Yong-Sheng Ge

Ligation of TLR2 by Versican: A Link Between Inflammation and Metastasis

Versican, a large extracellular matrix proteoglycan, accumulates both in tumor stroma and cancer cells. It participates in cell adhesion, migration, and angiogenesis, all features of invasion and metastasis. However, the mechanism(s) whereby versican promotes cancer invasion and metastasis is not yet fully understood. A recent study has documented that versican can activate tumor-infiltrating myeloid cells through toll-like receptor (TLR) 2 and its co-receptors TLR6 and CD14 and elicit the production of proinflammatory cytokines including TNF-alpha that enhance tumor metastasis. As both resident fibroblasts and endothelial cells (ECs) also express functional TLR2 and its co-receptors, we hypothesized that, in addition to myeloid cells, versican may trigger the activation of both fibroblasts and ECs. Of interest, TLR2-mediated activation of EC and fibroblast has been observed to increase the secretion of interleukin-8, a proinflammatory CXC chemokine that potentiates neutrophil infiltration and angiogenesis, as well as metastatic growth. Ligation of TLR2 by versican appears to be directly involved in the activation of multiple types of cells in tumor stroma and the induction of inflammatory cytokine secretion, providing a link between inflammation and cancer metastasis. Accordingly, antagonists of versican and TLR2 restrain the activation of tumor stromal cells, which may offer a novel approach to cancer therapy by targeting tumor microenvironment.

Effects of interferon treatment on development and progression of hepatocellular carcinoma in patients with chronic virus infection: A meta‐analysis of randomized controlled trials

Available literature on the effects of interferon (IFN) treatment on development and progression of hepatocellular carcinoma (HCC) in patients with chronic virus infection reports controversial results. The primary objective of this meta‐analysis was to evaluate the effect of IFN on HCC risk in patients with chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection; IFNs efficacy on local tumor progression and survival of advanced HCC patients was also assessed. All randomized controlled trials (RCTs) comparing IFN with no antiviral treatment were selected. Finally, we identified 11 RCTs including 1,772 patients, who met our inclusion criteria to perform this meta‐analysis. Our analysis results showed that IFN significantly decreased the overall HCC incidence in HCV‐infected patients [relative risk (RR) = 0.39; 95% confidence interval (CI) = 0.26–0.59; p = 0.000], subgroup analysis indicated that IFN decreased HCC incidence in HCV‐related cirrhotic patients evidently (RR = 0.44; 95% CI = 0.28–0.68; p = 0.000); but HCC incidence in nonresponders to initial antiviral therapy did not reduce by maintenance IFN therapy (RR = 0.96; 95% CI = 0.59–1.56; p = 0.864). Analysis results also demonstrated that IFN did not significantly affect the overall rate of HCC in HBV‐infected patients although there was a trend favoring IFN therapy (RR = 0.23; 95% CI = 0.05–1.04; p = 0.056). Besides, IFN did not improve one‐year overall survival of advanced HCC patients significantly (RR = 1.61; 95% CI = 0.96–2.69; p = 0.072); however, a quantitative analysis on local tumor progression could not be performed owing to lack of unified definitions among trials included in our study. By this meta‐analysis, we conclude that IFN therapy is effective in reducing overall HCC risk in chronic HCV‐infected patients; using it in this subpopulation seems promising, but its administration in other subpopulations still requires further exploration.

Prognostic significance of osteopontin in hepatocellular carcinoma: A meta‐analysis

Osteopontin (OPN) has been implicated in tumor development and progression for several years. However, the prognostic value of OPN overexpression in patients with hepatocellular carcinoma (HCC) remains controversial. We performed a meta‐analysis to assess the relationship between OPN overexpression and clinical outcome of HCC. A meta‐analysis of seven studies (1,158 patients) was carried out to evaluate the association between OPN and overall survival (OS) and disease‐free survival (DFS) in HCC patients. The correlation between OPN and tumor vascular invasion or other invasion‐related parameters was also assessed. Data were synthesized with random effect model of DerSimonian and Laird, hazard ratio (HR) or odds ratio (OR) with its 95% confidence interval (CI) was used as the effect size estimate. Our analysis results indicated that high OPN expression predicted poor OS (HR: 1.37, 95% CI: 1.21–1.55) and DFS (HR: 1.62, 95% CI: 1.24‐2.11) of HCC. OPN overexpression tended to be associated with the presence of tumor vascular invasion (OR: 1.93, 95% CI: 0.97–3.84) and advanced tumor grade (OR: 1.74, 95% CI: 0.95–3.18). By this study, we conclude that OPN overexpression indicates a poor prognosis for patients with HCC, it may also have predictive potential for HCC invasion and metastasis.

Effects of interferon alpha treatment on recurrence and survival after complete resection or ablation of hepatocellular carcinoma: a meta-analysis of randomized controlled trials.

