using solvent evaporation technology. As compared with bulk compound, aqueous solubility obtained with the optimal formulation (C086/PVP k30:1/6 (w/w)) was increased by 1.741 million-fold, and in the following oral administration experiment, bioavailability was found to be improved by an approximately 28-fold relative to C086-Suspension and accumulate preferably in the liver. Accordingly, C086-SD exhibited stronger potent anti-proliferative effects against liver cancer cell line (i.e. HepG2) than pure C086. Moreover, C086-SD was found to have an enhanced anti-hepatoma effect using the orthotopic hepatocellular carcinoma xenograft in BALB/C nude mice. The results above suggested the potential application of C086-SD in the treatment of liver cancer.

• Curcumin analog C086
• anti-hepatoma
• in vivo bioavailability
• liver accumulation
• solid dispersion

• cancer microenvironment
• cell growth

• Animals
• Carcinoma, Hepatocellular/complications
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/pathology
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Chemokines/metabolism
• Dexmedetomidine/chemistry
• Dexmedetomidine/pharmacology
• Dexmedetomidine/therapeutic use
• Disease Models, Animal
• Disease Progression
• Hepatic Stellate Cells/drug effects
• Hepatic Stellate Cells/pathology
• Humans
• Interleukin-6/metabolism
• Liver Cirrhosis/complications
• Liver Cirrhosis/pathology
• Liver Neoplasms/complications
• Liver Neoplasms/drug therapy
• Liver Neoplasms/pathology
• Male
• Mice, Inbred C57BL
• Neoplasm Metastasis
• Receptors, Adrenergic, alpha-2/metabolism
• STAT3 Transcription Factor/metabolism

• 81572797 National Natural Science Foundation of China (National Science Foundation of China)
• Nature Science Fund of Guangdong Province (2016A030311015)
• Science and Technology Program of Guangzhou, China (201704020128); Municipal University Science and Technology Program of Guangzhou Education Bureau (1201410075); Yangcheng Scholar Program (1201561579).

• Carcinoma, Hepatocellular/complications
• Carcinoma, Hepatocellular/therapy
• Female
• Humans
• Liver Neoplasms/complications
• Liver Neoplasms/therapy
• Male
• Portal Vein/abnormalities
• Thrombosis/etiology
• Treatment Outcome

Background: There is no guideline recommendation for preventing hepatocellular carcinoma (HCC) recurrence after hepatic resection. Moreover, an unmet need exists on the effectiveness of sorafenib therapy in recurrent HCC.

Purpose: We therefore assessed the efficacy and safety of sorafenib in Chinese HCC patients with high risk of recurrence.

Patients and methods: Data were collected retrospectively from 15 Chinese research centers from January 1, 2012 to November 15, 2013, by chart reviews of patients with moderate-advanced HCC who received hepatic carcinectomy. The primary end point was recurrence-free survival rate at 1 year in patients with a high recurrence risk. Secondary end points included 1-year survival rate, time to recurrence and safety assessment.

Results: A total of 209 high-risk patients (sorafenib, n=98; control, n=111) who underwent carcinectomy were analyzed. There was no significant difference in the proportion of patients with recurrence-free survival at 1 year between the sorafenib and control (70.43% vs 68.90%: χ²=0.007, P=0.934). One-year survival rate was significantly higher with sorafenib than observed with control (95.5% vs 83.35%; χ²=7.441, P=0.006). Time to recurrence between sorafenib and control groups was similar. Incidences of all the adverse events (AEs) were similar in both the groups and transaminase elevation was most common in both groups (20.37% vs 24.79%). Thrombocytopenia incidence was significantly lower with the sorafenib group than with control (1.85% vs 9.40%; P=0.015).

Conclusion: Sorafenib may be considered as a feasible option in the treatment of HCC recurrence.

• Chinese
• carcinectomy
• hepatocellular carcinoma
• recurrence
• sorafenib
• survival

Wnt1‐inducible signalling pathway protein 3 (WISP3/CCN6) belongs to the CCN (CYR61/CTGF/NOV) family of proteins, dysregulation of this family contributed to the tumorigenicity of various tumours. In this study, we need to explore its role in hepatocellular carcinoma that remains largely elusive.

The expression of WISP3/CCN6 was analysed by qRT‐PCR and Western blotting. Effects of WISP3 on proliferation and metastasis of HCC cells were examined, respectively, by MTT assay and Boyden Chamber. Roles of WISP3 on HCC tumour growth and metastatic ability in vivo were detected in nude mice. Related mechanism study was confirmed by immunofluorescence and Western blotting.

