Increased endostatin/collagen XVIII expression correlates with elevated VEGF level and poor prognosis in hepatocellular carcinoma

Abstract

Liver is the primary source for collagen XVIII, the precursor of angiogenesis inhibitor, endostatin. However, the role of endostatin/collagen XVIII expression during liver carcinogenesis remains elusive. Therefore, we studied its expression in five hepatoma cell lines and 105 hepatocellular carcinoma specimens. The poorly differentiated hepatoma cell lines exhibited increased endostatin/collagen XVIII levels compared with the well-differentiated ones. In hepatoma tissues, endostatin/collagen XVIII expression was detected in various types of liver cells and was significantly stronger in adjacent nontumor tissues than that in tumors (Po0.001). Endostatin/collagen XVIII expression in nontumor tissues correlated with tumor stages (P ¼ 0.014) and expression of vascular endothelial growth factor (P ¼ 0.007), but not the stages of hepatic fibrosis (P40.05). Kaplan-Meier analysis showed that patients with higher endostatin/collagen XVIII expression had significantly shorter overall survival (P ¼ 0.011) and disease-free survival (P ¼ 0.0034). Moreover, endostatin/collagen XVIII level was an independent prognostic factor for tumor recurrence (P ¼ 0.034) by multivariate analysis. In conclusion, increased endostatin/collagen XVIII expression correlated with hepatoma progression and predicted poor prognosis for patients with hepatocellular carcinoma.

Proteoglycans in normal physiology and carcinogenesis

“…Состав и структура ГСПГ подвергаются значитель-ным изменениям в опухолях яичников и молочной железы человека [46,47]; экспрессия синдекана 1, де-корина и люмикана значительно изменяется в опухолях молочной железы [48], глипиканы вовлечены в процесс канцерогенеза в тканях легкого [49] и поджелудочной железы [50]; синдеканы участвуют в патогенезе лимфомы Ходжкина [51]; экспрессия перлекана и серглицина значительно снижается в клетках лимфомы Беркитта [52]; уровень экспрессии коллагена 18 ассоциируется с прогрессированием и прогнозом гепатоцеллюлярной карциномы [53], а в опухолях прямой кишки проис-ходит одновременное снижение уровней экспрессии декорина и перлекана (в 2 раза) и повышение экспрес-сии бигликана и версикана (в 6 и 3 раза соответственно) [54]. ПГ глипиканы, агрин, версикан и декорин при-нимают активное участие в развитии злокачественных [55].…”

Prognostic relevance of collagen XVIII expression in metastatic gastric carcinoma

“…Phase II clinical trials using recombinant endostatin for treatment of advanced neuroendocrine tumors showed 80% of stable disease, although no patient displayed partial or complete response, according to the WHO criteria [9]. Elevated serum levels of endostatin are associated with poor outcome in several cancers [10][11][12][13][14][15][16][17][18]. Endogenous serum level of endostatin may reflect counteractions with active angiogenesis in tumor progression.…”

Proteoglycans in Chronic Liver Disease and Hepatocellular Carcinoma: An Update

“…Controversy exists, on the other hand, as to whether collagen XVIII levels in tumor hepatocytes increase or decrease with HCC progression. While some authors demonstrate that high tumoral expression of collagen XVIII correlates with increased VEGF activity and poor prognosis (Hu et al, 2005), others argue that, as it can be expected of an angiogenesis suppressor, collagen XVIII becomes downregulated by HCC cells in parallel with increasing tumor size, microvessel density, and clinical aggressiveness (Musso et al, 2001b). Since long collagen XVIII variants are regulated by liver-specific transcription factors, it has been suggested that their downregulation may reflect the loss of hepatocytic phenotype.…”