4-Methylumbelliferone improves Antitumor Immune Response Induced By Interleukin-12 By Decreasing the Expression of CD47 on Cancer Stem Cells in Mice with Advanced Hepatocellular Carcinoma

RODRIGUEZ MM; FIORE E; BAYO FINA JM; ATORRASAGASTI C; GARCIA M; ONORATO A; DOMINGUEZ L; MALVICINI M; MAZZOLINI G

San Francisco

Congreso; The Liver Meeting 2018; 2018

Background: The tumor microenvironment (TME) consists in a complex interaction between different cellular components, including tumor cells and cancer stem cells (CSCs), with the associated stroma; such interplay sustains tumor growth and dissemination. Several experimental approaches for cancer therapy are focused on TME remodeling resulting in increased antitumor effects. This is of particular importance for hepatocellular carcinoma (HCC) which incidence and mortality are increasing steadily in the lasts years. We previously demonstrated that the hyaluronan synthesis inhibitor 4-methylumbelliferone (4Mu) induces antitumor activity in HCC.Methods: We used 4Mu in combination with gene therapy of interleukin 12 mediated by an adenovirus (AdIL-12) in a murine model of hepatocellular carcinoma (HCC) associated with advanced fibrosis induced by thioacetamide (TAA). Male C3H mice received an intrahepatic injection of 1,25x10e5 Hepa 129 cells (day 0) after 4 weeks of TAA administration (200 mg/kg). On day 5 mice were distributed in experimental groups (n=8/group): saline; 4Mu 200 mg/Kg, drinking water (day 5); AdIL-12 1x10e9 DICT50/ml, i.v (day 9) and 4Mu + AdIL-12. Antitumoral efficacy and antitumoral immune response against HCC were monitored. We also evaluated the expression of CSCs markers by qPCR and flow cytometry.Results: We observed tumor growth inhibition, tumor satellites reduction and improved animal survival (p