Browsing by Subject "Colon"

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    A comparison between double and triple therapies of octreotide, galanin and serotonin on a rat colon carcinoma
    (Murcia : F. Hernández, 2003) Sitohy, B.; El-Salhy, M.
    Sixty female nude mice (C578L/6jBom-nu) were injected with 100µl cell suspension containing 2x106 viable cells of an N-methyl-N-nitroguanidineinduced rat colonic adenocarcinoma. After seven days the animals were divided into five groups. The first group received only saline and served as a control group. The second group received a triple therapy of octreotide, galanin and serotonin (20 µg/kg). The last three groups received double therapies of octreotide/galanin, octreotide/serotonin or galanin/serotonin (20 µg/kg). They were treated twice a day for five days. Tumour volume and weight, relative volume density of tumourfeeding blood vessels and of tumour necrotic tissue, as well as apoptotic and proliferation indices were determined. Animal weight, food consumption, faeces weight and its water content were recorded before and after treatment. Tumour volume was significantly reduced only in the group that received the triple therapy. The volume density of the tumour-feeding blood vessels was significantly reduced in the treated groups with the exception of the group that received octreotide and serotonin. Increased relative volume density of tumour necrotic tissue occurred only in the group treated with triple therapy. Apoptotic indices were significantly increased in all treated groups. No statistical difference was found between treated animals and controls regarding proliferation indices, food consumption, faeces weight and water content or animal weight. In conclusion, double therapy using two of the gastrointestinal bioactive substances, octreotide, galanin and serotonin, has certain effects on colon cancer cells. To cause a considerable tumour necrosis, triple therapy seems to be required. Both double and triple therapy seem to lack obvious side-effects.
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    Características y supervivencia de los pacientes diagnosticados de cáncer colorrectal en una campaña de cribado frente a pacientes diagnosticados en fase sintomática.
    (2013-07-01) Mengual Ballester, Mónica; Pellicer Franco, Enrique Manuel; Aguayo Albasini, José Luis; Departamento de Cirugía, Pediatría, Obstetricia y Ginecología
    Introducción: El diagnóstico del cáncer colorrectal (CCR) a partir de la clínica se hace en etapas demasiado tardías, siendo la estrategia para reducir su mortalidad la detección precoz y la extirpación de lesiones preneoplásicas y neoplásicas en sus estadios más tempranos, antes incluso de que aparezcan los primeros síntomas, mediante las campañas de cribado. Objetivos: Demostrar que los pacientes intervenidos de CCR diagnosticados mediante campaña de cribado presentan factores pronósticos más favorables, mayor supervivencia y supervivencia libre de enfermedad que los diagnosticados en fase sintomática. Material y métodos: Se toman como muestra todos los pacientes intervenidos de forma programada de CCR en el Hospital JM Morales Meseguer, entre 2004 -2010. Se recogen los distintos factores pronósticos de la serie de forma prospectiva. Resultados: Los pacientes con CCR diagnosticados mediante el cribado presentan factores pronósticos más favorables, una mayor supervivencia, menor recidiva y menor tratamiento adyuvante. Palabras clave:Cáncer colorrectal; screening cáncer colorrectal; supervivencia cáncer colorrectal; recidiva cáncer colorrectal; factores pronósticos cáncer colorrectal. ABSTRACT: Introduction: The diagnosis of colorectal cancer (CRC) from the clinic is done in stages too late, the strategy to reduce mortality is the early detection and removal of preneoplastic lesion and neoplasias in the earliest stages, even before the first symptoms appear, by screening campaigns. Objectives: Demonstrate that patients diagnosed of CRC in screening campaign have more favorable prognostic factors, longer survival and disease-free survival than those diagnosed in symptomatic phase. Material and methods: Are sampled all patients underwent programmed surgery for CRC in JM Morales Meseguer Hospital, between 2004 -2010. We collected different predictors factors prospectively. Conclusion: Patients with CRC diagnosed at screening have favorable prognostic factors, longer survival and lower recurrence rates and lower adjuvant treatment. Key words: Cancer Colorectal; Colorectal cancer screening; Colorectal cancer survival; Colorectal cancer recurrence; Colorectal cancer prognostic factors.
