Estudio de la formación del microambiente pre tumoral en el estroma mamario : rol de la reprogramación metabólica de fibroblastos para promover la malignidad epitelial y reclutamiento de células inmunes
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Fecha
2023
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es
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Universidad Andrés Bello
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Licencia CC
Licencia CC
Resumen
El cáncer de mama es uno de los tipos más comunes de cáncer epitelial y la principal causa de muerte en
mujeres a nivel mundial. El microambiente tumoral está conformado por una red de interacciones entre
células epiteliales tumorales y el estroma circundante, conformado principalmente por células adiposas,
fibroblastos y células del sistema inmune. En este microambiente, también participan, componentes de la
matriz extracelular y moléculas de señalización como quimioquinas y citoquinas inflamatorias. Las
interacciones entre la célula epitelial y el microambiente tumoral promueven entre otros, cambios en el ciclo
celular, la motilidad y el metabolismo, en los cuales el estrés oxidativo y la inflamación crónica juegan un
rol importante. Diversas investigaciones señalan que los fibroblastos mamarios, pueden promover la
activación del estroma y con ello, favorecer la formación de una estructura tisular más rígida y un ambiente
más inflamatorio. Esta condición de rigidez, que ha sido descrita incluso en ausencia de tumores, juega un
papel relevante en la reprogramación metabólica, un elemento clave de la progresión tumoral. Por otra parte,
la exposición a agentes que dañan el ADN, puede cambiar también el comportamiento celular, lo que
modifica los componentes de la matriz extracelular y favorece la expresión de moléculas proinflamatorias
capaces de reclutar células inmunes y promover la malignidad epitelial. En el presente estudio quisimos
evaluar el efecto de drogas que dañan el ADN (Doxorubicina y Cisplatino) en células estromales mamarias
humanas normales (RMF-EG), sobre cambios metabólicos y funcionales, que promueven la formación del
microambiente inflamatorio protumoral. El objetivo de esta tesis fue determinar si la exposición a estas
drogas permitía generar cambios en las células estromales en términos de su metabolismo y la secreción de
moléculas, que facilitaran, por una parte, el reclutamiento de células inflamatorias (THP-1) y por otra, la
adquisición de propiedades de malignidad en células epiteliales mamarias débilmente invasivas (MCF-7).
Los resultados muestran que Cisplatino y Doxorrubicina estimulan la expresión de transportadores Glut-1y
MCT-4 en células RMF-EG. Adicionalmente, los factores solubles secretados por células estromales
pretratadas con estas drogas son capaces de estimular el reclutamiento de monocitos THP-1 y la motilidad
de células MCF-7. También, los mismos factores, modularon la expresión de los marcadores de Transición
Epitelio-Mesénquima en las células epiteliales. Estos resultados nos permiten proponer que fibroblastos
mamarios expuestos a Cisplatino y Doxorrubicina, modifican su comportamiento metabólico y son capaces
de estimular la expresión de señales solubles que participan de la formación de un microambiente
inflamatorio y promueve la malignidad epitelial, lo que configuraría un escenario protumoral en el estroma
mamario.
