Fusion of cancer stem cells and mesenchymal stem cells contributes to glioma neovascularization

Abstract

Abstract. The ability of tumor cells to autonomously generate tumor vessels has received considerable attention in recent years. However, the degree of autonomy is relative. Meanwhile, the effect of bone marrow-derived mesenchymal stem cells (BMSCs) on tumor neovascularization has not been fully elucidated. The present study aimed to illuminate whether cell fusion between glioma stem cells and BMSC is involved in glioma neovascularization. BMSCs were isolated from transgenic nude mice, of which all nucleated cells express green fluorescent protein (GFP). The immunophenotype and multilineage differentiation potential of BMSC were confirmed. SU3 glioma stem/progenitor cells were transfected with red fluorescent protein (SU3-RFP cells). In a co-culture system of BMSC-GFP and SU3-RFP, RFP + /GFP + cells were detected and isolated by dual colors using FACS. The angiogenic effect of RFP + /GFP + cells was determined in vivo and in vitro. Flow cytometry analysis showed that BMSC expressed high levels of CD105, C44, and very low levels of CD45 and CD11b. When co-cultured with SU3-RFP, 73.8% of cells co-expressing RFP and GFP were identified as fused cells in the 5th generation. The fused cells exhibited tube formation ability in vitro and could give rise to a solid tumor and form tumor blood vessels in vivo. In the dual-color orthotopic model of transplantable xenograft glioma, yellow vessel-like structures that expressed CD105, RFP and GFP were identified as de novo-formed vessels derived from the fused cells. The yellow vessels observed in the tumor-bearing mice directly arose from the fusion of BMSCs and SU3-RFP cells. Thus, cell fusion is one of the driving factors for tumor neovascularization.

Current status and potential challenges of mesenchymal stem cell-based therapy for malignant gliomas

“…Moreover, Schichor et al found that the fusion of U87 and BMSCs facilitated the proliferation and migration of both in vitro, and the cross-talk of tumour cells and MSCs maintained the structural formation of syncytium [ 81 ]. Subsequently, Sun et al showed that the fused cells gave rise to an enhanced angiogenesis of gliomas in vitro and in vivo and a stabilised vascular framework, implying an improvement in glioma growth [ 82 ].…”

Mesenchymal stem cells promote glioma neovascularization in vivo by fusing with cancer stem cells

“…5 × 10 3 cells in logarithmic growth phase were added to each well, cultured for 12 h, and then fixed with 4% polyoxymethylene. Cells and transplanted tumor paraffin sections were immunolabeled using a previously reported immunocyte/histochemical staining method [8]. After incubation with the primary antibodies (Abcam; Nestin 1:300, CD105 1:200, CD31 1:200, CD34 1:200, VE-Cadherin 1:200, PDGFB 1:100, PDGFR-β 1:100, VEGF 1:100, VEGFR2 1:200, CD90 1:400, CD29 1:100 and CD44 1:200) at 4 °C overnight, the slides were incubated with secondary antibody (Beyotime, Shanghai), stained with diaminobenzidine (DAB), and then counterstained with hematoxylin.…”

ELAVL1 Role in Cell Fusion and Tunneling Membrane Nanotube Formations with Implication to Treat Glioma Heterogeneity

“…Both intercellular tunneling nanotubes and permanent intercellular membrane fusions are reported in gliomas and represent diverse multistep processes, which require an activation of the cellular stress response, the rearrangement of the actin-dependent cytoskeleton, the expression of the fusogenic proteins, and phosphatidylserine enrichment on the membrane surfaces [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. We utilized the literature search and the R2: Genomics Analysis and Visualization Platform (Rembrandt, Madhavan, Mas 5.0-U132p2 study for gliomas and Harris, Mas 5.0-U132p2 study for normal brain) and confirmed the significant expression of the following known fusogens in the glioma microenvironment: (i) the fusogen transcripts from genomes of pathogenic HCMV, HHV-6, HIV1, and Epstein–Barr enveloped viruses; (ii) the fusogen transcripts encoding endogenous retroviral envelope proteins (ERVW-1, ERVK13-1, ERV3-1, ERVMER34-1, ERVV-1, ERVFRD-1); (iii) the fusogen transcripts encoding proteins essential for sexual reproduction and gamete fusions (transcripts of IZUMO and IZUMOR families, GLIPR1L1, CD9); (iv) the muscle-specific fusogen transcripts (myomaker and myomixer) at low levels; (v) the transcripts of fusogens involved in intercellular and extracellular vesicle-specific transfers (SNARE-family transcripts, transcripts of small dynamin-like GTPases including atlastins, mitofusins, dynamins).…”

“…Glioma-to-stromal cell communication via intercellular gene transfer leads to gene reprogramming in fused cells and the creation of de novo tumorigenicity and plasticity of glioma stem cells. The following glioma/microenvironmental transfers of biological materials via permanent and temporal cell fusions have been identified: (i) the bidirectional acquisition of the whole genome between glioma stem cells and bone marrow mesenchymal cells, between glioma stem cells and endothelial cells or pericytes, between glioma stem cells and monocytes (macrophages and microglia), between glioma cells and neural stem cells, and between glioma stem cells and macrophages fused with T cells [ 28 , 29 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ]; (ii) the mitochondria and the cargo vesicle transfers through the tunneling membrane nanotubes between glioma cells and reactive astrocytes, between glioma and neuronal cells, between endothelial cells and pericytes in the glioma microenvironment, between glioma cells and macrophages, between glioma cells by themselves [ 22 , 23 , 30 , 31 , 32 , 33 , 34 , 84 ]; (iii) viruses and viral genome transfers between glioma cells by themselves, and between T cells and macrophages fused with glioma cells [ 32 , 33 , 85 ]. It is worth mentioning that proinflammatory monocytes and macrophages infiltrate the glioma microenvironment in a HuR-dependent manner and positively contribute to cell fusion and tunneling nanotube formations, and therefore promote glioma plasticity, tissue heterogeneity, and angiogenesis [ 86 , 87 ].…”