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    Caracterización morfológica, inmunohistoquímica y molecular del adenocarcinoma colorrectal del tipo serrado
    (2013-01-15) García Solano, José; Pérez-Guillermo García, Miguel; Conesa Zamora, Pablo; Facultad de Medicina
    RESUMEN El carcinoma serrado (CS) es un subtipo de carcinoma colorrectal (CCR) recientemente reconocido por la OMS. Hemos estudiado las características clínico-patológicas, factores histológicos con valor pronóstico, expresión inmunohistoquímica de proteínas relacionadas con la invasión tumoral y la reparación del ADN, y la incidencia de inestabilidad de microsatélites (IMS) y de mutaciones en KRAS y BRAF en una serie de 85 CS seleccionados tras la revisión de las piezas quirúrgicas de 927 CCR consecutivos. Concluimos que los CS tienen peor supervivencia que los CCR convencionales (CC) y presentan características histológicas de mal pronóstico y distinta expresión de proteínas en el frente invasor, así como un estatus IMS y perfil mutacional que es diferente del observado en los CC. Estos hallazgos nos permiten considerar al CS como una entidad distinta dentro del conjunto de los CCR que muestra peor pronóstico y un perfil de mutaciones diferente que justificaría su resistencia a las terapias anti-EGFR. PALABRAS CLAVE: carcinoma colorrectal, carcinoma serrado, pronóstico, adenomas serrados, frente invasor, estatus IMS, mutaciones KRAS, mutaciones BRAF, proteínas reparadoras de ADN, MGMT. Serrated carcinoma (SC) has been recently recognised by WHO as a pathological subtype of colorectal cancer (CRC). Out of 927 consecutive CRC 85 SC were identified by histological criteria. In this series we studied demographical, pathological and clinical features, 5-year survival, histological features with prognostic value, immunohistochemical expression pattern of several proteins related to tumour invasiveness and DNA repair, microsatellite instability (MSI) and incidence of KRAS and BRAF mutations. Our results demonstrate that SC shows worse 5-years survival than conventional colorectal cancer (CC), higher frequency of adverse histological prognostic features, and different protein expression pattern at the invasive front, MSI status and mutational profile that CC. Our findings confirm that SC is a different entity with poorer outcome and higher frequency of KRAS and BRAF mutation which suggest a potential resistance to anti-EGFR therapy. KEYWORDS: colorectal cancer, serrated carcinoma, prognosis, serrated adenomas, invasive front, MSI, KRAS mutations, BRAF mutations, mismatched repair proteins, MGMT.
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    Colonic endocrine cells in rats with chemically induced colon carcinoma
    (Murcia : F. Hernández, 2001) Sitohy, B.; El-Salhy, M.
    Colonic carcinoma was induced in male Sprague-Dawley rats by injecting them with 1,2- dimethylhydrazine dihydrochloride. Control rats were injected with EDTA solution. Tissue specimens of colon from four groups of animals: (i) rats without tumour, (ii) with dysplasia and lymphoid hyperplasia, (iii) with colonic adenocarcinoma, and (iv) controls, were investigated. The colonic endocrine cells were detected by immunocytochemistry and quantified by computerised image analysis. Peptide YY (PYY)- and serotonin-immunoreactive cells were found in the colon of al1 the groups investigated. There were few somatostatin- or enteroglucagon-immunoreactive cells and no pancreatic polypeptide (PP)-immunoreactive cells in the colon of any of the groups studied. The density of PYY-immunoreactive cells increased significantly in rats with dysplasia and lymphoid hyperplasia and in rats with colon carcinoma. There was no statistically significant difference as regards cell secretory index (CSI) or nuclear area of PYYimmunoreactive cells in any of treated groups examined. Nor was there any statistically significant difference between al1 treated animal groups and controls, as regards cell density, CSI, or nuclear area of serotoninimmunoreactive cells. The present observations in an animal model of human colon carcinoma support the assumption that neuroendocrine peptides in the gut are involved in the carcinogenesis of colorectal carcinoma. However, The nature of the changes in the colonic endocrine cells observed here differed from those in patients with colon carcinoma, possibly due to a difference between the response of young rats to an induced colon carcinoma and a spontaneously developed carcinoma in elderly humans, or due to a species difference.
