Chemotactic pathways involved in mesenchymal stromal cell recruitment towards hepatocellular carcinoma and liver fibrosis. Rol for autocrine motility factor, IL-8, GRO and MCP-1.

GARCIA MG

Congreso; Reunión anual conjunta de SAIC, SAI, SAFE, NANOMEDAR Y AACYTAL.; 2016

Hepatocellular carcinoma (HCC) is the 2nd cause of cancer-related death worldwide and the majority of patients are diagnosed at advanced stages. New therapies are needed and those focused on the delivery therapeutic genes by mesenchymal stromal cells (MSC) are gaining interest. Our aim was to investigate the chemotactic pathways involved in MSC recruitment towards HCC. We have demonstrated that soluble factors present in the conditioned media (CM) derived from HCC tumors induced in vitro and in vivo MSC chemotaxis towards the tumor. Autocrine Motility Factor (AMF), a cytokine released by HCC cells, has been previously described to stimulate tumor cell motility. In vitro chemotactic assays demonstrated that MSCs migrated to recombinant AMF (rAMF) and AMF blockage with a specific antibody reduced their migration toward HCC CM. Moreover, MSCs-primed with rAMF showed increased in vitro and in vivo migration towards HCC. Recently, we have demonstrated that HCC CM shared the presence ofGRO, MCP-1 and IL-8, being the latter with the highest concentration. Blocking and knockdown experiments of MCP-1, IL-8, CXCR1 and CXCR2 reduced >20 % MSC migration. Simultaneous blockage of AMF, CXCR1 and CXCR2 resulted in >60% inhibition of MSC migration to HCC. Stimulation of MSCs with HCC CM (sMSC) resulted in increased in vitro migration and differential expression of ~500 genes, being 46 genes related with cell migration and invasion. Factors produced by sMSC were able to increase fibroblasts, mononuclear and endothelial cells chemotaxis in comparison to factors produced by unstimulated MSCs. We also demonstrated that injection of MSCs, primed with AMF or with HCC CM, in tumor bearing- mice did not modify tumor growth. We conclude that AMF, IL-8, GRO and MCP-1 play a critical role in MSC recruitment to HCC, and stimulation of MSC with rAMF or HCC CM increased MSC homing to HCC, thus becoming a promising strategy to improve their therapeutic efficacy.