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

被引：2102

作者：

Costa-Silva, Bruno ^{[1
,2
]}

Aiello, Nicole M. ^{[3
]}

Ocean, Allyson J. ^{[4
]}

Singh, Swarnima ^{[1
,2
]}

Zhang, Haiying ^{[1
,2
]}

Thakur, Basant Kumar ^{[1
,2
,5
]}

Becker, Annette ^{[1
,2
]}

Hoshino, Ayuko ^{[1
,2
]}

Mark, Milica Tesic ^{[6
]}

Molina, Henrik ^{[6
]}

Xiang, Jenny ^{[7
]}

Zhang, Tuo ^{[7
]}

Theilen, Till-Martin ^{[1
,2
]}

Garcia-Santos, Guillermo ^{[1
,2
]}

Williams, Caitlin ^{[1
,2
]}

Ararso, Yonathan ^{[1
,2
]}

Huang, Yujie ^{[1
,2
]}

Rodrigues, Goncalo ^{[1
,2
,8
]}

Shen, Tang-Long ^{[9
]}

Labori, Knut Jorgen ^{[10
]}

Lothe, Inger Marie Bowitz ^{[11
,12
]}

Kure, Elm H. ^{[12
]}

Hernandez, Jonathan ^{[13
]}

Doussot, Alexandre ^{[13
]}

Ebbesen, Saya H. ^{[1
,2
]}

Grandgenett, Paul M. ^{[14
]}

Hollingsworth, Michael A. ^{[14
]}

Jain, Maneesh ^{[15
]}

Mallya, Kavita ^{[15
]}

Batra, Surinder K. ^{[15
]}

Jarnagin, William R. ^{[13
]}

Schwartz, Robert E. ^{[16
]}

Matei, Irina ^{[1
,2
]}

Peinado, Hector ^{[1
,2
,17
]}

Stanger, Ben Z. ^{[3
]}

Bromberg, Jacqueline ^{[18
,19
]}

Lyden, David ^{[1
,2
,20
]}

机构：

[1] Weill Cornell Med Coll, Meyer Canc Ctr, Childrens Canc & Blood Fdn Labs, Drukier Inst Childrens Hlth,Dept Pediat, New York, NY 10021 USA

[2] Weill Cornell Med Coll, Meyer Canc Ctr, Childrens Canc & Blood Fdn Labs, Drukier Inst Childrens Hlth,Dept Cell & Dev Biol, New York, NY 10021 USA

[3] Univ Penn, Sch Med, Abramson Family Canc Res Inst, Gastroenterol Div,Dept Med, Philadelphia, PA 19104 USA

[4] Weill Cornell Med Coll, New York Presbyterian Hosp, Div Hematol & Med Oncol, Dept Med, New York, NY 10021 USA

[5] Hannover Med Sch, Dept Pediat Hematol & Oncol, D-30625 Hannover, Germany

[6] Rockefeller Univ, Prote Resource Ctr, New York, NY 10065 USA

[7] Weill Cornell Med Coll, Genom Resources Core Facil, New York, NY 10021 USA

[8] Univ Porto, Abel Salazar Biomed Sci Inst, Grad Program Areas Basic & Appl Biol, P-4099003 Oporto, Portugal

[9] Natl Taiwan Univ, Dept Plant Pathol & Microbiol, Taipei 10617, Taiwan

[10] Oslo Univ Hosp, Dept Hepatopancreatobiliary Surg, N-0424 Oslo, Norway

[11] Oslo Univ Hosp, Dept Pathol, N-0424 Oslo, Norway

[12] Oslo Univ Hosp, Dept Genet, Inst Canc Res, N-0424 Oslo, Norway

[13] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA

[14] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA

[15] Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, Omaha, NE 68198 USA

[16] Weill Cornell Med Coll, Dept Med, Div Gastroenterol & Hepatol, New York, NY 10021 USA

[17] Spanish Natl Canc Res Ctr CNIO, Dept Mol Oncol, Microenvironm & Metaslasis Lab, Madrid 28029, Spain

[18] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[19] Weill Cornell Med Coll, New York, NY 10065 USA

[20] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA

来源：

NATURE CELL BIOLOGY | 2015年 / 17卷 / 06期

关键词：

GROWTH-FACTOR-BETA; INHIBITORY FACTOR EXPRESSION; TGF-BETA; MESENCHYMAL TRANSITION; EXTRACELLULAR VESICLES; DUCTAL ADENOCARCINOMA; KUPFFER CELLS; MOUSE MODEL; MACROPHAGES; ACTIVATION;

D O I：

10.1038/ncb3169

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 beta 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.

引用

页码：816 / +

页数：20

共 69 条

[1] Transforming Growth Factor-β in the Gastrointestinal and Hepatic Tumor Microenvironment [J].