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    Does diabetic state affect CO-localization of peptide W and enteroglucagon in colonic endocrine cells?
    (Murcia : F. Hernández, 2000) Spangeus, A.; Forsgren, Sture; El-Salhy, M.
    Background: Changes in the numbers of PYY- and enteroglucagon-immunoreactive cells in colon of animal models of human diabetes have been reported. As these peptides CO-localize in the same cells it is possible that the observed changes are a result of changes in CO-localization. Methods: Animal models of human type 1 and type 2 diabetes, namely the non-obese diabetic (NOD) mouse and the obese (oblob) mouse, were studied. As controls for the NOD mice, BALBIcJ mice were used and for oblob mice, homozygous lean (+l+) mice were used. Tissue samples from colon were double-immunostained for PYY and enteroglucagon according to the indirect immunofluorescence method. Results: CO-localization of enteroglucagon and PYY was found in colonic endocrine cells in all groups investigated. Compared with controls, pre-diabetic NOD mice showed a decreased proportion of enteroglucagon1PYY CO-localization. There was no difference in diabetic NOD mice or diabetic oblob mice when compared with controls. Conclusions: Whereas the number of cells containing solely enteroglucagon and solely PYY increases in pre-diabetic NOD mice, production of enteroglucagon in PYY-immunoreactive cells decreases. Although the numbers of PYY and enteroglucagon cells have been reported to be changed in both diabetic NOD mice and in obese mice, the balance between CO-expressing and mono-expressing cells seems to be preserved.
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    Effects of triple therapy with octreotide, galanin and serotonin on a human colon cancer cell line implanted in mice: comparison between different routes of administration
    (Murcia : F. Hernández, 2005) El-Salhy, M.
    A human colon cancer cell line was implanted subcutaneously in nude mice. After 7 days, the animals were divided into four groups. The first group received an intraperitoneal (i.p.) continuous infusion by an osmotic pump, the second was given i.p. bolus injections, the third received continuous subcutaneous (s.c.) infusion by an osmotic pump and the fourth group was given bolus s.c. injections. Each group was divided into 2 subgroups. The first subgroup received triple treatment with octreotide, galanin, and serotonin, 40 µg/kg body weight/day of each. The second subgroup was given sterile saline solution. Treatment lasted for 14 days. The volume and wet weight of the tumours in all treated groups tended to decrease, but was statistically significant only in the group with continuous i.p. infusion. The number of viable cells tended to decrease in all the treated groups, but was not statistically significant. Proliferation index was significantly reduced in mice given triple therapy i.p. as bolus injection and as continuous infusion, as compared with their respective controls. The apoptotic index increased significantly in mice receiving triple therapy as continuous i.p. infusion as revealed by both the TUNEL method and by poly (ADP-ribose) polymerase (PARP) expression. The number of tumour blood vessels was significantly reduced in the mice given triple therapy as continuous i.p. infusion, as compared with controls. There was no statistical difference between animals treated by different routes, regarding proliferation or apoptosis of the cancer cells, or the number or mean luminal area of tumour blood vessels. The present investigation showed that regardless of the route of administration, triple therapy with octreotide, galanin and serotonin generally reduced the volumes, weights, viable cells, vascularization and proliferation of the tumours, as well as inducing apoptosis. Continuous i.p. infusion appears, however, to be the most effective route of administration.
