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https://www.arca.fiocruz.br/handle/icict/33348
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2019-10-31
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EFFECTS OF IONIZING RADIATION AND HPSE1 INHIBITION ON THE INVASION OF ORAL TONGUE CARCINOMA CELLS ON HUMAN EXTRACELLULAR MATRICES IN VITRO
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Affilliation
Faculty of Medicine. University of Oulu. Cancer Research and Translational Medicine Research Unit. Oulu, Finland.
University of Oulu. Oulu University Hospital. Medical Research Center Oulu. Oulu, Finland.
Faculty of Medicine. University of Oulu. Cancer Research and Translational Medicine Research Unit. Oulu, Finland.
University of Oulu. Oulu University Hospital. Medical Research Center Oulu. Oulu, Finland.
Instituto de Radioproteção e Dosimetria. Comissão Nacional de Energia Nuclear. Laboratório de Radiobiologia. Rio de Janeiro, Brasil.
HUSLAB. University of Helsinki. Helsinki University Central Hospital. Department of Pathology. Helsinki, Finland.
Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil.
Faculty of Medicine. University of Oulu. Cancer Research and Translational Medicine Research Unit. Oulu, Finland.
University of Oulu. Oulu University Hospital. Medical Research Center Oulu. Oulu, Finland.
Faculty of Medicine. University of Oulu. Cancer Research and Translational Medicine Research Unit. Oulu, Finland.
University of Oulu. Oulu University Hospital. Medical Research Center Oulu. Oulu, Finland.
Instituto de Radioproteção e Dosimetria. Comissão Nacional de Energia Nuclear. Laboratório de Radiobiologia. Rio de Janeiro, Brasil.
HUSLAB. University of Helsinki. Helsinki University Central Hospital. Department of Pathology. Helsinki, Finland.
Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil.
Faculty of Medicine. University of Oulu. Cancer Research and Translational Medicine Research Unit. Oulu, Finland.
Abstract in Portuguese
A quimiorradiação é uma abordagem estabelecida no tratamento do carcinoma de células escamosas de língua oral avançada (OTSCC), mas a terapia pode causar efeitos colaterais graves devido a intercâmbios de sinais entre o carcinoma e o microambiente tumoral (TME). Neste estudo, examinamos o uso potencial de nossos modelos de disco de mioma 3D e Myogel em estudos de quimioradioterapia in vitro analisando os efeitos da radiação ionizante (IR) e o efeito combinado de inibidores de heparanase I (HPSE1) e IR na proliferação de células OTSCC , invasão e produção de MMP-2 e -9. Finalmente, analisamos os efeitos a longo prazo da RI estudando clones de células HSC-3 previamente irradiadas e invadidas. Descobrimos que em modelos de matriz extracelular baseados em leiomioma uterino humano, a IR inibiu a invasão de células HSC-3, mas o bloqueio da atividade de HPSE1 combinado com a IR induziu sua invasão. Baixas doses de IR aumentaram a expressão de MMP e iniciaram a transição epitelial-mesenquimal em células cultivadas em discos de mioma. Conclui-se que os modelos de mioma oferecem métodos consistentes para testar a invasão de células de carcinoma humano e alterações fenotípicas durante o tratamento quimioradioterapia. Além disso, mostramos que a RI teve efeitos a longo prazo nas MMP-2 e -9, o que pode induzir diferentes respostas de invasão de HSC-3 quando as células estavam sob o desafio de inibidores de HPSE1 e IR.
Abstract
Chemoradiation is an established approach in the treatment of advanced oral tongue squamous cell carcinoma (OTSCC), but therapy may cause severe side-effects due to signal interchanges between carcinoma and the tumour microenvironment (TME). In this study, we examined the potential use of our human 3D myoma disc and Myogel models in in vitro chemoradiation studies by analysing the effects of ionizing radiation (IR) and the combined effect of heparanase I (HPSE1) inhibitors and IR on OTSCC cell proliferation, invasion and MMP-2 and -9 production. Finally, we analysed the long-term effects of IR by studying clones of previously irradiated and invaded HSC-3 cells. We found that in both human uterine leiomyoma-based extracellular matrix models IR inhibited the invasion of HSC-3 cells, but blocking HPSE1 activity combined with IR induced their invasion. Low doses of IR increased MMP expression and initiated epithelial-mesenchymal transition in cells cultured on myoma discs. We conclude that myoma models offer consistent methods for testing human carcinoma cell invasion and phenotypic changes during chemoradiation treatment. In addition, we showed that IR had long-term effects on MMP-2 and -9, which might elicit different HSC-3 invasion responses when cells were under the challenge of HPSE1 inhibitors and IR.
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