RESUMEN
Mammary gland morphogenesis results from the coordination of proliferation, cohort migration, apoptosis and stem/progenitor cell dynamics. We showed earlier that the transcription repressor Slug is involved in these functions during mammary tubulogenesis. Slug is expressed by a subpopulation of basal epithelial cells, co-expressed with P-cadherin (Pcad). Slug-knockout mammary glands showed excessive branching, similarly to Pcad-knockout. Here, we found that Slug unexpectedly binds and activates Pcad promoter through E-boxes, inducing Pcad expression. We determined that Pcad can mediate several functions of Slug: Pcad promoted clonal mammosphere growth, basal epithelial differentiation, cell-cell dissociation and cell migration, rescuing Slug depletion. Pcad also promoted cell migration in isolated cells, in association with Src activation, focal adhesion reorganization and cell polarization. Pcad, similarly to Slug, was required for in vitro 3D tubulogenesis. Therefore, Pcad appears to be responsible for epithelial-mesenchymal transition-linked plasticity in mammary epithelial cells. In addition, we found that genes from the Slug/Pcad pathway components were co-expressed and specifically correlated in human breast carcinomas subtypes, carrying pathophysiological significance.
Asunto(s)
Neoplasias de la Mama/genética , Cadherinas/genética , Células Epiteliales/patología , Transición Epitelial-Mesenquimal/genética , Glándulas Mamarias Animales/metabolismo , Factores de Transcripción de la Familia Snail/metabolismo , Animales , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Cadherinas/metabolismo , Adhesión Celular/genética , Diferenciación Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Conjuntos de Datos como Asunto , Femenino , Humanos , Estimación de Kaplan-Meier , Queratinocitos , Glándulas Mamarias Animales/citología , Ratones , Morfogénesis/genética , Regiones Promotoras Genéticas , ARN Interferente Pequeño/metabolismo , Transducción de Señal/genética , Factores de Transcripción de la Familia Snail/genética , Esferoides Celulares , Células Madre/patologíaRESUMEN
PURPOSE: Optimal tissue oxygenation, as obtained by hyperbaric oxygen therapy, potentiates or restores the host's bactericidal mechanisms and wound healing activity in patients afflicted by serious synergeic aerobic and anaerobic infections of the cutaneous and subcutaneous tissues. Furthermore, hyperbaric oxygen therapy has a direct toxic effect on anaerobic bacteria. We describe our experience with hyperbaric oxygen therapy in the treatment of 11 patients with Fournier's syndrome. MATERIALS AND METHODS: The average age of our patients was 59.5 years; the most common predisponsing condition was diabetes. All patients were treated with antibiotic therapy and hyperbaric oxygen therapy (minimum 5 and maximum 24 cycles, consisting of 90 minutes 2.5 atmosphere absolute pressure). Furthermore, 6 of these patients underwent surgical débridement of the wounds and 3 patients underwent delayed reconstructive surgery. RESULTS: The results we obtained with hyperbaric oxygen therapy as an adjunctive measure for the treatment of these infections were excellent; our mortality rate for Fournier's disease was 0. Moreover, no complications whatsoever were observed. Furthermore, the 3 patients who underwent delayed corrective surgery presented with well healed tissues and their operations were not complicated by infections or other pathological conditions. CONCLUSIONS: We believe that our findings, although limited in number, underline the excellent results that can be obtained with hyperbaric oxygen therapy as an adjunct treatment in Fournier's disease.