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    Estimulación del asa eferente previa al cierre de ileostomía de protección. Estudio prospectivo randomizado / Israel Abellán Morcillo
    (2014-02-28) Abellán Morcillo, Israel; Parrilla Paricio, Pascual; Luján Mompeán, Juan Antonio; Facultad de Medicina
    Objetivo Pretendemos evaluar la utilidad de una nueva técnica en la disminución del íleo postoperatorio tras el cierre de ileostomía de protección. Introducción El íleo paralítico postoperatorio representa la complicación más frecuente tras el cierre de ileostomía con un aumento de la morbilidad, estancia hospitalaria y gasto sanitario. Pacientes y método Este estudio prospectivo randomizado incluye a 70 pacientes intervenidos de cierre de ileostomía. En 35 pacientes se realizó previamente a la cirugía, una estimulación diaria los 15 días previos a la intervención, del segmento intestinal excluido, a través del asa eferente de la ileostomía con una solución de consistencia espesa. En los otros 35 pacientes no se realizó estimulación previa a la cirugía. El estudio fue aprobado por el comité ético del Hospital y registrado en ClinicalTrials.gov con el número de inscripción NCT01881594. Resultados Ambos grupos de pacientes fueron homogéneos respecto a los datos demográficos, características de la primera intervención del cáncer de recto y periodo intercirugias. Tras el cierre de la ileostomía el grupo de pacientes estimulados presentaba un inicio más precoz de la tolerancia oral: 1,06 vs 2,57 días (p=0,007) y de la emisión de gases y/o heces: 1,14 vs 2,8 días (p<0,001) respecto al grupo de pacientes no estimulados. La incidencia de íleo postoperatorio: 2,8% vs 20 % (p=0,024) y la estancia hospitalaria: 2,4 vs 5,09 días (p=0,01) también fue menor en los pacientes estimulados. No hubo diferencias respecto al resto de complicaciones. Conclusiones La estimulación del asa eferente de la ileostomía previa a su cierre es una técnica segura y reproducible que en nuestra experiencia, disminuye el íleo postoperatorio y favorece un tránsito intestinal y una tolerancia oral precoces con una menor estancia hospitalaria postoperatoria. Palabras clave: cáncer de recto, ileostomía de protección, ileo postoperatorio, estimulación. Objective The aim of this study is to assess the utility of a new technique for reducing postoperative ileus after protective ileostomy closure. Background Postoperative ileus is the most common complication after ileostomy closure with an increase in morbidity, hospital stay and healthcare costs. Methods This prospective randomised study included 70 patients undergoing surgery for ileostomy closure. In 35 patients, over the 2 weeks prior to surgery, daily stimulation of the defunctionalised stomal segment was performed using a thick solution. In the other 35 patients stimulation was not performed prior to surgery. The study was approved by the Hospital Ethics Committee and registered on ClinicalTrials.gov with inscription number NCT01881594. Results Both groups of patients were homogenous for demographic data, characteristics of the first rectal cancer operation and intersurgery periods. After ileostomy closure, the stimulated group of patients had an earlier return to oral tolerance (1.06 vs 2.57 days; p=0.007) and passage of flatus or stool (1.14 vs 2.8 days; p<0.001) than the non-stimulated group of patients. The incidence of postoperative ileus (2.8% vs 20 %; p=0.024) and hospital stay (2.4 vs 5.09 days; p=0.01) was also lower in the stimulated patients. There were no differences in terms of the other complications. Conclusions Stimulation of the efferent limb of the ileostomy prior to closure is a safe and reproducible technique that reduces postoperative ileus and fosters early intestinal transit and oral tolerance with a shorter postoperative hospital stay. Keywords: rectal cancer, protective ileostomy, postoperative ileus, stimulation.
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    Functional morphology of the equine pelvic flexure and its role in disease. A review
    (F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2000) Lopes, M.A.F.; Pfeiffer, C. J.
