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Nat Cell Biol. 2015 Jun;17(6):816-26. doi: 10.1038/ncb3169. Epub 2015 May 18.

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

Author information

1
Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medical College, New York, New York 10021, USA.
2
Gastroenterology Division, Department of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
3
Department of Medicine, Division of Hematology and Medical Oncology, New York Presbyterian Hospital, Weill Cornell Medical College, New York, New York 10021, USA.
4
1] Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medical College, New York, New York 10021, USA [2] Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover 30625, Germany.
5
Proteomics Resource Center, The Rockefeller University, New York, New York 10065, USA.
6
Genomics Resources Core Facility, Weill Cornell Medical College, New York, New York 10021, USA.
7
1] Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medical College, New York, New York 10021, USA [2] Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, 4099-003 Porto, Portugal.
8
Department of Plant Pathology and Microbiology, National Taiwan University, Taipei 10617, Taiwan.
9
Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Nydalen, Oslo 0424, Norway.
10
1] Department of Pathology, Oslo University Hospital, Nydalen, Oslo 0424, Norway [2] Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Nydalen, Oslo 0424, Norway.
11
Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Nydalen, Oslo 0424, Norway.
12
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
13
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
14
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
15
Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medical College, New York, New York 10021, USA.
16
1] Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medical College, New York, New York 10021, USA [2] Microenvironment and Metastasis Laboratory, Department of Molecular Oncology, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
17
Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York 10065, USA.
18
1] Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medical College, New York, New York 10021, USA [2] Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.

Abstract

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.

PMID:
25985394
DOI:
10.1038/ncb3169
[Indexed for MEDLINE]
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