This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Primary liver cancer is one of the leading causes of cancer-related death worldwide. Our laboratory studies the role of hepatic progenitor cells (oval cells in rodents) in liver carcinogenesis. These progenitor cells are located within the ductules of the hepatic biliary tree and have been implicated in liver repair, regeneration and carcinogenesis. We previously developed a surface reactive monoclonal antibody, MAb OC.10, which recognizes an epitope shared by fetal liver ductal cells, hepatic progenitor cells, mature bile duct cells (cholangiocytes) and hepatocellular carcinomas (HCC). Preliminary data suggests that MAb OC.10 recognizes a conformation specific epitope of Hsc70 expressed at the cell surface of these cells that promotes proliferation and survival in vitro and morphogenesis of bile ducts in vivo. Here we will examine the hypothesis that MAb OC.10 activates signaling pathways that stimulates cell growth, prevents cell death and accelerates cellular maturation, activities essential for proper tissue organization and maintenance. A possibility presented in this proposal is that MAb OC.10 mimics a natural ligand that interacts with surface Hsc70/OC.10 to regulate signaling pathways critical to growth and survival. Dysregulation of surface Hsc70/OC.10 and/or its natural ligands could contribute to the development and progression of progenitor-derived liver cancers including HCC and cholangiocarcinomas originating from mature bile duct cells.
Aim 1 examines the in vitro effect of MAb OC.10 on growth and survival using the oval cell progenitor cell line CDE6, mature bile duct epithlial (BDE) cells, and the rat HCC line, H5D.
Aim 2 examines the in vivo effect of MAb OC.10 on survival and proliferation of developing bile ducts in newborn rat liver. These studies are intended to further our understanding of the role of surface Hsc70/OC.10 during liver development and hepatocarcinogenesis.
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