Possible contribution of circulating transforming growth factor‐β1 to immunity and prognosis in unresectable hepatocellular carcinoma

Abstract

Transforming growth factor-beta1 (TGF-beta1) has been implicated in tumor progression. The relationship of this cytokine as measured in plasma to anti-tumor immunity and prognosis was investigated. This study consisted of 70 consecutive patients with unresectable hepatocellular carcinoma (HCC) (median age, 65 years). Forty-four healthy age-matched subjects and 32 patients with cirrhosis but no carcinoma served as controls. Patients with HCC were divided into those with plasma TGF-beta1 concentrations above (group A, n=21) or below (group B, n=49) 10 ng/ml (the mean concentration+2SD in the concentrations of the controls with cirrhosis was 8.7 ng/ml). Age, gender, Child-Pugh grade, and tumor stage distributions were similar in groups A and B. Considering all tumor stages together and individually, group A had a significantly shorter survival (median for all stages, 2 months) than group B (median for all stages, 10 months; P<0.01, generalized Wilcoxon's test). Groups A and B had significantly shorter survival than controls with cirrhosis (P<0.001 for each). Lymphokine-activated killer (LAK) activity in group A was significantly lower than that in group B (P<0.001). Natural killer (NK) activity in group A was also significantly lower than that in group B (P<0.05). Plasma TGF-beta1 concentration was a significant predictor of survival by Cox's proportional-hazards regression analysis (multivariate analysis, P<0.01). LAK and NK activities were also weak but significant predictors (P<0.05 and <0.05, respectively). These data suggest that plasma TGF-beta1 concentration is a predictor of outcome of patients with unresectable HCC. Circulating TGF-beta1 supposedly contributes to the suppression of anti-tumor immunity in the advanced disease.

Dysregulation of growth factor signaling in human hepatocellular carcinoma

“…These data may explain that TGFb serum and urine levels are increased in patients with HCC (Tsai et al, 1997;Kim et al, 2000). High TGFb levels correlate with decreased median survival and have even been proposed as a serologic marker to support detection of HCCs (Song et al, 2002;Okumoto et al, 2004).…”

p53‐induced RING‐H2 protein, a novel marker for poor survival in hepatocellular carcinoma after hepatic resection

“…Although the identification of many prognostic markers of HCC, such as vascular endothelial growth factor, osteopontin, and transforming growth factor-b, resulted from extensive clinical as well as basic research efforts, the available markers still are not able to accurately predict the survival of patients with HCC. [9][10][11] Thus, exploring new prognosis markers of HCC is of great importance.…”

New Molecular Biomarkers Candidates for the Development of Multiparametric Platforms for Hepatocellular Carcinoma Diagnosis, Prognosis and Personalised Therapy

“…EGFR strongly reflects the biological aggressiveness of HCC and might be considered a possible prognostic factor of reduced survival of HCC patients. Suzuki et al, 1996;Mise et al, 1996;Li et al, 1999;Qin &Tang, 2004;Mann et al, 2007;Malaguarnera et al, 2010 Transforming Growth Factor 1 (TGF-1) Tissue/Serum HCC progression; prognostic factor for reduced survival in patients with HCC Ito et al, 1990;Grizzi et al, 2007;Mann et al, 2007;Okumoto et al, 2004;Tsai et al, 1997 Hepatocyte Growth Factor (HGF) Serum HCC prognosis; predictive of HCC recurrence and metastasis after hepatic resection Breuhan et al, 2006;Yamagamim et al, 2002;Wu et al, 2006;Malaguarnera et al, 2010 Epidermal Growth Factor Receptor (EGFR) Tissue HCC prognosis; predictive of reduced survival of HCC patients Daveau et al, 2003;Mann et al, 2007 p53 In the last years, some new candidates have been proposed as potential biological markers of HCC insurgence, recurrence and metastasis, that could be therefore useful for early diagnosis of this malignancy and improve patient's prognosis. In particular we focus on our recently published data that suggested an involvement of Nerve Growth Factor (NGF) in liver tissue remodelling processes and HCC progression, describing the correlation between NGF tissue distribution and serum levels in patients suffering from cirrhosis and/or HCC (Rasi et al, 2007).…”

“…Moreover, TGF-1 serum levels are reported to be increased in HCC patients (Grizzi et al, 2007). TGF-1 has been proposed as a possible prognostic factor for reduced survival in patients with HCC (Mann et al, 2007;Okumoto et al, 2004;Tsai et al, 1997) Hepatocyte growth factor (HGF) is a cytokine with a wide range of effects, including liver regeneration for protection and/or repair of different organs, including kidney, lung, and cardiovascular system (Birchmeier et al, 1998). It promotes proliferation in normal hepatocyte and in hepatocellular carcinoma cells (Breuhan et al, 2006) through expression of its high-affinity tyrosine kinase receptor (Met/HGF-R).…”