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1.
Cancer Biol Ther ; 21(9): 799-805, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32594830

RESUMEN

Most sporadic colorectal cancer reflects acquired mutations in the adenomatous polyposis coli (APC) tumor suppressor gene, while germline heterozygosity for mutant APC produces the autosomal dominant disorder Familial Adenomatous Polyposis (FAP) with a predisposition to colorectal cancer. In these syndromes, loss of heterozygosity (LOH) silences the remaining normal allele of APC, through an unknown mechanism, as the initiating step in transformation. Guanylyl cyclase C receptor (GUCY2C) and its hormones, uroguanylin and guanylin, have emerged as a key signaling axis opposing mutations driving intestinal tumorigenesis. Indeed, uroguanylin and guanylin are among the most commonly repressed genes in colorectal cancer. Here, we explored the role of APC heterozygosity in mechanisms repressing hormone expression which could contribute to LOH. In genetic mouse models of APC loss, uroguanylin and guanylin expression were quantified following monoallelic or biallelic deletion of the Apc gene. Induced biallelic loss of APC repressed uroguanylin and guanylin expression. However, monoallelic APC loss in Apcmin/+ mice did not alter hormone expression. Similarly, in FAP patients, normal colonic mucosa (monoallelic APC loss) expressed guanylin while adenomas and an invasive carcinoma (biallelic APC loss) were devoid of hormone expression. Thus, uroguanylin and guanylin expression by normal intestinal epithelial cells persists in the context of APC heterozygosity and is lost only after tumor initiation by APC LOH. These observations reveal a role for loss of the hormones silencing the GUCY2C axis in tumor progression following biallelic APC loss, but not in mechanisms creating the genetic vulnerability in epithelial cells underlying APC LOH initiating tumorigenesis.


Asunto(s)
Poliposis Adenomatosa del Colon/genética , Genes Supresores de Tumor , Receptores de Enterotoxina/genética , Poliposis Adenomatosa del Colon/patología , Animales , Transformación Celular Neoplásica , Silenciador del Gen , Humanos , Masculino , Ratones
2.
Cancer Res ; 77(18): 5095-5106, 2017 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-28916678

RESUMEN

High doses of ionizing radiation induce acute damage to epithelial cells of the gastrointestinal (GI) tract, mediating toxicities restricting the therapeutic efficacy of radiation in cancer and morbidity and mortality in nuclear disasters. No approved prophylaxis or therapy exists for these toxicities, in part reflecting an incomplete understanding of mechanisms contributing to the acute radiation-induced GI syndrome (RIGS). Guanylate cyclase C (GUCY2C) and its hormones guanylin and uroguanylin have recently emerged as one paracrine axis defending intestinal mucosal integrity against mutational, chemical, and inflammatory injury. Here, we reveal a role for the GUCY2C paracrine axis in compensatory mechanisms opposing RIGS. Eliminating GUCY2C signaling exacerbated RIGS, amplifying radiation-induced mortality, weight loss, mucosal bleeding, debilitation, and intestinal dysfunction. Durable expression of GUCY2C, guanylin, and uroguanylin mRNA and protein by intestinal epithelial cells was preserved following lethal irradiation inducing RIGS. Oral delivery of the heat-stable enterotoxin (ST), an exogenous GUCY2C ligand, opposed RIGS, a process requiring p53 activation mediated by dissociation from MDM2. In turn, p53 activation prevented cell death by selectively limiting mitotic catastrophe, but not apoptosis. These studies reveal a role for the GUCY2C paracrine hormone axis as a novel compensatory mechanism opposing RIGS, and they highlight the potential of oral GUCY2C agonists (Linzess; Trulance) to prevent and treat RIGS in cancer therapy and nuclear disasters. Cancer Res; 77(18); 5095-106. ©2017 AACR.


Asunto(s)
Rayos gamma/efectos adversos , Tracto Gastrointestinal/efectos de la radiación , Síndrome del Colon Irritable/prevención & control , Traumatismos Experimentales por Radiación/prevención & control , Receptores Acoplados a la Guanilato-Ciclasa/metabolismo , Receptores de Péptidos/metabolismo , Animales , Apoptosis/efectos de la radiación , Proliferación Celular/efectos de la radiación , Neoplasias del Colon/enzimología , Neoplasias del Colon/patología , Neoplasias del Colon/radioterapia , Femenino , Hormonas Gastrointestinales/metabolismo , Humanos , Síndrome del Colon Irritable/enzimología , Síndrome del Colon Irritable/etiología , Linfoma/enzimología , Linfoma/patología , Linfoma/radioterapia , Masculino , Melanoma Experimental/enzimología , Melanoma Experimental/patología , Melanoma Experimental/radioterapia , Ratones , Ratones Endogámicos C57BL , Péptidos Natriuréticos/metabolismo , Comunicación Paracrina/efectos de la radiación , Traumatismos Experimentales por Radiación/enzimología , Traumatismos Experimentales por Radiación/etiología , Receptores de Enterotoxina , Transducción de Señal/efectos de la radiación , Células Tumorales Cultivadas
3.
Expert Rev Clin Pharmacol ; 10(5): 549-557, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28162021

