Journal Article

Increased Migration of Human Mesenchymal Stromal Cells by Autocrine Motility Factor (AMF) Resulted in Enhanced Recruitment towards Hepatocellular Carcinoma

Mazzolini, Guillermo, Bolontrade, Marcela, Garcia, Mariana G., Andriani, Oscar, Alaniz, Laura, Rizzo, Manglio, Aquino, Jorge B., Podhajcer, Osvaldo, Piccioni, Flavia, Bayo, Juan, Malvicini, Mariana, Fiore, Esteban, Peixoto, Estanislao

2014

Overview

Several reports described the migration of human mesenchymal stromal cells (MSCs) towards tumor-released factors. Autocrine motility factor (AMF) is produced by several tumors including hepatocellular carcinoma (HCC). The aim of this study was to analyze AMF involvement on MSC migration towards human HCC. Production of AMF by HCC tumors was evaluated by western analysis. The effects of AMF on MSCs from different sources (bone marrow, adipose tissue and perivascular cells from umbilical cord) were analyzed using in vitro migration assay; metalloproteinase 2 (MMP2) activity and expression of critical genes were studied by zymography and qRT-PCR, respectively. To assess AMF involvement on the in vivo MSC migration, noninvasive fluorescence imaging was performed. To test the effect of AMF-primed MSCs on tumor development, in vitro proliferation and spheroids growth and in vivo tumor volume were evaluated. AMF produced by HCC was found to induce migration of different MSCs in vitro and to enhance their MMP2 activity. Stimulation of MSCs with recombinant AMF (rAMF) also induced the in vitro adhesion to endothelial cells in coincidence with changes in the expression levels of MMP3, AMF receptor, caveolin-1, and -2 and GDI-2. Importantly, stimulation of MSCs with rAMF increased the in vivo migration of MSCs towards experimental HCC tumors. AMF-priming of MSCs did not induce a pro-tumorigenic effect on HCC cells neither in vivo nor in vitro. AMF plays a role in MSC recruitment towards HCC. However, its ability to increase MSC migration to HCC for therapeutic purposes merits further evaluation.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adipose tissue / Animals / Autocrine signalling / Biology and Life Sciences / Bone marrow / Carcinoma, Hepatocellular - genetics / Carcinoma, Hepatocellular - metabolism / Carcinoma, Hepatocellular - pathology / Caveolin / Caveolin-1 / Cell Adhesion - drug effects / Cell Adhesion - genetics / Cell Line, Tumor / Cell Movement - drug effects / Chemokines / Chemotaxis - drug effects / Cytokines / Development and progression / Disease Models, Animal / Endothelial cells / Endothelial Cells - drug effects / Endothelial Cells - metabolism / Enzyme Activation - drug effects / Fluorescence / Gelatinase A / Gene expression / Gene therapy / Genes / Genetic aspects / Glucose-6-Phosphate Isomerase - metabolism / Glucose-6-Phosphate Isomerase - pharmacology / Hepatocellular carcinoma / Hepatoma / Heterografts / Humans / In vivo methods and tests / Kinases / Laboratories / Liver cancer / Liver Neoplasms - genetics / Liver Neoplasms - metabolism / Liver Neoplasms - pathology / Male / Medicine and Health Sciences / Mesenchymal stem cells / Mesenchymal Stromal Cells - drug effects / Mesenchymal Stromal Cells - metabolism / Mesenchyme / Metalloendopeptidases - metabolism / Metalloproteinase / Mice / Motility / Physiological aspects / Priming / Production methods / Recruitment / Research and Analysis Methods / Spheroids / Stem cells / Stimulation / Stromal cells / Therapeutic applications / Tumor Burden / Tumors / Umbilical cord