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

Abstract

Background and AimsSeveral 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.MethodsProduction 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.ResultsAMF 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.ConclusionAMF plays a role in MSC recruitment towards HCC. However, its ability to increase MSC migration to HCC for therapeutic purposes merits further evaluation.

Chemokine CCL15 Mediates Migration of Human Bone Marrow-Derived Mesenchymal Stem Cells Toward Hepatocellular Carcinoma

“…While the propensity of MSCs to migrate to tumors and areas of tissue damage has now been extensively documented, the factors that mediate this tropism have yet to be completely elucidated. It has been shown that macrophage migration inhibitory factor, platelet‐derived growth factor BB (PDGF‐BB), stromal cell‐derived factor‐1, monocyte chemotactic protein‐1, interleukin 8 (IL‐8), autocrine motility factor, and chemokine CCL25 may all play roles in the intrinsic tumor‐specific migration capacity of MSCs . Despite these promising results, the migratory properties of MSCs need to be further evaluated to ascertain any tumor‐type specificity as well as to investigate the possible signaling molecules involved.…”

Mesenchymal stem cell therapy of hepatocellular carcinoma in rats: Detection of cell homing and tumor mass by magnetic resonance imaging using iron oxide nanoparticles

“…15 The study investigated the role played by AMF in mediating the migration of MSCs, of various sources, towards human HCC. The AMF produced by HCC was found to induce the migration of different MSCs in vitro, and to enhance their metalloproteinase 2 activities.…”

Organ-specific migration of mesenchymal stromal cells: Who, when, where and why?

“…The main factors found to be secreted are IFN-γ, TNF-α, IL-6, IL-8, TGF-β, HGF, PDGF, VEGF and CXCL12 [108]. Many groups have shown that MSC can migrate to various types of tumors, such as gliomas [109], multiple myeloma [110], hepatocellular carcinomas [111], breast cancers [112], colon carcinomas [113], ovarian cancers [114] and lung carcinomas [115]. This is both important and complex as MSC can have pro-as well as anti-tumor properties [116].…”