Available literature on the benefit of interferon alpha (IFN‐α) as adjuvant postsurgical or ablative treatment of hepatocellular carcinoma reports discordant results. By meta‐analysis of the available data, we evaluated the effects of IFN‐α on recurrence and survival after complete resection or ablation of hepatocellular carcinoma. All randomized controlled trials comparing IFN‐α with placebo or no treatment after tumor resection or ablation were selected. Finally, 6 studies published in 2001 or later with a total of 600 patients were included in this meta‐analysis. Data on postsurgical or ablative early recurrence and 1 year survival of hepatocellular carcinoma in IFN‐α treated and untreated patients were extracted from each study. Proportions were combined, and the odds ratio (OR) with its 95% confidence interval (CI) was used as the effect size estimate. Analysis results show that IFN‐α significantly decreased postsurgical or ablative overall early recurrence (OR = 0.62; 95% CI = 0.42–0.93; p = 0.02) and improved overall 1 year survival (OR = 3.14; 95% CI = 1.79–5.52; p < 0.0001). Subgroup analyses show that IFN‐α decreased postsurgical early recurrence (OR = 0.58; 95% CI = 0.37–0.91; p = 0.02) and improved 1 year survival (OR = 3.19; 95% CI = 1.80–5.67; p < 0.0001) evidently. Subgroup analyses also show that IFN‐α reduced early recurrence after resection without pre‐resection ablation therapy (OR = 0.58; 95% CI = 0.37–0.91; p = 0.02) and improved 1 year survival (OR = 3.83; 95% CI = 2.01–7.27; p < 0.0001). These results suggest that IFN‐α treatment could significantly decrease early recurrence and improve 1 year survival of patients with hepatocellular carcinoma after complete resection or ablation. The use of IFN‐α as adjuvant postsurgical or ablative treatment seems promising but requires further study.

Expression and Correlation of Hypoxia-inducible Factor-1α, Vascular Endothelial Growth Factor and Microvessel Density in Experimental Rat Hepatocarcinogenesis

An experimental rat hepatocellular carcinoma (HCC) model was established using diethylnitrosamine and N-nitrosomorpholine to induce carcinogenesis in Sprague-Dawley rats. During hepatocarcinogenesis, seven rats were sacrificed at 0, 4, 8, 12 and 16 weeks and 10 rats were sacrificed at 20 weeks. The levels of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) protein and mRNA were examined by immunohistochemistry, Western blot and semi-quantitative reverse transcriptase-polymerase chain reaction at different stages in the rat HCC model. Twenty weeks after induction of hepatocarcinogenesis, the expression of HIF-1α and VEGF protein and mRNA significantly increased compared with week 0. Microvessel density (MVD) increased considerably once liver cancer developed. There was a significant positive correlation between MVD and both HIF-1α and VEGF, and between HIF-1α and VEGF levels. These results suggest that HIF-1α and VEGF play important roles in tumour occurrence and development during rat hepatocarcinogenesis, possibly through promoting tumour angiogenesis.

Combined Inhibitory Effects of Celecoxib and Fluvastatin on the Growth of Human Hepatocellular Carcinoma Xenografts in Nude Mice

This study was designed to investigate the in vivo growth inhibitory effects of celecoxib, a cyclo-oxygenase-2 inhibitor, and fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on the hepatocellular carcinoma (HCC) cell line, BEL-7402. Athymic nude mice implanted with BEL-7402 cells were given celecoxib and fluvastatin, either alone or in combination, and the effect of treatment on tumour growth was evaluated after 6 weeks. The combination of celecoxib and fluvastatin enhanced inhibition of tumour growth, induction of apoptosis, inhibition of tumour cell proliferation, and inhibition of tumour angiogenesis compared with either treatment alone. The combination of celecoxib and fluvastatin also increased levels of the cyclin-dependent kinase inhibitor p21Waf1/Cip1, decreased levels of p-Akt, myeloid cell leukaemia-1 (Mcl-1) and survivin protein, but had no effect on Akt protein levels in tumours. These results suggest that celecoxib combined with fluvastatin would be more efficacious for the treatment of HCC than either treatment alone and this combination of therapy warrants further research.

Prognostic value of polarized macrophages in patients with hepatocellular carcinoma after curative resection.

