Caracterización del contenido de exosomas asociados a tumor en una población con cáncer gástrico

ilustraciones (algunas a color), diagramas, fotografías

Autores:: Rincón-Riveros, Walter Andrés

Tipo de recurso:: Doctoral thesis

Fecha de publicación:: 2023

Institución:: Universidad Nacional de Colombia

Repositorio:: Universidad Nacional de Colombia

Idioma:: spa

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repository_id_str
dc.title.spa.fl_str_mv	Caracterización del contenido de exosomas asociados a tumor en una población con cáncer gástrico
dc.title.translated.eng.fl_str_mv	Characterizing the content of exosomes associated with tumors in a population of gastric cancer patients.
title	Caracterización del contenido de exosomas asociados a tumor en una población con cáncer gástrico
spellingShingle	Caracterización del contenido de exosomas asociados a tumor en una población con cáncer gástrico 610 - Medicina y salud::616 - Enfermedades Neoplasias gástricas Exosomas MicroARNs Carcinogénesis Proteómica Biomarcadores de tumor Perfilación de la expresión génica Stomach neoplasms Exosomes Proteomics Biomarkers, Tumor Cáncer gástrico Exosomas miRNAs Proteómica Biomarcadores Transcriptómica Gastric cancer Exosomes miRNAs Proteomic Biomarkers Transcriptomics
title_short	Caracterización del contenido de exosomas asociados a tumor en una población con cáncer gástrico
title_full	Caracterización del contenido de exosomas asociados a tumor en una población con cáncer gástrico
title_fullStr	Caracterización del contenido de exosomas asociados a tumor en una población con cáncer gástrico
title_full_unstemmed	Caracterización del contenido de exosomas asociados a tumor en una población con cáncer gástrico
title_sort	Caracterización del contenido de exosomas asociados a tumor en una población con cáncer gástrico
dc.creator.fl_str_mv	Rincón-Riveros, Walter Andrés
dc.contributor.advisor.spa.fl_str_mv	López Kleine, Liliana Villegas Galvez, Victoria Eugenia Rodríguez, Josefa Antonia
dc.contributor.author.spa.fl_str_mv	Rincón-Riveros, Walter Andrés
dc.contributor.researchgroup.spa.fl_str_mv	Grupo de Investigación en Bioinformática y Biología de Sistemas Moléculas Biológicas y Actividad Celular (Universidad del Rosario) Biología del Cáncer (Instituto Nacional de Cancerología)
dc.contributor.orcid.spa.fl_str_mv	0000-0002-6654-0195
dc.contributor.cvlac.spa.fl_str_mv	Rincón Riveros Walter Andrés
dc.subject.ddc.spa.fl_str_mv	610 - Medicina y salud::616 - Enfermedades
topic	610 - Medicina y salud::616 - Enfermedades Neoplasias gástricas Exosomas MicroARNs Carcinogénesis Proteómica Biomarcadores de tumor Perfilación de la expresión génica Stomach neoplasms Exosomes Proteomics Biomarkers, Tumor Cáncer gástrico Exosomas miRNAs Proteómica Biomarcadores Transcriptómica Gastric cancer Exosomes miRNAs Proteomic Biomarkers Transcriptomics
dc.subject.decs.spa.fl_str_mv	Neoplasias gástricas Exosomas MicroARNs Carcinogénesis Proteómica Biomarcadores de tumor Perfilación de la expresión génica
dc.subject.decs.eng.fl_str_mv	Stomach neoplasms Exosomes Proteomics Biomarkers, Tumor
dc.subject.proposal.spa.fl_str_mv	Cáncer gástrico Exosomas miRNAs Proteómica Biomarcadores Transcriptómica
dc.subject.proposal.eng.fl_str_mv	Gastric cancer Exosomes miRNAs Proteomic Biomarkers Transcriptomics
description	ilustraciones (algunas a color), diagramas, fotografías
publishDate	2023
dc.date.issued.none.fl_str_mv	2023-11-23
dc.date.accessioned.none.fl_str_mv	2024-01-15T20:41:51Z
dc.date.available.none.fl_str_mv	2024-01-15T20:41:51Z
dc.type.spa.fl_str_mv	Trabajo de grado - Doctorado
dc.type.driver.spa.fl_str_mv	info:eu-repo/semantics/doctoralThesis
dc.type.version.spa.fl_str_mv	info:eu-repo/semantics/acceptedVersion
dc.type.coar.spa.fl_str_mv	http://purl.org/coar/resource_type/c_db06
dc.type.content.spa.fl_str_mv	Text
dc.type.redcol.spa.fl_str_mv	http://purl.org/redcol/resource_type/TD
