Antibody Against Granulin-Epithelin Precursor Sensitizes Hepatocellular Carcinoma to Chemotherapeutic Agents
Menée sur des lignées cellulaires de carcinome hépatocellulaire et à l'aide de xénogreffes, cette étude évalue l'activité antitumorale d'un anticorps ciblant le précurseur de la granuline-épithéline en combinaison avec du cisplatine
Granulin-epithelin precursor (GEP) over-expression has been shown in many cancers with functional role on growth, and recently on regulating chemo-resistance and cancer stem cell properties. Here, we investigate the combined effect of GEP antibody and chemotherapeutic agent. Combination therapy was compared with monotherapy using hepatocellular carcinoma (HCC) cells in vitro and orthotopic liver tumor models in vivo. CD133 and related hepatic cancer stem cell marker expressions were investigated by flow cytometry. Antiproliferative and apoptotic effects, and signaling mechanisms were examined by immunohistochemistry, flow cytometry, and western blot. Secretary GEP levels in the serum and culture supernatant samples were measured by ELISA. We demonstrated that HCC cells that survived under chemo-therapeutic agents showed up-regulation of hepatic cancer stem cell (CSC) markers CD133/GEP/ABCB5, and enhanced colony and spheroid formation abilities. Importantly, GEP antibody sensitized HCC cells to the apoptosis induced by chemotherapy for both HCC cell lines and the chemo-resistant subpopulations, and counteracted the chemotherapy-induced GEP/ABCB5 expressions and Akt/Bcl-2 signaling. In human HCC orthotopic xenograft models, GEP antibody treatment alone consistently capable to inhibit the tumor growth. Notably, combination of GEP antibody with high dose of cisplatin resulted in the eradication of all established intrahepatic tumor in three weeks. This preclinical study demonstrated that GEP antibody sensitized HCC cells to apoptosis induced by chemotherapeutic agents. Combination treatment with GEP antibody and chemotherapeutic agent has the potential to be effective therapeutic regimen for GEP-expressing cancers.
http://mct.aacrjournals.org/content/early/2014/09/24/1535-7163.MCT-14-0012.abstract