title: The intrinsic fusogenicity of glioma cells as a factor of transformation and progression in the tumor microenvironment.
abstract: We have previously reported in vitro heterotypic fusion of glioma cells with neural progenitor cells, producing tetraploid cells expressing genetic complements of each partner. Herein, we investigated the fusogenicity of glioma cells. In 1:1 cocultures of single-labeled cells, U87MG cells presented high frequency of homotypic fusogenic events, producing cells that coexpressed both fluorescent proteins. Six percent of the total cells had 8n DNA content, consistent with the finding that the double-labeled cells were actively proliferating. In coculture with fibroblasts, glioma cell fusogenicity resulted in viable reprogrammed cells, thus emerging as a plausible source of tumor cell heterogeneity. As for heterotypic fusion to happen, glioma cells have to establish direct contact with other cells, the effect of stroma on glioma cells was analyzed. Proliferation assays and array analysis of cancer-related pathways established a promalignant effect of stroma. This effect was mediated by fibronectin and was nearly completely abolished by inhibitors of the epidermal-growth-factor receptor. That stroma elicited transduction signaling through the mitogen-activated-protein kinase/extracellular-signal-regulated kinase pathway, which is linked to increased tumor cell migration through extracellular matrix, suggested that glioma cells may actively approach nontumor cells in stromal niches. According to these results, the fusogenicity of glioma cells emerged as an inherent factor for phenotypic changes leading to glioma progression.
authors.affiliation: Division of Translational Science, Nevada Cancer Institute, Las Vegas, NV 89135, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Mercapide
authors.forename: Germana
authors.initials: G
authors.lastname: Rappa
authors.forename: Aurelio
authors.initials: A
authors.lastname: Lorico
mesh_terms: D000818:Animals; D002459:Cell Fusion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D018920:Coculture Techniques; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology; D005353:Fibronectins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000473:pathology* / Q000503:physiopathology*; D006822:Hybrid Cells / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015398:Signal Transduction; D059016:Tumor Microenvironment
chemical_list: D005353:Fibronectins; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases