Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.

Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive...

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Detalles Bibliográficos
Autores: Costa-Silva, Bruno, Aiello, Nicole M, Ocean, Allyson J, Singh, Swarnima, Zhang, Haiying, Thakur, Basant Kumar, Becker, Annette, Hoshino, Ayuko, Mark, Milica Tešić, Molina, Henrik, Xiang, Jenny, Zhang, Tuo, Theilen, Till-Martin, García-Santos, Guillermo, Williams, Caitlin, Ararso, Yonathan, Huang, Yujie, Rodrigues, Gonçalo, Shen, Tang-Long, Labori, Knut Jørgen, Lothe, Inger Marie Bowitz, Kure, Elin H, Hernandez, Jonathan, Doussot, Alexandre, Ebbesen, Saya H, Grandgenett, Paul M, Hollingsworth, Michael A, Jain, Maneesh, Mallya, Kavita, Batra, Surinder K, Jarnagin, William R, Schwartz, Robert E, Matei, Irina, Peinado, Héctor, Stanger, Ben Z, Bromberg, Jacqueline, Lyden, David
Tipo de recurso: artículo
Fecha de publicación:2015
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/17975
Acceso en línea:http://hdl.handle.net/20.500.12105/17975
Access Level:acceso abierto
Palabra clave:Animals
Base Sequence
Bone Marrow Cells
Carcinoma, Pancreatic Ductal
Cell Line, Tumor
Cell Movement
Exosomes
Female
Fibronectins
Gene Expression Regulation, Neoplastic
Hepatic Stellate Cells
Humans
Liver
Liver Neoplasms
Macrophage Migration-Inhibitory Factors
Macrophages
Mice
Mice, Inbred C57BL
Mice, Knockout
Pancreatic Neoplasms
Precancerous Conditions
RNA Interference
RNA, Small Interfering
Sequence Analysis, RNA
Signal Transduction
Transforming Growth Factor beta
Descripción
Sumario:Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared with patients whose pancreatic tumours did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.

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