Transforming growth factor (TGF)-β suppresses early hepatocellular carcinoma (HCC) development but triggers pro-oncogenic abilities at later stages. Recent data suggest that the receptor tyrosine kinase Axl causes a TGF-β switch toward dedifferentiation and invasion of HCC cells. Here, we analyzed two human cellular HCC models with opposing phenotypes in response to TGF-β. Both HCC models showed reduced proliferation and clonogenic growth behavior following TGF-β stimulation, although they exhibited differences in chemosensitivity and migratory abilities, suggesting that HCC cells evade traits of anti-oncogenic TGF-β. Transcriptome profiling revealed differential regulation of the chemokine CXCL5, which positively correlated with TGF-β expression in HCC patients. The expression and secretion of CXCL5 was dependent on Axl expression, suggesting that CXCL5 is a TGF-β target gene collaborating with Axl signaling. Loss of either TGF-β or Axl signaling abrogated CXCL5-dependent attraction of neutrophils. In mice, tumor formation of transplanted HCC cells relied on CXCL5 expression. In HCC patients, high levels of Axl and CXCL5 correlated with advanced tumor stages, recruitment of neutrophils into HCC tissue, and reduced survival. Conclusion: The synergy of TGF-β and Axl induces CXCL5 secretion, causing the infiltration of neutrophils into HCC tissue. Intervention with TGF-β/Axl/CXCL5 signaling may be an effective therapeutic strategy to combat HCC progression in TGF-β-positive patients.
Abstract Introduction Hepatocellular carcinoma (HCC) is the second most common cause of cancer‐related death worldwide with increasing incidence. Effective antiviral treatment for chronic hepatitis C (CHC) became available in the last 7 years but despite the WHO Hepatitis elimination targets, they are not universally available today in all regions for all the patients, indicating still a bleak outlook for CHC‐associated HCC in the next decades. Aim To assess the HCC incidence in relation to interferon (IFN)‐based antiviral treatment response and baseline characteristics of a large cohort of chronic hepatitis C (CHC) patients from a single institution. Methods We retrospectively collected data of CHC patients, who were diagnosed between 1989 and 2011 and treated at the AKH‐University Hospital of Vienna before the introduction of direct‐acting antiviral (DAA) only therapy. We analysed the HCC incidence in patients with a sustained virological response (SVR) and without SVR according to the patients' baseline characteristics. Results Our study included 2134 patients, who were treated or not treated with IFN‐based antiviral treatment and had long‐term follow‐up available. The overall HCC incidence in this cohort was 6.2% (132 HCC cases over a median follow‐up period of 9 years). According to the baseline fibrosis stage, the overall HCC incidence was: 1.1% in patients with baseline fibrosis stage F0‐2, 8.2% in F3 and 20.6% in F4 patients. The HCC incidence was significantly higher in non‐SVR and no‐treatment group as compared with SVR patients: 12.4% vs 1.9%, P < .0001, 7.3% vs 1.9%, P < .0001. In multivariate analysis, lower platelet count (odds ratio‐OR = ‐0.1, 95% CI: 0.15‐0.63), for the SVR group and presence of cirrhosis (OR = 3.6, 95% CI: 1.59‐8.17), ALBI grade >=2 (OR = 2.3, 95% CI: 1.0‐5.3) for the non‐SVR group were independently associated with HCC occurrence. For the group of patients with no treatment, the only predictor for HCC was high baseline alpha‐fetoprotein values (OR = 10.2, 95% CI: 2.2‐47.9). Conclusion The achievement of SVR significantly reduces the risk for HCC occurrence during long‐term follow‐up. However, the risk remains high in successfully treated patients with low platelet count and in patients who did not achieve SVR with more advanced liver disease. These risk factors should be considered in decision‐making of HCC surveillance in this settling.
Hypothyroidism has recently been proposed as predisposing factor for HCC development. However, the role of thyroid hormones (TH) in established HCC is largely unclear. We investigated the impact of TH on clinical characteristics and prognosis of HCC patients.Of 838 patients diagnosed with nonsurgical HCC at the Division of Gastroenterology and Hepatology/Medical University of Vienna between 1992 and 2012, 667 patients fulfilled the inclusion criteria. The associations of thyroid function tests with patient, liver, and tumor characteristics as well as their impact on overall survival (OS) were investigated.Thyroid hormone substitution was more often observed in patients with low thyroid-stimulating hormone (TSH) concentration and in patients with elevated free tetraiodthyronine (fT4). Patients with high TSH (>3.77uU/ml) concentrations had larger tumors, while the opposite was true for patients with low TSH (<0.44uU/ml) concentrations. Subjects with elevated fT4 (>1.66ng/dl) were more likely to have elevated CRP. While TSH was only associated with OS in univariate analysis (≤1.7 vs. >1.7uU/ml, median OS (95%CI), 12.3 (8.9-15.7 months) vs. 7.3 months (5.4-9.2 months); p = 0.003), fT4 (≤1.66 vs. >1.66ng/dl, median OS (95%CI), 10.6 (7.5-13.6 months) vs. 3.3 months (2.2-4.3 months); p = 0.007) remained an independent prognostic factor for OS (HR (95%CI) for fT4>1.66ng/dl, 2.1 (1.3-3.3); p = 0.002) in multivariate analysis.TSH and fT4 were associated with prognostic factors of HCC (i.e., tumor size, CRP level). Elevated fT4 concentrations were independently associated with poor prognosis in HCC. Further studies are needed to characterize the role of TH in HCC in detail.
We thank Han and co-workers for their commentary1 on our manuscript dealing with the Austrian experience with sorafenib in a real-life setting.2 In fact, clinical cirrhosis stage, being highly significant on univariate analysis, was included in the multivariate analysis in the original version of the manuscript submitted, but was no longer significant on multivariate analysis (P = 0.474). It was excluded from the final version of the manuscript because one of the reviewers thought that it could be a covariate with Child–Pugh stage, and should therefore be removed. With regard to an increased bleeding risk, we disagree with Han et al. Bleeding risk was not increased in the randomised controlled trials of sorafenib for HCC compared with placebo,3, 4 and as the risk of bleeding in any cirrhotic increases with more advanced stage liver disease and portal hypertension, the minimally increased risk of bleeding observed in the uncontrolled trials listed in their table 1 could be entirely due to the more advanced stage liver disease, rather than treatment with sorafenib. We agree that vascular invasion, Child–Pugh stage, and AFP are important prognostic factors for HCC, as we included them in the univariate, as well as multivariate analysis, although only Child–Pugh stage remained significant. Bilirubin and albumin are components of the Child–Pugh score and were therefore not analysed separately, whereas all other factors mentioned by Han et al., except tumour burden, were included in the analysis. However, neither TNM-stage nor extrahepatic spread, which are surrogate markers of tumour burden, was significantly associated with outcome of univariate analysis. For this reason, we believe that our analyses give an accurate account of relevant prognostic factors for patients undergoing treatment with sorafenib. Declaration of personal and funding interests: None.
Das hepatozelluläre Karzinom (HCC) steht in der Häufigkeit bei den Karzinomen weltweit an sechster und bei der krebsbedingten Mortalität an dritter Stelle. Derzeit ist die „Barcelona Clinic Liver Cancer” Klassifikation (BCLC) das am häufigsten genutzte System für Staging und Prognosebestimmung beim HCC. Ziel der vorliegenden Arbeit war es, einen einfachen Score zu entwickeln, um bei Patienten mit HCC das Überleben vorherzusagen.
