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Bone marrow-derived mesenchymal stem cells promote invasiveness and transendothelial migration of osteosarcoma cells via a mesenchymal to amoeboid transition.

ABSTRACT: There is growing evidence to suggest that bone marrow-derived mesenchymal stem cells (BM-MSCs) are key players in tumour stroma. Here, we investigated the cross-talk between BM-MSCs and osteosarcoma (OS) cells. We revealed a strong tropism of BM-MSCs towards these tumour cells and identified monocyte chemoattractant protein (MCP)-1, growth-regulated oncogene (GRO)-? and transforming growth factor (TGF)-?1 as pivotal factors for BM-MSC chemotaxis. Once in contact with OS cells, BM-MSCs trans-differentiate into cancer-associated fibroblasts, further increasing MCP-1, GRO-?, interleukin (IL)-6 and IL-8 levels in the tumour microenvironment. These cytokines promote mesenchymal to amoeboid transition (MAT), driven by activation of the small GTPase RhoA, in OS cells, as illustrated by the in vitro assay and live imaging. The outcome is a significant increase of aggressiveness in OS cells in terms of motility, invasiveness and transendothelial migration. In keeping with their enhanced transendothelial migration abilities, OS cells stimulated by BM-MSCs also sustain migration, invasion and formation of the in vitro capillary network of endothelial cells. Thus, BM-MSC recruitment to the OS site and the consequent cytokine-induced MAT are crucial events in OS malignancy.

SUBMITTER: Pietrovito L

PROVIDER: S-EPMC5928379 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Bone marrow-derived mesenchymal stem cells promote invasiveness and transendothelial migration of osteosarcoma cells via a mesenchymal to amoeboid transition.

Pietrovito Laura L Leo Angela A Gori Valentina V Lulli Matteo M Parri Matteo M Becherucci Valentina V Piccini Luisa L Bambi Franco F Taddei Maria Letizia ML Chiarugi Paola P

Molecular oncology 20180331 5

There is growing evidence to suggest that bone marrow-derived mesenchymal stem cells (BM-MSCs) are key players in tumour stroma. Here, we investigated the cross-talk between BM-MSCs and osteosarcoma (OS) cells. We revealed a strong tropism of BM-MSCs towards these tumour cells and identified monocyte chemoattractant protein (MCP)-1, growth-regulated oncogene (GRO)-α and transforming growth factor (TGF)-β1 as pivotal factors for BM-MSC chemotaxis. Once in contact with OS cells, BM-MSCs trans-diff ...[more]

PMID: 29517849

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Project description:BACKGROUND:Mesenchymal stem cells (MSCs) are known to home to injured and inflamed regions via the bloodstream to assist in tissue regeneration in response to signals of cellular damage. However, the factors and mechanisms that affect their transendothelial migration are still unclear. In this study, the mechanisms involved in interleukin-1? (IL-1?) enhancing the transendothelial migration of MSCs were investigated. METHODS:Immunofluorescence staining and Western blotting were used to observe IL-1?-induced CXC chemokine receptor 3 (CXCR3) expression on MSCs. Quantitative real-time PCR and ELISA were used to demonstrate IL-1? upregulated both chemokine (C-X-C motif) ligand 9 (CXCL9) mRNA and CXCL9 ligand secretion in human umbilical vein endothelial cells (HUVECs). Monolayer co-cultivation, agarose drop chemotaxis, and transwell assay were conducted to investigate the chemotaxis invasion and transendothelial migration ability of IL-1?-induced MSCs in response to CXCL9. RESULTS:In this study, our immunofluorescence staining showed that IL-1? induces CXCR3 expression on MSCs. This result was confirmed by Western blotting. Following pretreatment with protein synthesis inhibitor cycloheximide, we found that IL-1? induced CXCR3 on the surface of MSCs via protein synthesis pathway. Quantitative real-time PCR and ELISA validated that IL-1? upregulated both CXCL9 mRNA and CXCL9 ligand secretion in HUVECs. In response to CXCL9, chemotaxis invasion and transendothelial migration ability were increased in IL-1?-stimulated MSCs. In addition, we pretreated MSCs with CXCR3 antagonist AMG-487 and p38 MAPK inhibitor SB203580 to confirm CXCR3-CXCL9 interaction and the role of CXCR3 in IL-1?-induced chemotaxis invasion and transendothelial migration. CONCLUSION:We found that IL-1? induces the expression of CXCR3 through p38 MAPK signaling and that IL-1? also enhances CXCL9 ligand secretion in HUVECs. These results indicated that IL-1? promotes the transendothelial migration of MSCs through CXCR3-CXCL9 axis. The implication of the finding could enhance the efficacy of MSCs homing to target sites.

Project description:Cellular plasticity confers cancer cells the ability to adapt to microenvironmental changes, a fundamental requirement for tumour progression and metastasis. The epithelial to mesenchymal transition (EMT) is a transcriptional programme associated with increased cell motility and stemness. Besides EMT, the mesenchymal to amoeboid transition (MAT) has been described during tumour progression but to date, little is known about its transcriptional control and involvement in stemness. The aim of this manuscript is to investigate (i) the transcriptional profile associated with the MAT programme and (ii) to study whether MAT acquisition in melanoma cancer cells correlates with clonogenic potential to promote tumour growth.By using a multidisciplinary approach, we identified four different treatments able to induce MAT in melanoma cells: EphA2 overexpression, Rac1 functional inhibition using its RacN17 dominant negative mutant, stimulation with Ilomastat or treatment with the RhoA activator Calpeptin. First, gene expression profiling identified the transcriptional pathways associated with MAT, independently of the stimulus that induces the MAT programme. Notably, gene sets associated with the repression of mesenchymal traits, decrease in the secretion of extracellular matrix components as well as increase of cellular stemness positively correlate with MAT. Second, the link between MAT and stemness has been investigated in vitro by analysing stemness markers and clonogenic potential of melanoma cells undergoing MAT. Finally, the link between MAT inducing treatments and tumour initiating capability has been validated in vivo.Taken together, our results demonstrate that MAT programme in melanoma is characterised by increased stemness and clonogenic features of cancer cells, thus sustaining tumour progression. Furthermore, these data suggest that stemness is not an exclusive feature of cells undergoing EMT, but more generally is associated with an increase in cellular plasticity of cancer cells.

Dataset Information

Bone marrow-derived mesenchymal stem cells promote invasiveness and transendothelial migration of osteosarcoma cells via a mesenchymal to amoeboid transition.

Publications

Bone marrow-derived mesenchymal stem cells promote invasiveness and transendothelial migration of osteosarcoma cells via a mesenchymal to amoeboid transition.

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