Abstract
1289
Delta-like protein (Dlk) is a transmembrane and secreted protein, which is known as Pref-1 and is a member of the epidermal growth factor (EGF)-like family including Notch/Delta/Serrate. Previously, we demonstrated that Dlk/Pref-1 is strongly expressed in hepatoblasts in murine fetal liver from embryonic day (ED) 10.5 to ED16.5. Its expression was downregulated in late gestation and completely disappeared in the neonatal and adult liver. The expression of Dlk/Pref-1 was also observed in a subpopulation of oval cells, which are considered as adult hepatic stem/progenitor cells, in the rat 2-acetylaminofluorene/partial hepatectomy model. These data suggest that Dlk/Pref-1 is a cell surface antigen of liver stem/progenitor cells. In the present study, we produced monoclonal antibodies against human Dlk and investigated the expression of Dlk in human liver and hepatocellular carcinoma. Northern blot analysis showed that Dlk mRNA was detected from 6 to 22 weeks in embryonic liver, but not in liver at 38 weeks and the normal adult liver. Then, we examined Dlk expression in hepatocellular carcinoma using a commercially available tissue array. Dlk was positive in 14 of 60 cases and was localized in both cytoplasm and cell membrane. The Dlk1 staining in Edmondson′s classification showed that Dlk was expressed in 20.5% of Grade II(8/39) and 46.2% of Grade III(6/13), but not in Grade I(0/8). This correlation suggests that Dlk expressed in highly malignant hepatocellular carcinoma or in undifferenciated tumor cells such as stem/progenitor cells. The Dlk immunoreactivity was independent of sex and age. The expression was not observed in liver cirrhosis. Another two monoclonal antibodies to Dlk recognizing a different epitope showed about the same results. Thus, Dlk is an oncofetal protein and may be a potential target for monoclonal antibody-based therapy for hepatocellular carcinoma.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA
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