format	http://purl.org/coar/resource_type/c_db06
status_str	acceptedVersion
dc.identifier.uri.none.fl_str_mv	https://repositorio.unal.edu.co/handle/unal/85302
dc.identifier.instname.spa.fl_str_mv	Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv	Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv	https://repositorio.unal.edu.co/
url	https://repositorio.unal.edu.co/handle/unal/85302 https://repositorio.unal.edu.co/
identifier_str_mv	Universidad Nacional de Colombia Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv	spa
language	spa
dc.relation.indexed.spa.fl_str_mv	Bireme
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spelling	Reconocimiento 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2López Kleine, Liliana9c5b8dea895d5ed7db5c3cb9b48fb925Villegas Galvez, Victoria Eugeniaf90d3bd1992c42472f2ccf7aec4955dfRodríguez, Josefa Antonia76f507b35ecb2c04dbaf12a36def5210Rincón-Riveros, Walter Andrés3cd1dd4fd399d3e0dfea9cfe38e973a6Grupo de Investigación en Bioinformática y Biología de SistemasMoléculas Biológicas y Actividad Celular (Universidad del Rosario)Biología del Cáncer (Instituto Nacional de Cancerología)0000-0002-6654-0195Rincón Riveros Walter Andrés2024-01-15T20:41:51Z2024-01-15T20:41:51Z2023-11-23https://repositorio.unal.edu.co/handle/unal/85302Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones (algunas a color), diagramas, fotografíasA nivel mundial, uno de los tipos de cáncer con mayor incidencia y mortalidad es el cáncer gástrico, que ocupa el quinto lugar en incidencia con más de 1. 000.000 de casos nuevos en 2020, lo que correspondió al 5.6% del total de casos de cáncer a nivel mundial, y con una mortalidad que supera los 750.000 decesos, de acuerdo con lo reportado en Globocan 2020. El cáncer gástrico es 50% más común en hombres que en mujeres. Según Cancer Today de la Agencia Internacional para la investigación en cáncer (IARC), el cáncer gástrico es la principal causa de muerte por cáncer en hombres en Colombia, con aproximadamente 3.963 muertes y la quinta causa de muerte en mujeres con más de 2.488 muertes, por lo cual es considerado como un problema de salud pública. Su alta mortalidad es debida en parte, a la dificultad para realizar un diagnóstico oportuno, y aunque la prueba de oro para el diagnóstico de este cáncer es la endoscopia-biopsia, esta prueba no es costo-efectiva para ser implementada como prueba de tamizaje en países que están en vías de desarrollo. Los exosomas son vesículas de entre 30 y 100nm de diámetro, secretadas por las células cuya síntesis, en el sistema endosomal, es mediada por la formación de cuerpos multivesiculares (MVB) que se fusionan con la membrana celular para liberarlas al ambiente extracelular. Poseen una membrana bi-lipídica rica en colesterol, ceramidas, y residuos de fosfatidilserina; y transportan una amplia variedad de DNA, RNA, proteínas y lípidos que les confieren una gran variedad de funciones en diferentes escenarios, que abarcan desde el transporte de moléculas y la comunicación célula-célula a nivel local o sistémico, hasta la regulación inmunológica. Los exosomas derivados de células tumorales juegan un papel fundamental en el microambiente tumoral al favorecer la comunicación entre las células tumorales, o entre éstas y las células del sistema inmune. Se considera que su secreción es un mecanismo mediante el cual el tumor es capaz de favorecer su propio desarrollo al transportar moléculas moduladoras del sistema inmune tales como HLA-G, PD1, PD-L1, CTLA-4, oncoproteínas y factores de crecimiento. También se ha descrito su papel en la transferencia horizontal de diversos tipos de RNA capaces de incrementar la agresividad de las células tumorales. Dada la importancia de los exosomas en el desarrollo y progresión del cáncer gástrico, este estudio tuvo como objetivo identificar y caracterizar los contenidos biológicos de los