Transición Epitelio-Mesenquimal y funciones stem: Papel de la IL-8 en la funcionalidad de las células de la línea celular de cáncer de seno MCF-7 en condiciones de resistencia a la anoikis

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dc.contributor.advisorVernot Hernandez, Jean Paulspa
dc.contributor.authorOspina Muñoz, Nataliaspa
dc.contributor.researchgroupFisiología Celular y Molecularspa
dc.date.accessioned2021-01-22T16:55:12Zspa
dc.date.available2021-01-22T16:55:12Zspa
dc.date.issued2020-11-04spa
dc.description.abstractLa Interleuquina 8 (IL-8) es un importante regulador del microambiente tumoral (MAT), promoviendo la transición epitelio mesenquimal (EMT) y la adquisición de propiedades de células stem por parte de las células tumorales (CSC). El ensayo de formación de mamoesferas se ha utilizado para la identificación y enriquecimiento de las CSC. La IL-8 induce la formación de mamoesferas más grandes, lo que sugiere el enriquecimiento de CSC. En el presente trabajo nuestro objetivo fue estudiar las características fenotípicas y funcionales de las células presentes en las mamoesferas de las células MCF-7 previamente tratadas con IL-8. Las células MCF-7 adheridas fueron tratadas con IL-8 durante 5 días y luego fueron cultivadas por 5 días más en condiciones no adherentes (resistencia a la anoikis). Demostramos que la presencia de mamoesferas con mayor tamaño en la condición IL-8, no fue consecuencia de una mayor proliferación mediada por esta citoquina. Se encontró que a pesar del mantenimiento del fenotipo EMT con presencia de células híbridas que expresaban tanto E-cadherina como SNAI2, las propiedades esenciales de células stem se vieron afectadas en las mamoesferas tratadas con IL-8. La capacidad de autorrenovación se incrementó en las células tratadas con IL-8 solo en la primera generación de mamoesferas, pero este incremento no se sostuvo en ensayos consecutivos. En consecuencia, la autorrenovación, la reprogramación, la capacidad de diferenciación a adipocitos y la clonogenicidad también se vieron afectadas. También, mostramos que las mamoesferas estaban enriquecidas en células luminales diferenciadas (EpCAM+/CD49f-). Además, las células MCF-7 aisladas de mamoesferas derivadas de IL-8 también presentaron una mayor migración e invasión dirigida por IL-8. Adicionalmente, las células dentro de las mamoesferas derivadas del tratamiento con IL-8 fueron altamente resistentes al Paclitaxel (PLX) y la Doxorrubicina (DOX). Por lo tanto, mostramos aquí que la línea de cáncer de seno no agresiva MCF-7, a pesar de un índice bajo de funciones stem, podría adquirir selectivamente atributos particulares de células stem muy relevantes para la progresión del cáncer.spa
dc.description.abstractThe Interleukin 8 (IL-8) is an important regulator of the tumor microenvironment (TME), promoting the epithelial-mesenchymal transition (EMT) and the acquisition of stem-like cell properties in cancer cells (CSC). The mammosphere-formation assay has been used for the identification of CSC. IL-8 induces the formation of larger mammospheres, suggesting CSC enrichment. In the present work, we aimed to study the phenotypic and functional characteristics of the cells present within the mammospheres of MCF-7 cells previously treated with IL-8. MCF-7 cells treated for 5 days or not with this cytokine, were further cultivated in ultralow attachment (anoikis) plates for another 5 days to allow mammospheres formation. We showed that the enhanced mammospheres formation by MCF-7 cells was not a consequence of higher cell proliferation by IL-8 stimulation. Despite maintaining an EMT phenotype with the presence of hybrid cells expressing both E-cadherin and SNAI2, essential stemness properties were impaired in mammospheres treated with IL-8. Self-renewal capacity was increased in IL-8-treated cells only in the first generation of mammospheres but was not sustained in consecutive assays. Accordingly, self-renewal and reprogramming gene expression, differentiation capacity to adipocytes and clonogenicity were also impaired. We showed also that mammospheres were enriched in differentiated luminal cells (EpCAM+/CD49f-). Furthermore, MCF-7 cells isolated from IL-8-derived mammospheres presented also higher IL-8-directed-migration and -invasion. Consistent with this, they were also highly resistant to Paclitaxel (PLX) and Doxorubicin (DOX). Therefore, we showed here that the non-aggressive breast cancer line MCF-7, despite having a low stemmess index, might selectively acquire particular stem-like cell attributes very relevant for cancer progression.spa
dc.description.degreelevelDoctoradospa
dc.format.extent122spa
dc.format.mimetypeapplication/pdfspa
dc.identifier.urihttps://repositorio.unal.edu.co/handle/unal/78877
dc.language.isospaspa
dc.publisher.branchUniversidad Nacional de Colombia - Sede Bogotáspa
dc.publisher.programBogotá - Medicina - Doctorado en Ciencias Biomédicasspa
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dc.rightsDerechos reservados - Universidad Nacional de Colombiaspa
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dc.rights.licenseAtribución-NoComercial-SinDerivadas 4.0 Internacionalspa
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dc.subject.ddc570 - Biología::571 - Fisiología y temas relacionadosspa
dc.subject.proposalMamoesferas (Msph)spa
dc.subject.proposalMammospheres (Msph)eng
dc.subject.proposalInterleuquina 8 IL-8spa
dc.subject.proposalInterleukin 8eng
dc.subject.proposalEpithelial-Mesenchymal Transition (EMT)eng
dc.subject.proposalTransición epitelio- mesenquimal (EMT)spa
dc.subject.proposalCélulas stem tumorales (CSC)spa
dc.subject.proposalCancer stem cells (CSC)eng
dc.subject.proposalTumor microenvironment (TME)eng
dc.subject.proposalMicroambiente tumoral (MAT)spa
dc.titleTransición Epitelio-Mesenquimal y funciones stem: Papel de la IL-8 en la funcionalidad de las células de la línea celular de cáncer de seno MCF-7 en condiciones de resistencia a la anoikisspa
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Doctorado en Ciencias Biomédicas