The expression of WISP3 was significantly downregulated in HCC clinical samples and cell lines, and reversely correlated with the tumour size. Forced expression of WISP3 in HCC cells significantly suppressed cell growth and migration in vitro as well as tumour growth and metastatic seeding in vivo. In contrast, downregulation of WISP3 accelerated cell proliferation and migration, and promoted in vivo metastasis. Further study revealed that WISP3 inhibited the translocation of β‐catenin to the nucleus by activating glycogen synthase kinase‐3β (GSK3β). Moreover, constitutively active β‐catenin blocked the suppressive effects of WISP3 on HCC.

Our study showed that WISP3 suppressed the progression of HCC by negative regulation of β‐catenin/TCF/LEF signalling, providing WISP3 as a potential therapeutic candidate for HCC.

• WISP3
• hepatocellular carcinoma
• metastasis
• tumorigenesis
• β-catenin

• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/prevention & control
• Case-Control Studies
• Female
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Liver Neoplasms/epidemiology
• Liver Neoplasms/prevention & control
• Liver Transplantation
• Male
• Middle Aged
• Neoplasm Recurrence, Local/epidemiology
• Neoplasm Recurrence, Local/prevention & control
• Regression Analysis
• Risk Factors
• Treatment Outcome

• Ministry of Science, ICT and Future Planning (MSIP)

Microvascular invasion (MVI) has been proved to be an independent risk factor for the recurrence of HCC. If promptly treated, the recurrence rate can be reduced and the total survival time can be prolonged. The aim of this study is to analyze the effect of sorafenib on the clinical outcomes in HCC patients with MVI after curative hepatectomy.

HCC patients who underwent hepatectomy and were pathologically diagnosed with MVI were retrospectively analyzed. Patients were divided into sorafenib group and control group. Sorafenib 400 mg, twice daily, was administered orally after surgery in the sorafenib group. The recurrence-free survival (RFS) and overall survival (OS) were observed during follow-up, and associated factors were analyzed using univariate and multivariate COX regression.

There was no significant difference in demographics, clinical staging, and tumor index between sorafenib group (16 patients) and control group (33 matched patients). The RFS and OS were both longer in the sorafenib group, and the 3-years RFS rates of the sorafenib group and control group were 56.3% (9 of 16) and 24.2% (8 of 33), respectively (P=0.027). The 3-year OS rate of the sorafenib group was 81.3% (13 of 16), which was significantly higher than that of the control group (39.4%, P=0.006). The results of multivariate COX regression indicated that treatment with sorafenib was an independent associated factor for RFS and OS.

We believe that using sorafenib therapy after curative hepatectomy in HCC patients with MVI is effective and beneficial as it can reduce recurrence and prolong the survival time.

• hepatectomy
• hepatocellular carcinoma
• microvascular invasion
• sorafenib
• survival rate

• Animals
• Apoptosis/drug effects
• Carcinoma, Hepatocellular/pathology
• Cell Line, Tumor
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Cell Survival/drug effects
• Drug Synergism
• Endoplasmic Reticulum Stress/drug effects
• Epithelial-Mesenchymal Transition/drug effects
• Female
• Humans
• Liver Neoplasms/pathology
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Oligopeptides/pharmacology
• Signal Transduction/drug effects
• Sorafenib/pharmacology
• Xenograft Model Antitumor Assays

• R01 CA099004 NCI NIH HHS
• R01 CA123391 NCI NIH HHS
• R01 CA166575 NCI NIH HHS

As a multi-kinase inhibitor, sorafenib is beneficial in around 30% of hepatocellular carcinoma (HCC) patients; however, HCC patients develop acquired drug resistance quickly. Clinical benefits of sorafenib, in combination with transarterial chemoembolization (TACE), radiotherapy, and other chemodrugs are limited. We investigated the efficacy and mechanisms of Notch signaling inhibition as adjuvant to sorafenib in HCC spheroid-derived in vitro and in vivo tumor models, using the γ-secretase inhibitor (GSI), PF-03084014. The combination of PF-03084014 plus sorafenib inhibited proliferation and self-renewal of HCC spheroids (stem-like cancer cells). PF-03084014 significantly enhanced antitumor activity of sorafenib; both agents at low dose reached synergistic tumor growth suppression of HCC spheroid-derived orthotopic tumors. The Notch1-Snail1 signaling pathway contributed to sorafenib resistance via increasing epithelial-mesenchymal transition (EMT) and EMT-mediated cancer stem cell (CSC) features, such as increased expression of Snail1, N-cadherin, ABCG2, and the stem cell related genes Nanog and Oct4, and decreased expression of E-cadherin. Anti-tumor activity of the combination therapy was associated with decreased expression of survival signals (Mek/Erk, PI3K/Akt) and reduced microvessel density. PF-03084014 plus sorafenib targets Notch1-Snail1 signaling to reverse EMT and EMT-mediated CSC stemness in the tumors. These synergistic effects provide a rationale to utilize GSIs, in combination with sorafenib, as a new therapeutic strategy for the treatment of HCC.

