Glypican‐3 expression is correlated with poor prognosis in hepatocellular carcinoma

Abstract

The relationship between overexpression of glypican (GPC)-3 that is specific for hepatocellular carcinoma (HCC) and the prognosis has not yet been clarified. We attempted to determine the expression profile of GPC3 in association with the clinicopathological factors by immunohistochemical analysis in HCC patients and investigated the potential prognostic value of GPC3 by comparing the survival rate between the GPC3-positive and GPC3-negative HCC patients. Primary HCC tissue samples (n = 107) obtained from patients who had undergone hepatectomy between 2000 and 2001 were analyzed. GPC3 expression was less frequently observed in welldifferentiated HCC than in moderately and poorly differentiated HCC, the difference in the frequency being statistically significant. GPC3-positive HCC patients had a significantly lower 5-year survival rate than the GPC3-negative HCC patients (54.5 vs 87.7%, P = 0.031). Among 80 of the 107 (74.6%) patients with initial treatment who underwent hepatectomy, none of GPC3-negative HCC patients (n = 16, 20.0%) died during the follow-up period. No deaths were noted in the GPC3-negative HCC patients among the 71 (88.7%) patients with moderately and poorly differentiated HCC. Multivariate analysis identified GPC3 expression (P = 0.034) as an independent prognostic factor for the overall survival. We showed that GPC3 expression is correlated with a poor prognosis in HCC patients. (Cancer Sci 2009; 100: 1403-1407) H epatocellular carcinoma (HCC) is one of the most common malignancies and is ranked as the third most common cause of cancer-related death worldwide. HCC is generally associated with a poor prognosis, the 5-year survival rate after surgery has been reported to be as low as 25-39%, and systemic therapy with cytotoxic agents provides only marginal benefit.(1) Even in those patients in whom the tumor has been successfully removed, the 2-year recurrence rate can be as high as 50%. (2,3) Several clinicopathological factors including poor levels of differentiation of the cancer cells, large size of the tumor, portal venous invasion, and intrahepatic metastasis have been shown to contribute to the poor prognosis in patients of HCC. Despite the critical need for better methods for the diagnosis and treatment of HCC, the mechanisms underlying the development of HCC remain unclear.Glypican (GPC)-3 was discovered as a potential serological and histochemical marker that is specific for HCC. GPC3 is a member of the glypican family and belongs to a group of heparan sulfate proteoglycans bound to the outer surface of the cell membrane through a glycosylphosphatidylinositol anchor. (4) In mammals, this family comprises six members, GPC1 to GPC6. GPC are released from the cell surface by a lipase called Notum to regulate the signaling of Wnts, Hedgehogs, fibroblast growth factors, and bone morphogenetic proteins.(5-9) Depending on the context, their functions exerted may either be stimulatory or inhibitory through these pathways. GPC3 has been detected in the placenta and fetal liver, but not in othe...

Novel Therapeutic Targets for Hepatocellular Carcinoma Treatment

“…Consistent with the high GPC3 protein expression found in clinical samples, numerous HCC cell lines have high expression level of GPC3 (Midorikawa et al, 2003). In addition, GPC3 expression is correlated with the prognosis of HCC, where GPC3-positive HCC patients have a significantly lower 5-year survival rate than patients who are GPC3-negative (Shirakawa et al, 2009). …”

Morphophenotypic changes in human multistep hepatocarcinogenesis with translational implications

“…This is in keeping with the biology of the molecule, which has been associated to tumor dedifferentiation, unfavorable prognosis and recurrence [21] [22].…”

Therapeutically targeting glypican-2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma

“…There has been evidence that GPC3 expression or other glypicans (e.g., GPC1) has been correlated with poor prognosis in hepatocellular carcinoma or other types of cancer (30)(31)(32)(33). To analyze a possible correlation between GPC2 mRNA levels and survival of patients with neuroblastoma, we used the R2 Genomics Analysis and Visualization Platform.…”