exosomas asociados a tumor, con el fin de obtener información relevante acerca del papel de los exosomas en el desarrollo y establecimiento de la enfermedad. La investigación fue desarrollada en dos fases: inicialmente se realizó un estudio in-silico en el cual se ejecutó un metaanálisis con 7 bases de datos de miRNAs provenientes de exosomas aislados de diferentes tipos de cáncer, en búsqueda de un patrón molecular común a todos ellos. Posteriormente se desarrolló la fase experimental, en la cual se incluyeron exosomas aislados del plasma de 30 pacientes: 20 con cáncer gástrico y 10 con enfermedades gástricas benignas. La metodología empleada para desarrollar la etapa experimental incluyó un protocolo ajustado para la obtención de los exosomas a partir de plasma humano, su caracterización por microscopía electrónica de barrido, análisis de nano-partículas y detección de la expresión de proteínas propias de los exosomas. Una vez caracterizados los exosomas, se realizó la extracción de los miRNAs y las proteínas, y luego, mediante el uso de técnicas de nueva generación como RNA-seq y espectrometría de masas, se determinó su composición en cuanto a miRNAs y proteínas. Se identificó una firma de 9 miRNAs y 35 proteínas con expresión diferencial entre los pacientes con cáncer gástrico y aquellos con enfermedades gástricas benignas, asociadas con procesos biológicos y rutas metabólicas involucradas en la carcinogénesis. En cuanto a la caracterización a nivel de proteínas, se identificaron más de 700 proteínas en los exosomas de pacientes con cáncer gástrico y con enfermedades gástricas benignas. Se determino 5 proteínas con implicaciones en el desarrollo del cáncer y que pueden ser estudiadas con el fin de establecer su utilidad como biomarcadores. Los resultados aquí presentados pueden ser tomados como punto de partida para el descubrimiento de nuevos biomarcadores para el diagnóstico y seguimiento del cáncer gástrico a partir de exosomas aislados en biopsia liquida. (Texto tomado de la fuente)Gastric cancer is a prevalent and deadly type of cancer worldwide, ranking fifth in terms of incidence with over 1,000,000 new cases in 2020, accounting for 5.6% of total cancer cases globally. Furthermore, according to the Globocan 2020 report, the number of deaths resulting from the issue surpasses 750,000. Men are 50% more likely to develop gastric cancer than women. In Colombia, gastric cancer is the leading cause of cancer-related death among men, with approximately 3,963 deaths, and the fifth leading cause of death among women, with over 2,488 deaths. Consequently, it poses a significant public health concern. The high mortality is partly attributed to challenges in achieving timely diagnosis, with endoscopy-biopsy being the gold standard but not cost-effective for screening in developing countries. Exosomes, small vesicles ranging from 30 to 100 nm in diameter, are secreted by cells through the endosomal system. They are formed through the fusion of multivesicular bodies (MVBs) with the cell membrane, releasing them into the extracellular environment. Exosomes possess a cholesterol-rich bilipid membrane containing ceramides and phosphatidylserine residues. They serve as vehicles for transporting a diverse range of DNA, RNA, proteins, and lipids, enabling various functions in different contexts. These functions include molecular transportation, local or systemic cell-to-cell communication, and immunoregulation. Exosomes derived from tumor cells play a crucial role in the tumor microenvironment by facilitating communication among tumor cells and between tumor cells and immune cells. Their secretion serves as a mechanism through which tumors promote their own development by transporting immune system-modulating molecules, such as HLA-G, PD1, PD-L1, CTLA-4, oncoproteins, and growth factors. Additionally, they have been implicated in the