Breast cancer is one of the most common types of epithelial cancer and the leading cause of death in women worldwide. The tumor microenvironment comprises a network of interactions between tumor epithelial cells and the surrounding stroma, mainly of adipose cells, fibroblasts and cells of the immune system. In this microenvironment, components of the extracellular matrix and signaling molecules such as chemokines and inflammatory cytokines also participate. The interactions between the epithelial cell and the tumor microenvironment promote, among others, changes in the cell cycle, motility and metabolism, in which oxidative stress and chronic inflammation play an important role. Various investigations indicate that mammary fibroblasts can promote the activation of the stroma and favor the formation of a more rigid tissue structure and a more inflammatory environment. This condition of rigidity, which has been described even in the absence of tumors, plays an essential role in metabolic reprogramming, a key element in tumor progression. On the other hand, exposure to agents that damage DNA can also change cell behavior, which modifies the components of the extracellular matrix and favors the expression of proinflammatory molecules capable of recruiting immune cells and promoting epithelial malignancy. In the present study, we wanted to evaluate the effect of drugs that damage DNA (Doxorubicin and Cisplatin) in normal human mammary stromal cells (RMF-EG) on metabolic and functional changes, which promote the formation of the protumoral inflammatory microenvironment. The objective of this thesis was to determine if the exposure to these drugs allowed to generate changes in the stromal cells in terms of their metabolism and the secretion of molecules that facilitated, on the one hand, the recruitment of inflammatory cells (THP-1) and on the other, the acquisition of malignancy properties in weakly invasive mammary epithelial cells (MCF-7). The results show that Cisplatin and Doxorubicin stimulate the expression of Glut-1 and MCT4 transporters in RMF-EG cells. Additionally, the soluble factors secreted by stromal cells pretreated with these drugs can produce the recruitment of THP-1 monocytes and the motility of MCF-7 cells. Also, the same factors modulated the expression of the markers of Epithelial-Mesenchymal Transition in epithelial cells. These results allow us to propose that mammary fibroblasts exposed to cisplatin and doxorubicin modify their metabolic behavior and can stimulate the expression of soluble signals that participate in the formation of an inflammatory microenvironment and promote epithelial malignancy, which would configure a pro-tumor scenario in the mammary stroma.
Breast cancer is one of the most common types of epithelial cancer and the leading cause of death in women worldwide. The tumor microenvironment comprises a network of interactions between tumor epithelial cells and the surrounding stroma, mainly of adipose cells, fibroblasts and cells of the immune system. In this microenvironment, components of the extracellular matrix and signaling molecules such as chemokines and inflammatory cytokines also participate. The interactions between the epithelial cell and the tumor microenvironment promote, among others, changes in the cell cycle, motility and metabolism, in which oxidative stress and chronic inflammation play an important role. Various investigations indicate that mammary fibroblasts can promote the activation of the stroma and favor the formation of a more rigid tissue structure and a more inflammatory environment. This condition of rigidity, which has been described even in the absence of tumors, plays an essential role in metabolic reprogramming, a key element in tumor progression. On the other hand, exposure to agents that damage DNA can also change cell behavior, which modifies the components of the extracellular matrix and favors the expression of proinflammatory molecules capable of recruiting immune cells and promoting epithelial malignancy. In the present study, we wanted to evaluate the effect of drugs that damage DNA (Doxorubicin and Cisplatin) in normal human mammary stromal cells (RMF-EG) on metabolic and functional changes, which promote the formation of the protumoral inflammatory microenvironment. The objective of this thesis was to determine if the exposure to these drugs allowed to generate changes in the stromal cells in terms of their metabolism and the secretion of molecules that facilitated, on the one hand, the recruitment of inflammatory cells (THP-1) and on the other, the acquisition of malignancy properties in weakly invasive mammary epithelial cells (MCF-7). The results show that Cisplatin and Doxorubicin stimulate the expression of Glut-1 and MCT4 transporters in RMF-EG cells. Additionally, the soluble factors secreted by stromal cells pretreated with these drugs can produce the recruitment of THP-1 monocytes and the motility of MCF-7 cells. Also, the same factors modulated the expression of the markers of Epithelial-Mesenchymal Transition in epithelial cells. These results allow us to propose that mammary fibroblasts exposed to cisplatin and doxorubicin modify their metabolic behavior and can stimulate the expression of soluble signals that participate in the formation of an inflammatory microenvironment and promote epithelial malignancy, which would configure a pro-tumor scenario in the mammary stroma.
Notas
Tesis (Ingeniero en Biotecnología)
Palabras clave
Cáncer Mamario, Células Estromales Mamarias, Fibroblastos, Cisplatino, Doxorrubicina, Efectos