mTORC1 Prevents Epithelial Damage During Inflammation and Inhibits Colitis-Associated Colorectal Cancer Development.

Epithelial cells lining the intestinal mucosa constitute a selective-semipermeable barrier acting as first line of defense in the organism. The number of those cells remains constant during physiological conditions, but disruption of epithelial cell homeostasis has been observed in several pathologies. During colitis, epithelial cell proliferation decreases and cell death augments. The mechanism responsible for these changes remains unknown. Here, we show that the pro-inflammatory cytokine IFNγ contributes to the inhibition of epithelial cell proliferation in intestinal epithelial cells (IECs) by inducing the activation of mTORC1. Activation of mTORC1 in response to IFNγ was detected in IECs present along the crypt axis and in colonic macrophages. mTORC1 inhibition enhances cell proliferation, increases DNA damage in IEC. In macrophages, mTORC1 inhibition strongly reduces the expression of pro-inflammatory markers. As a consequence, mTORC1 inhibition exacerbated disease activity, increased mucosal damage, enhanced ulceration, augmented cell infiltration, decreased survival and stimulated tumor formation in a model of colorectal cancer CRC associated to colitis. Thus, our findings suggest that mTORC1 signaling downstream of IFNγ prevents epithelial DNA damage and cancer development during colitis.

Tumor neuroepitelial disembrioplásico durante el embarazo. Reporte de un caso / Dysembryoplastic neuroepithelial tumor during pregnancy. A case report

Resumen ANTECEDENTES: el tumor neuroepitelial disembrioplásico es una neoplasia poco frecuente del sistema nervioso central que causa crisis convulsivas focales resistentes al tratamiento farmacológico en pacientes jóvenes; su manifestación durante el embarazo es excepcional. CASO CLÍNICO: paciente femenina de 33 años de edad, con antecedente de tres embarazos y que, durante el cuarto, en la semana 12, inició con crisis convulsivas. El diagnóstico, por resonancia magnética nuclear, fue de tumor en el lóbulo frontal izquierdo, razón por la que se vigiló estrechamente hasta el final del embarazo, que concluyó por parto, sin ninguna complicación. Debido a que en la segunda resonancia magnética se evidenció el crecimiento de la lesión, se decidió la resección quirúrgica. El diagnóstico histopatológico informó que se trató de un tumor neuroepitelial disembrioplásico. Aunque hubo una influencia del embarazo en el comportamiento y crecimiento de este tipo de tumor, no fue posible observar la expresión de receptores hormonales en las células del tumor y el tratamiento no se modificó por la gestación. CONCLUSIONES: la repercusión del embarazo en el tumor neuroepitelial disembrioplásico no se explica por la influencia de las hormonas; este tipo de tumor sigue siendo una neoplasia benigna en el contexto de una gestación, porque no ha mostrado complicaciones que pongan en riesgo la vida de la madre y su feto.

Abstract BACKGROUND: Dysembryoplastic neuroepithelial tumor is a less frequently primary central nervous system neoplasm that causes focal seizures resistant to pharmacological treatment in young patients and its presentation during pregnancy is very rare. CASE REPORT: We report here the case of a 33 years old woman who started with seizures at 12th week of her fourth gestation. She was diagnosed by cerebral magnetic resonance imaging with a left frontal lobe tumor and was observed carefully until the end of pregnancy solved by delivery without any complication. Second magnetic resonance was performed that evidenced enlargement of the injury, therefore resection was carried out and histopathological diagnosis was for dysembryoplastic neuroepithelial tumor. Although it was observed an influence of pregnancy on clinical behavior and growth of this kind of tumor we did not find expression of hormonal receptors in the cells of the lesion and treatment was not modified by gestation. CONCLUSIONS: So impact of pregnancy on dysembryoplastic neuroepithelial tumor is not explained by a hormonal influence and this kind of tumor stills being a benign neoplasm in the context of gestation, since it has shown no risk of maternal and fetal life threatening complications.

Cortactin deficiency causes increased RhoA/ROCK1-dependent actomyosin contractility, intestinal epithelial barrier dysfunction, and disproportionately severe DSS-induced colitis.

The intestinal epithelium constitutes a first line of defense of the innate immune system. Epithelial dysfunction is a hallmark of intestinal disorders such as inflammatory bowel diseases (IBDs). The actin cytoskeleton controls epithelial barrier integrity but the function of actin regulators such as cortactin is poorly understood. Given that cortactin controls endothelial permeability, we hypothesized that cortactin is also important for epithelial barrier regulation. We found increased permeability in the colon of cortactin-KO mice that was accompanied by reduced levels of ZO-1, claudin-1, and E-cadherin. By contrast, claudin-2 was upregulated. Cortactin deficiency increased RhoA/ROCK1-dependent actomyosin contractility, and inhibition of ROCK1 rescued the barrier defect. Interestingly, cortactin deficiency caused increased epithelial proliferation without affecting apoptosis. KO mice did not develop spontaneous colitis, but were more susceptible to dextran sulfate sodium colitis and showed severe colon tissue damage and edema formation. KO mice with colitis displayed strong mucus deposition and goblet cell depletion. In healthy human colon tissues, cortactin co-localized with ZO-1 at epithelial cell contacts. In IBDs patients, we observed decreased cortactin levels and loss of co-localization with ZO-1. Thus, cortactin is a master regulator of intestinal epithelial barrier integrity in vivo and could serve as a suitable target for pharmacological intervention in IBDs.