    The hindgut is the major site in the horse for nutrient digestion and absorption . Most of this activity occurs in the large intestinal compartments, i.e., cecum, right and left ventral colon and left and right dorsal colon. The colonic pelvic flexure is a short and narrow loop connecting the left ventral and left dorsal colon. It is not significant directly in digestive and absorptive processes but plays an important functional role in regulating colonic aboral and retropropulsive transit of digesta through its motility pacemaker activity. The pelvic flexure also contributes to the pathophysiology of colic, the leading cause of death in horses. Its narrow lumen may contribute to colonic impaction, and malfunctions of the pacemaker may contribute to volvuli and colonic displacements. Neuronal and ganglion density of the myenteric plexus is increased at the pelvic flexure and adjacent left dorsal colon pacemaker region. Contractile activity, vasoactive intestinal peptide (VIP) and neurokinins-l and -3 are all enhanced in the pelvic flexure. The mucosa histologically resembles that of the ventral and dorsal colon , with apically-granulated principal cells and goblet cells lining the luminal surface. Clustered intranuclear inclusions resembling the cytoplasmic granules are also observed by electron microscopy in the principal cells as elsewhere in the horse colon. Further neuroendocrine and morphologic investigation of the pelvic flexure is warranted due to the great importance of this localized region for normal function and pathophysiology.
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    Histopathological changes associated to an absorbable fibrin patch (Tachosil®) covering in an experimental model of high-risk colonic anastomoses
    (Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) García Vásquez, C.; Gómez García de las Heras, S.; Pastor Idoate, C.; De Pablo, D.; Fernández Aceñero, M.J.
    Background. TachoSil® is a fibrin sponge that contains fibrinogen and thrombin and is a useful adjuvant to enhance control of air leaks in thoracic surgery and to control bleeding in vascular and general surgery. Its use in intestinal surgery to prevent suture dehiscence is currently under investigation. Material and Methods. We report the results of a prospective randomized experimental study on 33 large white pigs in which a high-risk suture was created by induction of ischemia. We randomly employed TachoSil® to cover the anastomosis in half of the animals compared to a control group of uncovered anastomosis. After euthanasia, postmortem analysis was performed describing the findings related to anastomotic leakage, peritonitis and grade of adhesions. The entire anastomosis was resected in bloc and sent for histopathological analysis. A single blinded-pathologist evaluated the histopathological features of the specimens. Results. We found statistically significant differences favouring the patch in decreasing leakage in the covered group. The healing process did not show significant differences between groups, although a higher rate of microscopic abscess was observed in the covered group. Conclusion. The use of fibrin sealants covering highrisk intestinal sutures has a positive effect in avoiding macroscopic anastomotic leakage. The patch did not have any influence in the anastomotic healing process, however, as a result of the effect in containing the inflammatory response, it may increase the rate of abscess.
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    Macrophages in the external muscle layers of mammalian intestines
    (Murcia : F. Hernández, 1995) Mikkelsen, H.B.
    The literature on macrophages in the muscularis extema of mouse, rat, guinea pig, cat, dog and human gut is reviewed. In smaller mammals macrophages are regularly situated in two locations: in the serosa and at the level of Auerbach's plexus between the longitudinal and circular muscle layers. In addition a few solitary cells are present at the level of the deep muscular plexus. At the level of Auerbach's plexus the macrophages occur as a constant and regularly distributed cell population with intimate associations between macrophages and interstitial cells of Cajal. Morphologically they differ from most resident macrophages in being irregular in shape with 4-6 primary cytoplasmic processes, which branch and give a stellate appearance. They have been demonstrated with endocytotic markers (trypan red, FWC-dextran, cholera toxin), immunocytochemically with macrophage antibodies (F4180, M1170) and antibodies against MHC class-I1 antigen, GABA and cGMP. In muscularis externa of the human gut a regularly distributed cell population of macrophages is not obvious. However, a phenotypically distinct subgroup is identified by light microscopy with the pan macrophage antibodies (EBM11, C3bl and partly by ~1 5 0 . 9 5a)n~d shows MHC class-I1 antigen. By electron microscopy muscularis extema macrophages, in all species investigated, appear to be endocytically downregulated, and since they are lysozyme, prostaglandine H synthase (both constitutive and activated) and acid phosphatase negative, they appear to be inactivated cells. Both origin and function of these cells are unknown. They may be immunocompetent, participate in a neuroimmune axis, tissue growth and modulation or other regulations of specific cell functions.
