Hipoxia promueve la liberación de vesículas extracelulares proangiogénicas que contienen conexina-46 en células de cáncer de mama
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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
La comunicación entre célula-célula ocurre gracias a las uniones de hendidura (UH). Una UH está
formada por la unión de dos hemicanales, y cada hemicanal (HC) está formado por la oligomerización
de seis proteínas de transmembrana llamadas conexinas (Cx). Las conexinas presentan una amplia
distribución en los diferentes tejidos y órganos de nuestro cuerpo. Los canales formados por Cx
permiten el intercambio de iones, nucleótidos, pequeños metabolitos, entre otras pequeñas moléculas
con permeabilidades alrededor de los 1.2 kDa. Los canales formados por conexinas han sido descritos
en diferentes procesos celulares, tales como, proliferación, diferenciación y apoptosis. Sin embargo,
no solo en la comunicación paracrina ejercen su importancia, sino que últimamente han sido descritos
en la comunicación endocrina, estando presentes en vesículas extracelulares (EV) quienes median
esta comunicación tanto en condiciones fisiológicas normales, así como también en condiciones
patológicas como el cáncer. Se ha descrito que alteraciones en el patrón de expresión de conexinas
está relacionado con diferentes enfermedades, dentro de estas el cáncer y su progresión. De los
diferentes tipos de cáncer, el cáncer de mama presenta tasas de incidencia y mortalidad del 47.8 y
13.6 respectivamente, siendo la principal causa de muerte por cáncer en mujeres en el mundo. Cx46,
perteneciente a la familia de proteínas transmembrana, se ha descrito la expresión de Cx46 en la
glándula mamaria en condiciones fisiológicas normales, sin embargo, presenta mayor expresión en
la condición patológica del cáncer de mama. Cx46 se expresa endógenamente en el cristalino,
favoreciendo la sobrevida de las células del cristalino al ambiente hipóxico que se presenta en este
tejido, atribuyéndose esta funcion a las células de cáncer de mama cuando estas estan en hipoxia
debido a las células hiperproliferantes que forman un microambiente tumoral hipóxico, siendo esta
misma, una característica de tumores sólidos a vasculares. Antecedentes de nuestro laboratorio
muestran que el aumento en la expresión de conexina 46 (Cx46) en células de cáncer de mama MCF7, favorece el aumento tanto de genes relacionados a la transición epitelio mesénquima (TEM) como
de células madre cancerosas. Nuestro laboratorio también ha descrito la presencia de Cx46 en
vesículas extracelulares (EVs-Cx46) liberadas por células de cáncer de mama MCF-7 que sobre
expresan Cx46, observándose un aumento en la migración e invasión en células receptoras, lo que no
fue apreciado al incubar EVs que no contienen Cx46, atribuyendo un nuevo rol a las EV que
contienen Cx46 en la progresión de los procesos pro-tumorales. Sin embargo, el efecto de la hipoxia
en la expresión de Cx46 en células MCF-7 de cáncer de mama, su posterior liberación en EV y
finalmente la contribución de las vesículas que contienen Cx46 por el estímulo hipóxico en el proceso
de angiogénesis, son interrogantes que intentamos responder en el presente proyecto de tesis. En base
a los objetivos anteriores se postula que el proceso de angiogénesis es promovido por EV que
contienen Cx46 provenientes de células de cáncer de mama sometidas a hipoxia.
