Clinical Significance of Thrombospondin 1 Expression in Hepatocellular Carcinoma

Abstract

Purpose: Thrombospondin 1 (THBS 1) is a matricellular protein capable of modulating angiogenesis. However, the actual role of THBS 1 in angiogenesis and tumor progression remains controversial. Hepatocellular carcinoma (HCC) is a hypervascular tumor characterized by neovascularization. The significance of THBS 1 in HCC remains unknown. In this study, the significance of THBS 1 in HCC was evaluated by correlating its expression with clinicopathological data. The possible role of THBS 1 in the angiogenesis of HCC was also studied by correlating its expression with vascular endothelial growth factor (VEGF) expression.Experimental Design: Sixty HCC patients were recruited in this study. THBS 1 and VEGF protein expression in tumorous livers were localized by immunohistochemical staining and quantified by ELISA. THBS 1 mRNA was quantified by quantitative reverse transcription-PCR.Results: Immunohistochemical staining of THBS 1 was positive in HCC cells in 51.7% of patients and in stromal cells in 65% of patients. Tumor THBS 1 protein level was significantly correlated with its mRNA expression (P ‫؍‬ 0.001) and was significantly correlated with tumor VEGF protein levels (P ‫؍‬ 0.001). Its expression was significantly associated with the presence of venous invasion (P ‫؍‬ 0.008) and advanced tumor stage (P ‫؍‬ 0.049). High THBS 1 expression was also a prognostic marker of poor survival in HCC patients.Conclusions: This study shows that high expression of THBS 1 is associated with tumor invasiveness and progression in HCC. THBS 1 appears to be a proangiogenic factor that stimulates angiogenesis in HCC in view of its positive correlation with VEGF expression.

Expression of ADAMTS-8, a secreted protease with antiangiogenic properties, is downregulated in brain tumours

“…It has been shown that continuous expression of the antiangiogenic TSP1 in brain tumours can induce a more aggressive angiogenic phenotype by inducing VEGF expression (Filleur et al, 2001;Filleur et al, 2003). In hepatocellular carcinoma, TSP-1 protein expression (in vivo) is significantly associated with tumour invasiveness and progression (Poon et al, 2004). Furthermore, in GBM, it has been demonstrated that tumour perfusion was the same in TSP-1 transfected tumours and controls, and that although tumour growth in vivo is slowed by TSP-1 overexpression, tumours still reach a large size (300 mm 3 ) (Kragh et al, 2002).…”

“…Moreover, like VEGF, the expression of TSP1 was coincident with a vascular proliferation in nine out of 10 tumours. In hepatocellular carcinoma there is a significant relationship between tumour TSP1 levels and venous invasion even in patients with high and low tumour VEGF levels (Poon et al, 2004). It is thought that TSP1 expression in brain tumours is influenced by several factors including hypoxia, cell density (in vitro) and cell type (Tenan et al, 2000;Kawataki et al, 2000;Laderoute et al, 2000;Filleur et al, 2001;Naganuma et al, 2003).…”

Regulation of thrombospondin-1 by natural and synthetic progestins in human breast cancer cells

“…For example, TSP-1 is constitutively expressed at a high level in fast-growing aggressive MDA-MB-231 human breast cancer cells (Uray et al 2004). However, TSP-1 may also have context-and tissue-dependent roles, and may stimulate wound healing, cell proliferation, and adhesion of some but not all human tumor cells (Incardona et al 1995, DiPietro et al 1996, Wang et al 1996a,b, Patel et al 1997, Tobita et al 2002, Wang-Rodriguez et al 2003, Poon et al 2004, Fontana et al 2005.…”

The role of angiocidin in sarcomas

“…9,12,13 The protumor effects of angiocidin are the result of highaffinity binding interactions with extracellular matrix proteins including thrombospondin-1 (TSP-1), a matrix protein produced in tumors by activated stromal cells of mesenchymal origin. 14,15 These angiocidin-stromal protein binding interactions lead to an up-regulation in gelatinase expression and matrix remodeling, critical steps in the metastatic cascade. 9,16 We have recently synthesized 2 angiocidin-inhibitory peptides that block the activity of angiocidin through competitive inhibition of its stromal protein-binding interactions.…”

“…Preliminary data have demonstrated that these peptides are excellent inhibitors of angiogenesis and tumor cell invasion in vitro. 9,10,14 The first of these peptides, a 6-amino acid residue peptide with the sequence CSVTCG, blocks the binding of angiocidin to TSP-1. The second peptide, a 25-amino acid sequence derived from the TSP-1 binding site within the angiocidin molecule, also competitively inhibits the binding of angiocidin to TSP-1.…”