• GSI
• HCC
• PF-03084014
• antitumor
• sorafenib

Liver resection combined with postoperative sorafenib to prevent recurrence remains a controversial approach for cases of hepatocellular carcinoma (HCC), especially cases with a high risk of recurrence. This study aimed to investigate the efficacy and safety of liver resection combined with sorafenib for HCC with a high risk of recurrence.

Most of the cases of HCC were caused by hepatitis B virus (HBV) infection (23 cases, 92%). Most of these tumors (21 cases, 84%) were stage III according to the TNM staging system (12 cases with IIIa, 9 cases with IIIb). In the months after hepatic resection, 19 of the 25 cases (76%) were diagnosed with HCC recurrence or metastasis. Based on the tumor histological biomarker grading system, the group with higher expression levels of c-Raf-1 showed significantly longer overall survival than the group with lower expression of c-Raf-1 (P = 0.012). However, the long-term tumor-free survival advantage disappeared (P = 0.061). Univariate and multivariate analyses indicated that higher expression of c-Raf-1 was significantly associated with better overall survival (hazard ratio [HR]: 1.842; 95% confidence interval [CI]: 1.211–2.542; P = 0.031) and tumor-free survival (HR: 1.319; 95% CI: 1.017–1.543; P = 0.046) in HCC patients who underwent radical hepatic resection.

We retrospectively collected 25 HCC cases with a high risk of recurrence who underwent radical liver resection and who took sorafenib postoperatively from Jan 2010 to Dec 2012. Factors that might contribute to tumor recurrence and treatment failure such as clinical factors, tumor features, and molecular biomarkers were included in our analysis.

HCC patients with a high risk of post-hepatic resection recurrence may benefit from postoperative sorafenib administered as an adjuvant therapy, especially in cases with high levels of c-Raf-1 expression on histological examination.

• hepatocellular carcinoma
• liver resection
• recurrence
• risk factors
• sorafenib

• HCC
• RHEB
• RNA interference
• gene microarray
• metastasis
• prognosis

Portal vein tumor thrombus (PVTT) usually worsens prognosis of hepatocellular carcinoma (HCC), as characterized by aggressive disease progression, impaired liver function and tolerance to treatment. Conventionally, the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) accepted the Barcelona Clinical Liver Cancer (BCLC) treatment algorithms, identifying PVTT as an absolute contra-indication of surgical resection for HCC. HCC-PVTT patients are offered sorafenib as the standard treatment. Evidently, SHARP and Asia-Pacific trials demonstrated that sorafenib only improves overall survival by approximately 3 months in patients with advanced HCC. Besides, BCLC treatment algorithm does not provide different therapeutic recommendations for different degree of PVTT, and only supports single treatment option for each stage of HCC rather than a combination of comprehensive treatments, which limited individual and best care for every HCC-PVTT patients. In the past few years, many surgeons do not restrict surgical resection to HCC with PVTT. There have been new reports demonstrated that surgical treatment is feasible for selected HCC-PVTT patients with resectable tumor and moderate liver function to prolong survival period and elevate life quality as long as PVTT limited to the first-order branch, whereas non-surgical treatments fail to provide comparable therapeutic effects. At present, guidelines on HCC management from mainland China, Japan, and Hong Kong have been updated and a consensus of Asia-Pacific experts has established that portal venous invasion is not an absolute contradiction of surgical resection for HCC. This review summarized the emerging data on surgical resection for HCC-PVTT patients beyond the BCLC treatment algorithms and discussed recent therapeutic conceptualchanges in the Asia-Pacific region.

• hepatocellular carcinoma
• portal vein tumor thrombus
• surgical resection