Extracellular vesicles induce fibroblasts metalloproteinases expression in thyroid tumor microenvironment

BRAVO MIANA R; GUANTAY L; GILARDONI MB; DE PAUL AL; BORIOLI G; PELLIZAS CG; DONADIO A

Barcelona

Congreso; Annual Meeting International Society of Extracellular Vesicles (ISEV 2018); 2018

International Society for Extracellular Vesicles (ISEV)

Background: The tumour microenvironment (TME), conformed bycellular and non-cellular components, promotes tumourigenesis inmany solid malignancies. Extracellular vesicles (EVs) are related withintercellular communication in the TME. Fibroblasts (Fb), present in theTME, foster tumour growth stimulating cell proliferation and secretingextracellular matrix-remodelling proteases such as matrix metalloproteinases(MMPs). CD147, a glycoprotein implicated in MMPs expression,is related to thyroid tumour progression. Previous studies showed thatthyroid tumour cell?Fb interactions promoted the secretion of MMPs toculture supernatants (CMs) and a migratory phenotype in tumour cells.Our goal was to identify EVs production and their role as mediators ofMMPs expression in thyroid TME.Methods: As an in vitro tumour?stroma cell interaction model, nontumourcells (NThyOri), thyroid papillary carcinoma cells (TPC-1) andthyroid anaplastic cells (8505c) were co-cultured with normal Fb. EVs, obtained by ultracentrifugation of cell and cell-Fb CMs, were characterizedby transmission electron microscopy and dynamic light scattering.MMPs were studied by zymography in EVs and CMs of Fb incubatedwith EVs. CD147 expression was analysed in EVs by gold-immunocytochemistryand western blot.Results: EVs ranged between 50 and 600 nm. No MMP activity wasdetected in EVs, but Fb incubated with EVs secreted MMP9 and MMP2to CMs. Interestingly, an increase in MMP9 and active MMP2 wasobserved in Fb treated with EVs collected from tumour cell?Fb cocultures.Equally, an increased MMP2 and MMP9 expression was previouslydetected by immunocytochemistry in Fb cocultured with thyroidtumour cells. CD147 expression was detected in EVs and significantlyincreased in TPC-1-Fb and 8505c-Fb cocultures, without changes inNThyOri-Fb cocultures.Summary/conclusion: The results suggest that EVs play an active role inintercellular communication events in thyroid TME, stimulating the Fbrelease of MMPs and the consequent tumour cell migration.Funding: Secretaría de Ciencia y Tecnología de la Universidad Nacionalde Córdoba (SECyT-UNC). Consejo Nacional de InvestigacionesCientíficas y Técnicas (CONICET). Fundación Sales (Fundación parala Investigación en Cáncer).