Antibody therapy against granulin-epithelin precursor sensitizes liver cancer to chemotherapy

Abstract

The novel growth factor granulin-epithelin precursor (GEP, also named progranulin, acrogranin, or PC-derived growth factor) has shown to be upregulated in breast, ovary, prostate, liver and various human cancers. Our group has shown that GEP associated with chemo-resistance, recurrence and cancer stem cell properties in liver cancer [Gastroenterology 2011 and PLoS One 2011]. In the current study, we demonstrated that, both in vivo and in vitro, liver cancer cells that survived after chemotherapeutic agents demonstrated up-regulation of hepatic cancer stem cell marker CD133/GEP/ABCB5, and enhanced cancer stem cell properties, including colony formation and spheroid formation abilities. Importantly, combination of GEP antibody therapy and chemotherapy reversed the phenotypes induced by chemotherapy alone in the liver cancer cells and also the chemo-resistant subpopulations. Notably, combination of GEP antibody and cisplatin resulted in the eradication of all established intrahepatic human xenografts. This preclinical study demonstrated that combination treatment has the potential to be effective therapeutic regimen for GEP positive cancers.