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    Nucleolar organiser regions in colonic dysplasia. A preliminary study
    (Murcia : F. Hernández, 1989) Sutherland, C.G.G.; McMeekin, W.
    As a preliminary investigation in the evaluation of the argyrophilic nucleolar organiser region (AgNOR) technique in colonic dysplasia, quantitation of AgNORs was carried out in biopsies of normal rectal mucosa and tubulovillous adenomas. The AgNOR counts in the lower third of the normal crypts were approximately twice those in the surface mucosa but there was no significant difference between counts in normal crypt bases and adenomas. It is concluded that the AgNOR technique is unlikely to be of value in the assessment of colonic dysplasia.
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    Structural organization of enteric
    (Murcia : F. Hernández, 1995) Ibba-Manneschi, L.; Martini, M.; Zecchi-Orlandini, S.; Faussone-Pellegrini, M.S
    The organization of the Enteric Nervous System (ENS) was studied in the human colon. Fragments of the whole colonic wall were either routinely processed or Zinc-Iodide Osmium impregnated. Single-layer preparations were also obtained from some of the Zinc-Iodide Osmium-impregnated specimens. The results showed some differences in the organization of human colonic ENS from that of other mammals. In fact, the human submucous plexus was made up of three interconnected ganglionated networks arranged along three different planes. With respect to the myenteric plexus, its ganglia were large sized and irregularly shaped. Moreover, during the microdissection of the colonic wall, we found the absence of a cleavage plane between the circular and longitudinal muscle layers; on the other hand the cleavage plane between mucosa and submucosa was not immediately below the muscularis mucosae, but slightly deeper, since the innermost part of the submucosa remained adhering to overlying layers.
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    Ultrastructural changes of the human enteric nervous system and interstitial cells of Cajal in diverticular disease.
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Alaburda, Paulius; Lukosiene, Jaune I.; Pauza, Audrys G.; Kyguoliene, Kristina Rysevaite; Kupcinskas, Juozas; Saladzinskas, Zilvinas; Pauziene, Neringa
    Background. In spite of numerous advances in understanding diverticular disease, its pathogenesis remains one of the main problems to be solved. We aimed to investigate the ultrastructural changes of the enteric nervous system in unaffected individuals, in asymptomatic patients with diverticulosis and in patients with diverticular disease. Methods. Transmission electron microscopy was used to analyse samples of the myenteric, outer submucosal and inner submucosal plexuses from patients without diverticula (n=9), asymptomatic patients with diverticulosis (n=7) and in patients with complicated diverticular disease (n=9). We described the structure of ganglia, interstitial cells of Cajal and enteric nerves, as well as their relationship with each other. The distribution and size of nerve processes were analysed quantitatively. Results. In complicated diverticular disease, neurons exhibited larger lipofuscin-like inclusions, their membranous organelles had larger cisterns and the nucleus showed deeper indentations. Nerve remodeling occurred in every plexus, characterised by an increased percentage of swollen and fine neurites. Interstitial cells of Cajal had looser contacts with the surrounding cells and showed cytoplasmic depletion and proliferation of the rough endoplasmic reticulum. In asymptomatic patients with diverticulosis, alterations of enteric nerves and ICC were less pronounced. Conclusions. In conclusion, the present findings suggest that most ultrastructural changes of the enteric nervous system occur in complicated diverticular disease. The changes are compatible with damage to the enteric nervous system and reactive remodeling of enteric ganglia, nerves and interstitial cells of Cajal. Disrupted architecture of enteric plexuses might explain clinical and pathophysiological changes associated with diverticular disease