Cell-to-cell communication occurs mainly through gap junctions (GJs), which are formed by the junction of two hemichannels (HC). Each HC is composed of the oligomerization of six transmembrane protein subunits called connexins (Cx). Cx have a wide distribution in different tissues and organs of our body, allowing the exchange of ions, nucleotides and small metabolites through GJs or HCs, with permeabilities around 1.2 kDa. Channels formed by connexins have been described in different cellular processes, such as proliferation, differentiation, and apoptosis. However, its importance is not limited to paracrine communication. Recently, channels formed by connexins, specifically hemichannels, have been described in endocrine communication, being present in extracellular vesicles (EVs). EVs are small microvesicles with sizes between 50 and 150 nm, which mediate intercellular communication both in normal physiological conditions and in pathological conditions such as cancer. It has been described that alterations in the expression pattern of connexins are related to different diseases, including cancer and its progression. Among the different types of connexins, it has been described that connexin 46 (Cx46) is expressed in the mammary gland, both under normal physiological conditions and in the pathological state of breast cancer, showing increased expression in relation to the progression of the connexin. disease. Initially, the presence of Cx46 in the lens was identified, favoring the survival of lens cells in the hypoxic environment present in this tissue, a function that was confirmed in breast cancer cells subjected to hypoxia, a key component in the tumor microenvironment generated in the cancer progression. . Background from our laboratory shows that increased Cx46 expression in MCF-7 breast cancer cells favors the upregulation of genes related to epithelial-mesenchymal transition (EMT) and cancer stem cells (CSC). In addition, our laboratory has described the presence of Cx46 in extracellular vesicles (EVs-Cx46) released by MCF-7 breast cancer cells that overexpress Cx46, showing increased migration and invasion in recipient cells. This behavior was not observed when incubated with EVs that do not contain Cx46 (EVs-Cx46-sans), which attributes a new role to EVs that contain Cx46 in the promotion of protumoral processes. However, the effect of hypoxia on Cx46 expression in MCF-7 breast cancer cells, its subsequent release in electric vehicles, and finally the contribution of these Cx46-containing vesicles in promoting the angiogenesis process are questions. that we intend to answer in this thesis project. Based on the above objectives, it is postulated that the angiogenesis process is promoted by Cx46-containing EVs from breast cancer cells subjected to hypoxia.
Cell-to-cell communication occurs mainly through gap junctions (GJs), which are formed by the junction of two hemichannels (HC). Each HC is composed of the oligomerization of six transmembrane protein subunits called connexins (Cx). Cx have a wide distribution in different tissues and organs of our body, allowing the exchange of ions, nucleotides and small metabolites through GJs or HCs, with permeabilities around 1.2 kDa. Channels formed by connexins have been described in different cellular processes, such as proliferation, differentiation, and apoptosis. However, its importance is not limited to paracrine communication. Recently, channels formed by connexins, specifically hemichannels, have been described in endocrine communication, being present in extracellular vesicles (EVs). EVs are small microvesicles with sizes between 50 and 150 nm, which mediate intercellular communication both in normal physiological conditions and in pathological conditions such as cancer. It has been described that alterations in the expression pattern of connexins are related to different diseases, including cancer and its progression. Among the different types of connexins, it has been described that connexin 46 (Cx46) is expressed in the mammary gland, both under normal physiological conditions and in the pathological state of breast cancer, showing increased expression in relation to the progression of the connexin. disease. Initially, the presence of Cx46 in the lens was identified, favoring the survival of lens cells in the hypoxic environment present in this tissue, a function that was confirmed in breast cancer cells subjected to hypoxia, a key component in the tumor microenvironment generated in the cancer progression. . Background from our laboratory shows that increased Cx46 expression in MCF-7 breast cancer cells favors the upregulation of genes related to epithelial-mesenchymal transition (EMT) and cancer stem cells (CSC). In addition, our laboratory has described the presence of Cx46 in extracellular vesicles (EVs-Cx46) released by MCF-7 breast cancer cells that overexpress Cx46, showing increased migration and invasion in recipient cells. This behavior was not observed when incubated with EVs that do not contain Cx46 (EVs-Cx46-sans), which attributes a new role to EVs that contain Cx46 in the promotion of protumoral processes. However, the effect of hypoxia on Cx46 expression in MCF-7 breast cancer cells, its subsequent release in electric vehicles, and finally the contribution of these Cx46-containing vesicles in promoting the angiogenesis process are questions. that we intend to answer in this thesis project. Based on the above objectives, it is postulated that the angiogenesis process is promoted by Cx46-containing EVs from breast cancer cells subjected to hypoxia.
Notas
Tesis (Ingeniero en Biotecnología)
Palabras clave
Anoxia, Vesículas Extracelulares, Neovascularización Fisiológica, Cáncer Mamario