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1.
Cell ; 164(5): 1031-45, 2016 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-26898330

RESUMEN

During development, sensory axons compete for limiting neurotrophic support, and local neurotrophin insufficiency triggers caspase-dependent axon degeneration. The signaling driving axon degeneration upon local deprivation is proposed to reside within axons. Our results instead support a model in which, despite the apoptotic machinery being present in axons, the cell body is an active participant in gating axonal caspase activation and axon degeneration. Loss of trophic support in axons initiates retrograde activation of a somatic pro-apoptotic pathway, which, in turn, is required for distal axon degeneration via an anterograde pro-degenerative factor. At a molecular level, the cell body is the convergence point of two signaling pathways whose integrated action drives upregulation of pro-apoptotic Puma, which, unexpectedly, is confined to the cell body. Puma then overcomes inhibition by pro-survival Bcl-xL and Bcl-w and initiates the anterograde pro-degenerative program, highlighting the role of the cell body as an arbiter of large-scale axon removal.


Asunto(s)
Axones/patología , Neuronas/patología , Transducción de Señal , Secuencia de Aminoácidos , Animales , Apoptosis , Proteínas Reguladoras de la Apoptosis/química , Proteínas Reguladoras de la Apoptosis/metabolismo , Axones/metabolismo , Ratones , Datos de Secuencia Molecular , Degeneración Nerviosa/patología , Neuronas/metabolismo , Proteínas/metabolismo , Proteínas Supresoras de Tumor/química , Proteínas Supresoras de Tumor/metabolismo , Proteína bcl-X/metabolismo
2.
Nature ; 527(7578): 329-35, 2015 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-26524530

RESUMEN

Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6ß4 and α6ß1 were associated with lung metastasis, while exosomal integrin αvß5 was linked to liver metastasis. Targeting the integrins α6ß4 and αvß5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.


Asunto(s)
Encéfalo/metabolismo , Exosomas/metabolismo , Integrinas/metabolismo , Hígado/metabolismo , Pulmón/metabolismo , Metástasis de la Neoplasia/patología , Metástasis de la Neoplasia/prevención & control , Tropismo , Animales , Biomarcadores/metabolismo , Encéfalo/citología , Línea Celular Tumoral , Células Endoteliales/citología , Células Endoteliales/metabolismo , Células Epiteliales/citología , Células Epiteliales/metabolismo , Femenino , Fibroblastos/citología , Fibroblastos/metabolismo , Genes src , Humanos , Integrina alfa6beta1/metabolismo , Integrina alfa6beta4/antagonistas & inhibidores , Integrina alfa6beta4/metabolismo , Cadenas beta de Integrinas/metabolismo , Integrina beta4/metabolismo , Integrinas/antagonistas & inhibidores , Macrófagos del Hígado/citología , Macrófagos del Hígado/metabolismo , Hígado/citología , Pulmón/citología , Ratones , Ratones Endogámicos C57BL , Especificidad de Órganos , Fosforilación , Receptores de Vitronectina/antagonistas & inhibidores , Receptores de Vitronectina/metabolismo , Proteínas S100/genética
3.
Nat Cell Biol ; 21(11): 1403-1412, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31685984

RESUMEN

The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP+ exosomes. Moreover, uptake of CEMIP+ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating the pro-inflammatory cytokines encoded by Ptgs2, Tnf and Ccl/Cxcl, known to promote brain vascular remodelling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.


Asunto(s)
Neoplasias Encefálicas/genética , Exosomas/metabolismo , Regulación Neoplásica de la Expresión Génica , Hialuronoglucosaminidasa/genética , Neovascularización Patológica/genética , Microambiente Tumoral/genética , Animales , Encéfalo/metabolismo , Encéfalo/patología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Quimiocina CCL1/genética , Quimiocina CCL1/metabolismo , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Células Endoteliales/metabolismo , Células Endoteliales/patología , Exosomas/patología , Humanos , Hialuronoglucosaminidasa/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Metástasis de la Neoplasia , Neovascularización Patológica/metabolismo , Neovascularización Patológica/mortalidad , Neovascularización Patológica/patología , Transducción de Señal , Análisis de Supervivencia , Carga Tumoral , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
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