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    Urolithins, pomegranate ellagitannin microbial metabolites, as potential modulators of cell and molecular events associated with colorectal cancer: in vitro vs.: human studies= Potencial de las urolitinas, metabolitos microbianos derivados de los elagitaninos de la granada, como moduladores de procesos celulares y moleculares asociados a cáncer colorrectal: in vitro vs.: estudios en humanos
    (2016-12-02) Núñez Sánchez, María Ángeles; Espín De Gea, Juan Carlos; García Conesa, Mª Teresa; González Sarrías, Antonio; Facultad de Medicina
    El principal objetivo de esta Tesis fue evaluar los potenciales efectos anticancerígenos del consumo de un extracto de granada (EG) en pacientes con cáncer colorrectal (CCR), así como investigar los cambios moleculares asociados a esos efectos tanto in vitro como en humanos. Se investigó: i) el perfil metabólico de los polifenoles de la granada y sus derivados metabólicos en tejidos de colon, sangre y orina obtenidos de pacientes con CCR tras el consumo de dos EGs; ii) los cambios producidos en diversos marcadores moleculares en tejidos de colon tras consumo de EGs; iii) los efectos ejercidos por las urolitinas, así como el papel del metabolismo de Fase II y la relación estructura-actividad de las urolitinas; iv) los efectos anti-proliferativos del ácido elágico (EA) y urolitinas contra el CCR, y los mecanismos moleculares asociados; y v) explorar la actividad anticancerígena de estos compuestos en un modelo de células tipo madre de CCR. Nuestros resultados permitieron describir por primera vez concentraciones significativas de ácido gálico, derivados del EA y hasta 12 urolitinas distintas en tejido colónico (también algunos de ellos en plasma y orina) de pacientes con CCR tras el consumo de EG. Se observaron mayores niveles de estos metabolitos en el tejido sano que en el tumoral. También, se pudo clasificar a los pacientes en tres metabotipos según las urolitinas detectadas: metabotipo A (pacientes que solo producían urolitina A como metabolito final), metabotipo B (además de urolitina A, se detectaba isourolitina A y/o urolitina B) y metabotipo 0 (no productores de urolitinas). Además, describimos por primera vez diferencias significativas en la expresión de determinados marcadores moleculares (microRNAs (miRs) y genes) entre los tejidos sanos y malignos, e identificamos la gran influencia del protocolo experimental, especialmente la cirugía, en la expresión de dichos marcadores; algo bastante subestimado y que puede llevar a error en la propuesta de marcadores de CCR. A pesar de esta influencia y de la variabilidad inter-individual en la expresión de los marcadores estudiados, se observó cierta modulación en varios miRs y genes de pacientes que consumieron los EG, lo que sugiere un posible efecto asociado a si ingesta. Así mismo, se evaluaron los efectos ejercidos por las urolitinas mediante estudios in vitro empleando diferentes modelos celulares de colon, tanto comerciales (células normales y cancerosas) como en cultivos primarios con fenotipo de célula madre aisladas de un paciente. Los resultados mostraron que: i) las urolitinas ejercen diferentes efectos anti-proliferativos dependiendo de la urolitina y la línea celular empleada; ii) los transportadores ABC y el metabolismo de Fase II son mecanismos de resistencia contra las urolitinas; iii) las urolitinas glucurónidos ejercen un efecto antiproliferativo menor que sus equivalentes agliconas; y iv) diferentes mezclas de metabolitos ejercían efectos antiproliferativos similares e inducían el bloqueo del ciclo celular y apoptosis. Además, determinamos cambios relevantes en marcadores clave de cáncer, incluida la inducción de CDKN1A (p21) como mecanismo común de las urolitinas en su actividad anticancerígena. Por último, en el estudio con células de CCR con fenotipo de células madre describimos el efecto de dos mezclas de urolitinas, siendo la mezcla representativa del metabotipo A más eficaz que la del metabotipo B. Los estudios realizados en esta Tesis han permitido caracterizar el perfil metabólico de las urolitinas en tejido colónico de pacientes con CCR, así como describir cambios en marcadores moleculares (miRs y genes específicos relacionados con el CCR) asociados al consumo de EG. Los ensayos in vitro