Research Papers:

IL-8, GRO and MCP-1 produced by hepatocellular carcinoma microenvironment determine the migratory capacity of human bone marrow-derived mesenchymal stromal cells without affecting tumor aggressiveness

Juan Bayo _, Alejandrina Real, Esteban J. Fiore, Mariana Malvicini, Leonardo Sganga, Marcela Bolontrade, Oscar Andriani, Carolina Bizama, Cristóbal Fresno, Osvaldo Podhajcer, Elmer Fernandez, Manuel Gidekel, Guillermo Mazzolini and Mariana G. García

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Oncotarget. 2017; 8:80235-80248. https://doi.org/10.18632/oncotarget.10288

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Juan Bayo1, Alejandrina Real1, Esteban J. Fiore1, Mariana Malvicini1, Leonardo Sganga6, Marcela Bolontrade2, Oscar Andriani3, Carolina Bizama4, Cristóbal Fresno5, Osvaldo Podhajcer6, Elmer Fernandez5, Manuel Gidekel7,8, Guillermo D. Mazzolini1,3,*, Mariana G. García1,*

1Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET, Universidad Austral, Buenos Aires, Argentina

2Stem Cells Laboratory, IBYME, CONICET, Buenos Aires, Argentina

3Liver Unit, Hospital Universitario Austral, Derqui-Pilar, Argentina

4Universidad Católica, Santiago, Chile

5BioScience Data Mining Group, Catholic University of Córdoba, Córdoba, Argentina

6Fundación Instituto Leloir, CONICET, Buenos Aires, Argentina

7Universidad de la Frontera, Temuco, Chile

8Universidad Autónoma de Chile, Santiago, Chile

*Both authors share credits for senior authorship

Correspondence to:

Guillermo D. Mazzolini, email: gmazzoli@austral.edu.ar

Mariana G. García, email: mggarcia@conicet.gov.ar

Keywords: human mesenchymal stromal cells, tumor microenvironment, IL-8, human hepatocellular carcinoma, migration

Received: October 29, 2015     Accepted: May 22, 2016     Published: June 25, 2016


New therapies are needed for advanced hepatocellular carcinoma (HCC) and the use of mesenchymal stromal cells (MSCs) carrying therapeutic genes is a promising strategy. HCC produce cytokines recruiting MSCs to the tumor milieu and modifying its biological properties. Our aim was to study changes generated on human MSCs exposed to conditioned media (CM) derived from human HCC fresh samples and xenografts. All CM shared similar cytokines expression pattern including CXCL1-2-3/GRO, CCL2/MCP-1 and CXCL8/IL-8 being the latter with the highest concentration. Neutralizing and knockdown experiments of CCL2/MCP-1, CXCL8/IL-8, CXCR1 and CXCR2 reduced in vitro MSC migration of ≥20%. Simultaneous CXCR1 and CXCR2 neutralization resulted in 50% of MSC migration inhibition. MSC stimulated with CM (sMSC) from HuH7 or HC-PT-5 showed a 2-fold increase of migration towards the CM compared with unstimulated MSC (usMSC). Gene expression profile of sMSC showed ~500 genes differentially expressed compared with usMSC, being 46 genes related with cell migration and invasion. sMSC increased fibroblasts and endothelial cells chemotaxis. Finally, sMSC with HuH7 CM and then inoculated in HCC tumor bearing-mice did not modify tumor growth. In this work we characterized factors produced by HCC responsible for the changes in MSC chemotactic capacity with would have an impact on therapeutic use of MSCs for human HCC.

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