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1.
Cancer Res ; 73(22): 6654-66, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-24085786

RESUMO

Tumorigenesis is a multistep process that reflects intimate reciprocal interactions between epithelia and underlying stroma. However, tumor-initiating mechanisms coordinating transformation of both epithelial and stromal components are not defined. In humans and mice, initiation of colorectal cancer is universally associated with loss of guanylin and uroguanylin, the endogenous ligands for the tumor suppressor guanylyl cyclase C (GUCY2C), disrupting a network of homeostatic mechanisms along the crypt-surface axis. Here, we reveal that silencing GUCY2C in human colon cancer cells increases Akt-dependent TGF-ß secretion, activating fibroblasts through TGF-ß type I receptors and Smad3 phosphorylation. In turn, activating TGF-ß signaling induces fibroblasts to secrete hepatocyte growth factor (HGF), reciprocally driving colon cancer cell proliferation through cMET-dependent signaling. Elimination of GUCY2C signaling in mice (Gucy2c(-/-)) produces intestinal desmoplasia, with increased reactive myofibroblasts, which is suppressed by anti-TGF-ß antibodies or genetic silencing of Akt. Thus, GUCY2C coordinates intestinal epithelial-mesenchymal homeostasis through reciprocal paracrine circuits mediated by TGF-ß and HGF. In that context, GUCY2C signaling constitutes a direct link between the initiation of colorectal cancer and the induction of its associated desmoplastic stromal niche. The recent regulatory approval of oral GUCY2C ligands to treat chronic gastrointestinal disorders underscores the potential therapeutic opportunity for oral GUCY2C hormone replacement to prevent remodeling of the microenvironment essential for colorectal tumorigenesis.


Assuntos
Proliferação de Células , Transformação Celular Neoplásica/genética , Neoplasias Colorretais/patologia , Intestinos/patologia , Receptores Acoplados a Guanilato Ciclase/fisiologia , Receptores de Peptídeos/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Células CACO-2 , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Regulação para Baixo , Transição Epitelial-Mesenquimal/genética , Fibrose , Células HCT116 , Humanos , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Enterotoxina , Nicho de Células-Tronco/genética
2.
Toxins (Basel) ; 2(8): 2028-54, 2010 08.
Artigo em Inglês | MEDLINE | ID: mdl-22069671

RESUMO

Heat-stable toxins (STs) produced by enterotoxigenic bacteria cause endemic and traveler's diarrhea by binding to and activating the intestinal receptor guanylyl cyclase C (GC-C). Advances in understanding the biology of GC-C have extended ST from a diarrheagenic peptide to a novel therapeutic agent. Here, we summarize the physiological and pathophysiological role of GC-C in fluid-electrolyte regulation and intestinal crypt-villus homeostasis, as well as describe translational opportunities offered by STs, reflecting the unique characteristics of GC-C, in treating irritable bowel syndrome and chronic constipation, and in preventing and treating colorectal cancer.


Assuntos
Toxinas Bacterianas/uso terapêutico , Enterotoxinas/uso terapêutico , Receptores Acoplados a Guanilato Ciclase/fisiologia , Receptores de Peptídeos/fisiologia , Sequência de Aminoácidos , Animais , Toxinas Bacterianas/toxicidade , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/prevenção & controle , Constipação Intestinal/tratamento farmacológico , Enterotoxinas/toxicidade , Proteínas de Escherichia coli , Humanos , Síndrome do Intestino Irritável/tratamento farmacológico , Síndrome do Intestino Irritável/etiologia , Dados de Sequência Molecular , Estadiamento de Neoplasias , Peptídeos/uso terapêutico , Receptores de Enterotoxina , Receptores Acoplados a Guanilato Ciclase/agonistas , Receptores Acoplados a Guanilato Ciclase/genética , Receptores de Peptídeos/agonistas , Receptores de Peptídeos/genética , Transdução de Sinais
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