permitieron profundizar en los mecanismos implicados en los efectos anticancerígenos ejercidos por las urolitinas y EA, tanto de manera individual como en mezclas que representan los diferentes metabotipos y a concentraciones fisiológicamente relevantes. ABSTRACT The principal aim of this Thesis was to investigate the potential anti-cancer effects of pomegranate extracts (PEs) containing ellagitannins and ellagic acid (EA) in colorectal cancer (CRC) patients, and to further clarify the molecular changes that may underlie these effects by in vitro studies. In these works we studied: i) the metabolic profiling of pomegranate phenolics and derived metabolites in colon tissue samples, blood and urine from CRC patients after the intake of PEs; ii) the potential molecular changes in these colonic tissues associated with the intake of PEs; iii) the effects of urolithins against CRC as well as the role of Phase-II metabolism and the structure-activity relationship of urolithins; iv) the anti-proliferative effects and molecular mechanisms associated with the response to EA and urolitinas against CRC; and v) to explore new potentialities of these compounds to battle CRC using a CRC stem cell model. Our results showed for the first time the presence of significant levels of EA derivatives and urolithins in colon tissues from CRC patients after the consumption of PE as well as the presence of these metabolites in plasma and urine. Individual and total metabolites levels were higher in normal than in malignant colon tissues. Furthermore, patients could be classified into three metabotypes according to the urolithins detected: metabotype A (only Uro-A is produced as final urolithin), metabotype B (in addition to Uro-A, also IsoUro-A and/or Uro-B are specifically produced in this metabotype), and metabotype 0 (urolithin non-producers). These studies were critical to design more reliable in vitro studies. Next, we described significant differences in the expression of specific molecular markers (microRNAs (miRs) and specific genes) between healthy and malignant tissues, and the critical influence of the experimental protocol, mostly the surgical procedure, in the expression of these markers. However, despite the influence of the experimental procedures and the inter-individual variability in the expression of the molecular markers studied, we discriminated a moderate modulation of several miRs and specific genes in patients who consumed the PEs suggesting a potential effect associated with their intake. In addition, the effects of urolithins were evaluated in in vitro studies using different commercial colon cell lines (normal and malignant) and primary cultures with stem cell-like phenotype isolated from a CRC patient. These results showed that: i) urolithins exerted different anti-proliferative effects depending on the urolithin and the cell line used; ii) the role of ABC transporters and Phase II metabolism as mechanisms of cancer resistance against urolithins; iii) urolithin glucuronides exerted lower effect then their aglycone counterparts; and iv) the two mixtures of urolithins and EA, resembling the human urolithin metabotypes, exerted similar anti-proliferative effects and induced cell cycle arrest and apoptosis. Furthermore, we described significant changes in key cancer markers and corroborated that CDKN1A (p21) induction is a common mechanism underlying the anticancer effect of urolithins. Finally, we carried out a study with colorectal CSC where the effect of the two mixtures mimicking both metabotypes A and B were evaluated. Herein, we reported that metabotype A exerted higher anticancer properties (lower number and size of colonospheres and lower expression of the cancer chemoresistant marker ALDH) than metabotype B in this cell model. The studies included in this Thesis allowed us to describe the metabolic profiling of urolithins in colon tissue of patients with CRC and to describe changes in molecular markers (miRs and specific genes related to CRC) associated with the intake of PEs. The in vitro studies allowed to deepen into the mechanisms involved in the anti-cancer effects exerted by the urolithins and EA, both individually and in mixtures representative of different human metabotypes.