INVESTIGADORES
ATORRASAGASTI FERNANDEZ Maria Catalina
congresos y reuniones científicas
Título:
ANTITUMORAL EFFECTS OF HYALURONIC ACID INHIBITION BY 4-METHYLUMBELLIFERONE (4MU) IN AN ORTHOTOPIC HEPATOCELLULAR CARCINOMA MODEL IN MICE
Autor/es:
ALANIZ L; PICCIONI F; RIZZO MM; GARCIA MG; RODRIGUEZ A; MALVICINI M; AQUINO JB; ATORRASAGASTI C; BAYO F; SILVA M; MAZZOLINI G
Reunión:
Congreso; AASLD Liver Meeting 2010; 2010
Institución organizadora:
American Association for the Study of Liver Diseases (AASLD)
Resumen:
Introduction: Liver fibrosis is characterized by an excessive
accumulation of extracellular matrix (ECM) components including
hyaluronic acid (HA) that leads to progressive liver failure.
In addition, cirrhosis is considered a pre-neoplastic disease for
hepatocellular carcinoma (HCC). Altered HA deposition and
composition has the ability to modulates tumor aggressiveness
but its role in HCC is unknown. 4-Methylumbelliferone (4-MU)
is a HA synthesis inhibitor with reported anticancer properties.
Aim: To analyze the effects of HA inhibition by 4MU on HCC
growth and fibrogenesis. Methods: We used an orthotopic in
vivo model of HCC (Hepa129 cell line syngeneic with C3H/He
mice) established in fibrotic livers. Fibrosis was induced by i.p.
administration of thioacetamide (TAA) for 4 weeks. 4MU treatment
was started 2 days before HCC cell implantation and
continued up to 2 weeks. Fibrosis degree was quantified by
applying Ishak score system. Hepatic HA levels were analyzed
by histological staining using a HA-binding protein and systemic
HA by ELISA. Surface markers (CD11c, CMH-II, CD40,
CD80, CD86) were analyzed in hepatic dendritic cells (DCs)
by flow cytometry. Antitumoral effects of 4MU were analyzed
by measuring the main hepatic tumor mass and its satellites.
Proliferation (3H-thymidine) and apoptosis (anexin V) assays
were performed to analyze a direct effect of 4MU on tumor
cells. Results: Hepa129 cells expressed CD44 and have the
ability to bind and to produce HA. In vitro results showed that
treatment of tumor cells with 4MU (1mM, 5mM) significantly
reduced HCC cell proliferation and induced apoptosis (26.2%
for 5mM) while non-tumoral cells were unaffected. 4MU therapy
reduced hepatic and systemic levels of HA. Macroscopic
tumor size was similar in mice treated or not with 4MU but
microscopic analysis showed important areas of necrosis only
in treated animals. In addition, the number of tumor satellites
was found 2-3-folds reduced in 4MU-treated mice. No signs of
toxicity were observed and aminotransferases were not modified
after 4MU treatment. We observed that untreated animals
developed a F4-F5 fibrosis degree while mice treated with 4MU
showed a reduced amount (F3). In addition, 4MU therapy
improved maturation of intra-hepatic DCs (MHC-II and CD86),
decreased IL-10 production (218 vs 86 pg/ml) and significantly
enhanced MLR activity. In conclusion: These results suggest a
role for 4-MU as anticancer agent in HCC. The potential antitumoral
mechanisms of 4MU in this model could involve: i) inhibition
of fibrogenesis, ii) stimulation of the immune system by
dendritic cells activation, and iii) a direct antitumoral effect.