RESUMEN
Neoplastic cells originating from a primary cancer can uncommonly spread to the skin, where they suggest a poor prognosis for the patient. In women, melanoma, breast, ovarian, oral cavity, and lung are the most common primary sources; in men, melanoma, lung, colon, and squamous cell carcinoma of the head and neck predominate. The classic presentation of cutaneous metastases is a firm, painless, flesh-colored to an erythematous dermal nodule (or nodules); however, several other presentations, including inflammatory, cicatricial, and bullous lesions, have been reported. Cutaneous metastases may also mimic benign conditions such as lipomas, hemangiomas, or cellulitis. A high degree of clinical suspicion is necessary, and the diagnosis is confirmed by biopsy, which may also be used to establish the primary malignancy if unknown, as the histopathologic appearance of the metastatic tissue may mimic the primary tumor. Treatments include excision of the metastases, chemotherapy, immunotherapy, radiation, and/or palliative care.
Asunto(s)
Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/secundario , Piel/patología , Biopsia , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Neoplasias Cutáneas/patologíaRESUMEN
The mechanisms regulating hematopoietic stem and progenitor cell (HSPC) fate choices remain ill-defined. Here, we show that a signalling network of p190-B RhoGAP-ROS-TGF-ß-p38MAPK balances HSPC self-renewal and differentiation. Upon transplantation, HSPCs express high amounts of bioactive TGF-ß1 protein, which is associated with high levels of p38MAPK activity and loss of HSC self-renewal in vivo. Elevated levels of bioactive TGF-ß1 are associated with asymmetric fate choice in vitro in single HSPCs via p38MAPK activity and this is correlated with the asymmetric distribution of activated p38MAPK. In contrast, loss of p190-B, a RhoGTPase inhibitor, normalizes TGF-ß levels and p38MAPK activity in HSPCs and is correlated with increased HSC self-renewal in vivo. Loss of p190-B also promotes symmetric retention of multi-lineage capacity in single HSPC myeloid cell cultures, further suggesting a link between p190-B-RhoGAP and non-canonical TGF-ß signalling in HSPC differentiation. Thus, intracellular cytokine signalling may serve as 'fate determinants' used by HSPCs to modulate their activity.
Asunto(s)
Diferenciación Celular/fisiología , Autorrenovación de las Células/fisiología , Proteínas Activadoras de GTPasa/metabolismo , Células Madre Hematopoyéticas/fisiología , Transducción de Señal/fisiología , Animales , Células Cultivadas , Citocinas/metabolismo , Proteínas Activadoras de GTPasa/genética , Trasplante de Células Madre Hematopoyéticas , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Cultivo Primario de Células , Especies Reactivas de Oxígeno/metabolismo , Análisis de la Célula Individual , Factor de Crecimiento Transformador beta/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Extracellular acidification has been observed in allergic inflammatory diseases. Recently, we demonstrated that the proton-sensing receptor G protein-coupled receptor 65 (GPR65) regulates eosinophil survival in an acidic environment in vitro and eosinophil accumulation in an allergic lung inflammation model. For mast cells, another inflammatory cell type critical for allergic responses, it remains unknown whether GPR65 is expressed and/or regulates mast cell viability. Thus, in the present study, we employed in vitro experiments and an intestinal anaphylaxis model in which both mastocytosis and eosinophilia can be observed, particularly in the gastrointestinal tract, to enable us to directly compare the effect of GPR65 expression on these two cell types. We identified GPR65 expression on mast cells; however, unlike eosinophil viability, mast cell viability in vitro is not affected by acidification or GPR65 expression. Mechanistically, we determined that mast cells do not respond to extracellular acidification with increased cAMP levels. Furthermore, in the intestinal anaphylaxis model, we observed a significant reduction of eosinophils (59.1 ± 9.2% decrease) in the jejunum of allergen-challenged GPR65-deficient mice compared with allergen-challenged wild-type mice, despite the degree of antigen sensitization and the expression levels of Th2 cytokines (Il4, Il13) and eosinophil chemokines (Ccl11, Ccl24) in the jejunum being comparable. In contrast, the accumulation of mast cells in allergen-challenged mice was not affected by GPR65 deficiency. In conclusion, our study demonstrates differential regulation of eosinophils and mast cells in inflammatory tissue, with mast cell viability and accumulation being independent of GPR65.
Asunto(s)
Supervivencia Celular/fisiología , Eosinófilos/fisiología , Inflamación/metabolismo , Mastocitos/fisiología , Animales , Técnicas de Cultivo de Célula , Proliferación Celular , Eosinófilos/citología , Femenino , Yeyuno/citología , Masculino , Mastocitos/citología , Ratones , Ratones Noqueados , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
BACKGROUND: Proton currents are required for optimal respiratory burst in phagocytes. Recently, HVCN1 was identified as the molecule required for the voltage-gated proton channel activity associated with the respiratory burst in neutrophils. Although there are similarities between eosinophils and neutrophils regarding their mechanism for respiratory burst, the role of proton channels in eosinophil functions has not been fully understood. RESULTS: In the present study, we first identified the expression of the proton channel HVCN1 in mouse eosinophils. Furthermore, using HVCN1-deficient eosinophils, we demonstrated important cell-specific effector functions for HVCN1. Similar to HVCN1-deficient neutrophils, HVCN1-deficient eosinophils produced significantly less reactive oxygen species (ROS) upon phorbol myristate acetate (PMA) stimulation compared with WT eosinophils. In contrast to HVCN1-deficient neutrophils, HVCN1-deficient eosinophils did not show impaired calcium mobilization or migration ability compared with wild-type (WT) cells. Uniquely, HVCN1-deficient eosinophils underwent significantly increased cell death induced by PMA stimulation compared with WT eosinophils. The increased cell death was dependent on NADPH oxidase activation, and correlated with the failure of HVCN1-deficient cells to maintain membrane polarization and intracellular pH in the physiological range upon activation. CONCLUSIONS: Eosinophils require proton channel HVCN1 for optimal ROS generation and prevention of activation-induced cell death.