Abstract

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.

Highlights

  • Hepatocellular carcinoma (HCC) is the 2nd cause of cancer-related death worldwide and its incidence is steadily increasing despite the advances in the understanding of hepatocarcinogenesis [1]

  • We reported that mesenchymal stromal cells (MSCs) in vitro migration toward hepatocellular carcinoma (HCC) is mediated in part by autocrine motility factor (AMF) [12], other cytokines and growth factors could be involved

  • We wondered if these factors are specific for the tumoral tissue (TT) or if they can be found in the adjacent non-tumoral liver parenchyma (AT) derived from the same patients with HCC; primary biliary cirrhosis (PT-7) or cryptogenic cirrhosis (PT-12)

Read more

Summary

Introduction

Hepatocellular carcinoma (HCC) is the 2nd cause of cancer-related death worldwide and its incidence is steadily increasing despite the advances in the understanding of hepatocarcinogenesis [1]. Most patients with HCC are diagnosed at advanced stages when curative options such as liver resection, transplantation or radiofrequency ablation are not feasible. A multikinase inhibitor drug, is the standard of care for patients with advanced HCC, median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group [3]. Development of new therapeutic approaches is required for HCC. In this scenario, cells armed with antitumor genes or carrying oncolytic viruses have been be proposed as therapeutic tools in several preclinical models [4]. Mesenchymal stromal cells (MSCs) have shown the capability to migrate to tumors in vivo making them a promising therapeutic strategy in cancer therapy

Objectives
Methods
Results
Conclusion
Full Text
Paper version not known

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.