As the most predominant tumour‐infiltrating immune cells, tumour‐associated macrophages (TAMs) are significant for fostering tumour growth, progression and metastasis. CD68‐positive TAMs display dissimilarly polarized programmes comprising CD11c‐positive pro‐inflammatory macrophages (M1) and CD206‐positive immunosuppressive macrophages (M2). The aim of this study is to determine the prognostic significance of diametrically polarized TAMs in hepatocellular carcinoma (HCC) and their application to risk stratification of patients according to their specific prognostic values. This study included 80 consecutive patients with HCC, and we evaluated diametrically polarized functional status of macrophages by immunohistochemical staining of CD68, CD11c and CD206. Prognostic values and clinicopathologic features were assessed in these patients. High versus low CD11c‐positive TAM density (P = 0.005) and low versus high CD206‐positive TAM density (P = 0.002) were associated with better overall survival, whereas CD68‐positive TAM density had no prognostic significance (low versus high, P = 0.065). Furthermore, the presence of these positive staining macrophages did not show any prognostic significance for recurrence‐free survival (all P > 0.05). Multivariate Cox regression analysis identified CD11c‐positive and CD206‐positive TAMs as an independent prognostic factor (P < 0.001, P = 0.031, respectively). Intratumoural infiltration of diametrically polarized TAMs, a novel identified independent prognostic factor for survival in patients with HCC, could be combined with the TNM stage and the Barcelona Clinic Liver Cancer stage to improve a risk stratification system.

Protective effect of S-adenosylmethionine on hepatic ischemia-reperfusion injury during hepatectomy in HCC patients with chronic HBV infection.

BackgroundAlthough hepatectomy is often performed with the Pringle maneuver, the problem of hepatic ischemia-reperfusion injury (HIRI) can also be serious. Thus, the present study was designed to investigate the protective effect of S-adenosylmethionine (SAMe) on HIRI, especially for patients with hepatocellular carcinoma (HCC) associated with chronic hepatitis B virus (HBV) infection and cirrhosis.MethodsEighty-one HCC patients with chronic HBV infection, undergoing partial hepatectomy with inflow occlusion, were divided into three groups. In the pretreatment group (PR group, n = 26), patients were given SAMe two hours before surgery. In the post-treatment group (PO group, n = 25), patients were given SAMe six hours after surgery. And in the control group (control group, n = 30), patients received partial hepatectomy without any SAMe. All pre-, intra- and postoperative blood samples were collected to measure the plasma levels of transaminases, bilirubin and cytokines. The results were compared among the three groups.ResultsThere were no statistically significant intergroup differences observed in age, gender, hepatic inflow occlusion time and the results of liver function tests. Preoperative administration of SAMe (PR group) significantly reduced the plasma levels of alanine transaminase (ALT), aspartate transferase (AST), total bilirubin (TBIL) and direct bilirubin (DBIL) as compared to the other two groups. In the PO group, TBIL and DBIL were significantly lower than in the control group. Significant differences were also seen in IL-6 and TNF-α between the PR group and the other groups. In all groups, postoperative liver reserve function in the PR group as revealed by ICGR15 (Post ICGR15) was at its best before abdominal closure. Compared to the control group, the risk of complications and the hospital stay after surgery were significantly meliorated in the PR group. Additionally, patients with cirrhosis had a more acute rate of change in ALT and AST than non-cirrhotic patients.ConclusionsTaken together, our preliminary findings suggest that preoperative administration of SAMe is useful and safe for reducing the HIRI in partial hepatectomy, especially for HCC patients whose disease is associated with chronic HBV infection and cirrhosis.

Beneficial effects of S-adenosyl-L-methionine on post-hepatectomy residual liver function: a prospective, randomized, controlled clinical trial.

BACKGROUND/AIMS Hepatectomy is associated with high rates of postoperative liver dysfunction in patients with cirrhosis. Since S-adenosyl-L-methionine (SAMe) can be used to treat liver disease, we performed a prospective clinical trial to investigate whether it could be used after hepatectomy to benefit residual liver function. METHODOLOGY We studied 79 hepatitis-related chronic patients who underwent resection of hepatocellular carcinoma; 39 patients were randomly assigned to receive postoperative intravenous SAMe treatment, and 40 were randomly assigned to a control group. The postoperative SAMe treatment consisted of SAMe 1,000mg given intravenously for seven days. The other treatment was standardized. RESULTS At inclusion into the trial no significant differences were observed between the two groups with respect to gender, age, Child classification, preoperative liver function tests, blood loss, total time of hepatic pedicle occlusion and the extent of liver resection. The overall frequency of postoperative liver insufficiency decreased from 42% in the control group to 31% in the SAMe group, although not statistically significant (p=0.121). When the patients who underwent hepatic pedicle occlusion by Pringle’s maneuver over 15min were analyzed, the frequency of postoperative liver insufficiency (p=0.028), serum total bilirubin levels on days 5 (p=0.025) and 7 (p=0.032) preoperatively, and the maximum value of postoperative serum total bilirubin (p=0.040) were significantly greater in the control than in the SAMe group. CONCLUSIONS The results indicate that the postoperative SAMe therapy can benefit residual liver function of the patients with cirrhosis, especially in those suffering greater ischemia reperfusion injury.