horizontal transfer of various types of RNA, which can enhance the aggressiveness of tumor cells. Given the significance of exosomes in the development and progression of gastric cancer, this study aimed to identify and characterize the biological contents of tumor-associated exosomes to gain relevant insights into their role in disease development and establishment. The research comprised two phases. Firstly, an in-silico study involved a meta-analysis of miRNAs from exosomes isolated from different types of cancer using seven databases to identify common molecular patterns. Subsequently, the experimental phase encompassed the isolation of exosomes from the plasma of 30 patients, including 20 with gastric cancer and 10 with benign gastric diseases. The experimental methodology entailed a customized protocol for exosome isolation from human plasma, followed by their characterization using scanning electron microscopy, nanoparticle analysis, and detection of exosome-specific protein expression. After characterizing the exosomes, miRNAs and proteins were extracted, and their composition was determined using advanced techniques such as RNA-seq and mass spectrometry. The protein characterization identified over 700 proteins in the exosomes, 35 of them exhibiting differential expression between patients with gastric cancer and those with benign gastric. Five proteins with implications in cancer development were identified, warranting further investigation to evaluate their potential as biomarkers. These molecules are associated with biological processes and metabolic pathways involved in carcinogenesis. On the other hand, 156 miRNAs were identified in the exosomes, 9 of them differentially expressed between gastric cancer patients and controls. The findings presented in this study serve as a promising foundation for the discovery of novel biomarkers for the diagnosis and monitoring of gastric cancer using exosomes isolated from liquid biopsies.DoctoradoDoctor en Oncología151 páginasapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Medicina - Doctorado en OncologíaFacultad de MedicinaBogotá, ColombiaUniversidad Nacional de Colombia - Sede Bogotá610 - Medicina y salud::616 - EnfermedadesNeoplasias gástricasExosomasMicroARNsCarcinogénesisProteómicaBiomarcadores de tumorPerfilación de la expresión génicaStomach neoplasmsExosomesProteomicsBiomarkers, TumorCáncer gástricoExosomasmiRNAsProteómicaBiomarcadoresTranscriptómicaGastric cancerExosomesmiRNAsProteomicBiomarkersTranscriptomicsCaracterización del contenido de exosomas asociados a tumor en una población con cáncer gástricoCharacterizing the content of exosomes associated with tumors in a population of gastric cancer patients.Trabajo de grado - Doctoradoinfo:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/acceptedVersionhttp://purl.org/coar/resource_type/c_db06Texthttp://purl.org/redcol/resource_type/TDBiremeWagner AD, Syn NL, Moehler M, Grothe W, Yong WP, Tai B-C, et al. 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Available from: https://doi.org/10.1126/scitranslmed.abo3958Instituto Nacional de CancerologíaEstudiantesInvestigadoresLICENSElicense.txtlicense.txttext/plain; charset=utf-85879https://repositorio.unal.edu.co/bitstream/unal/85302/1/license.txteb34b1cf90b7e1103fc9dfd26be24b4aMD51ORIGINAL1024488908_2023.pdf1024488908_2023.pdfTesis de Doctorado en Oncologíaapplication/pdf4636804https://repositorio.unal.edu.co/bitstream/unal/85302/2/1024488908_2023.pdfec03faafb084a8722f1bff73754a62c1MD52THUMBNAIL1024488908_2023.pdf.jpg1024488908_2023.pdf.jpgGenerated Thumbnailimage/jpeg3797https://repositorio.unal.edu.co/bitstream/unal/85302/3/1024488908_2023.pdf.jpg08fe549ea7c76306983c01a14522e43cMD53unal/85302oai:repositorio.unal.edu.co:unal/853022024-08-20 23:10:49.351Repositorio Institucional Universidad Nacional de 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