RESUMEN

INTRODUCTION: Colorectal cancer remains the second leading cause of cancer death in the United States, and new strategies to prevent, detect, and treat the disease are needed. The receptor, guanylate cyclase C (GUCY2C), a tumor suppressor expressed by the intestinal epithelium, has emerged as a promising target. Areas covered: This review outlines the role of GUCY2C in tumorigenesis, and steps to translate GUCY2C-targeting schemes to the clinic. Endogenous GUCY2C-activating ligands disappear early in tumorigenesis, silencing its signaling axis and enabling transformation. Pre-clinical models support GUCY2C ligand supplementation as a novel disease prevention paradigm. With the recent FDA approval of the GUCY2C ligand, linaclotide, and two more synthetic ligands in the pipeline, this strategy can be tested in human trials. In addition to primary tumor prevention, we also review immunotherapies targeting GUCY2C expressed by metastatic lesions, and platforms using GUCY2C as a biomarker for detection and patient staging. Expert commentary: Results of the first GUCY2C targeting schemes in patients will become available in the coming years. The identification of GUCY2C ligand loss as a requirement for colorectal tumorigenesis has the potential to change the treatment paradigm from an irreversible disease of genetic mutation, to a treatable disease of ligand insufficiency.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Terapia Molecular Dirigida , Receptores Acoplados a la Guanilato-Ciclasa/metabolismo , Receptores de Péptidos/metabolismo , Animales , Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Diseño de Fármacos , Humanos , Inmunoterapia/métodos , Ligandos , Estadificación de Neoplasias , Receptores de Enterotoxina
4.
Infect Immun ; 84(10): 3083-91, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27481254

RESUMEN

Enterotoxigenic Escherichia coli (ETEC) causes ∼20% of the acute infectious diarrhea (AID) episodes worldwide, often by producing heat-stable enterotoxins (STs), which are peptides structurally homologous to paracrine hormones of the intestinal guanylate cyclase C (GUCY2C) receptor. While molecular mechanisms mediating ST-induced intestinal secretion have been defined, advancements in therapeutics have been hampered for decades by the paucity of disease models that integrate molecular and functional endpoints amenable to high-throughput screening. Here, we reveal that mouse and human intestinal enteroids in three-dimensional ex vivo cultures express the components of the GUCY2C secretory signaling axis. ST and its structural analog, linaclotide, an FDA-approved oral secretagog, induced fluid accumulation quantified simultaneously in scores of enteroid lumens, recapitulating ETEC-induced intestinal secretion. Enteroid secretion depended on canonical molecular signaling events responsible for ETEC-induced diarrhea, including cyclic GMP (cGMP) produced by GUCY2C, activation of cGMP-dependent protein kinase (PKG), and opening of the cystic fibrosis transmembrane conductance regulator (CFTR). Importantly, pharmacological inhibition of CFTR abrogated enteroid fluid secretion, providing proof of concept for the utility of this model to screen antidiarrheal agents. Intestinal enteroids offer a unique model, integrating the GUCY2C signaling axis and luminal fluid secretion, to explore the pathophysiology of, and develop platforms for, high-throughput drug screening to identify novel compounds to prevent and treat ETEC diarrheal disease.


Asunto(s)
Toxinas Bacterianas/metabolismo , Escherichia coli Enterotoxigénica/fisiología , Enterotoxinas/fisiología , Infecciones por Escherichia coli/microbiología , Mucosa Intestinal/metabolismo , Receptores Acoplados a la Guanilato-Ciclasa/metabolismo , Receptores de Péptidos/metabolismo , Análisis de Varianza , Animales , GMP Cíclico/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Diarrea/metabolismo , Modelos Animales de Enfermedad , Escherichia coli Enterotoxigénica/metabolismo , Enterotoxinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Infecciones por Escherichia coli/fisiopatología , Proteínas de Escherichia coli/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Enterotoxina , Transducción de Señal/fisiología
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