Tumour exosome integrins determine organotropic metastasis

被引：3870

作者：

Hoshino, Ayuko ^{[1
,2
]}

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

Shen, Tang-Long ^{[1
,2
,3
,4
]}

Rodrigues, Goncalo ^{[1
,2
,5
]}

Hashimoto, Ayako ^{[1
,2
,6
]}

Mark, Milica Tesic ^{[7
]}

Molina, Henrik ^{[7
]}

Kohsaka, Shinji ^{[8
]}

Di Giannatale, Angela ^{[1
,2
]}

Ceder, Sophia ^{[9
]}

Singh, Swarnima ^{[1
,2
]}

Williams, Caitlin ^{[1
,2
]}

Soplop, Nadine ^{[10
]}

Uryu, Kunihiro ^{[10
]}

Pharmer, Lindsay ^{[11
]}

King, Tari ^{[11
]}

Bojmar, Linda ^{[1
,2
,12
,13
]}

Davies, Alexander E. ^{[14
]}

Ararso, Yonathan ^{[1
,2
]}

Zhang, Tuo ^{[15
]}

Zhang, Haiying ^{[1
,2
]}

Hernandez, Jonathan ^{[1
,2
,16
]}

Weiss, Joshua M. ^{[1
,2
]}

Dumont-Cole, Vanessa D. ^{[17
]}

Kramer, Kimberly ^{[17
]}

Wexler, Leonard H. ^{[17
]}

Narendran, Aru ^{[18
]}

Schwartz, Gary K. ^{[19
]}

Healey, John H. ^{[20
]}

Sandstrom, Per ^{[12
,13
]}

Labori, Knut Jorgen ^{[21
]}

Kure, Elin H. ^{[22
]}

Grandgenett, Paul M. ^{[23
]}

Hollingsworth, Michael A. ^{[23
]}

de Sousa, Maria ^{[1
,2
,5
]}

Kaur, Sukhwinder ^{[24
]}

Jain, Maneesh ^{[24
]}

Mallya, Kavita ^{[24
]}

Batra, Surinder K. ^{[24
]}

Jarnagin, William R. ^{[16
]}

Brady, Mary S. ^{[1
,2
,25
]}

Fodstad, Oystein ^{[26
,27
]}

Muller, Volkmar ^{[28
]}

Pantel, Klaus ^{[29
]}

Minn, Andy J. ^{[30
]}

Bissell, Mina J. ^{[14
]}

Garcia, Benjamin A. ^{[31
]}

Kang, Yibin ^{[32
,33
]}

Rajasekhar, Vinagolu K. ^{[34
]}

Ghajar, Cyrus M. ^{[35
]}

机构：

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

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

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

[4] Natl Taiwan Univ, Ctr Biotechnol, Taipei 10617, Taiwan

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

[6] Univ Tokyo, Dept Obstet & Gynecol, Fac Med, Tokyo 1138655, Japan

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

[8] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[9] Karolinska Inst, Dept Pathol & Oncol, S-17176 Stockholm, Sweden

[10] Rockefeller Univ, EMRC, New York, NY 10065 USA

[11] Mem Sloan Kettering Canc Ctr, Dept Surg, Breast Serv, New York, NY 10065 USA

[12] Linkoping Univ, Fac Hlth Sci, Dept Surg, Cty Council Ostergotland, S-58185 Linkoping, Sweden

[13] Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, S-58185 Linkoping, Sweden

[14] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA

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

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

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

[18] Alberta Childrens Prov Gen Hosp, Div Pediat Oncol, Calgary, AB T3B 6A8, Canada

[19] Columbia Univ, Sch Med, Div Hematol Oncol, New York, NY 10032 USA

[20] Mem Sloan Kettering Canc Ctr, Dept Surg, Orthopaed Serv, New York, NY 10065 USA

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

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

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

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

[25] Mem Sloan Kettering Canc Ctr, Dept Surg, Gastr & Mixed Tumor Serv, New York, NY 10065 USA

[26] Oslo Univ Hosp, Norwegian Radium Hosp, Dept Tumor Biol, N-0424 Oslo, Norway

[27] Univ Oslo, Inst Clin Med, Fac Med, N-0318 Oslo, Norway

[28] Univ Med Ctr, Dept Gynecol, D-20246 Hamburg, Germany

[29] Univ Med Ctr Hamburg Eppendorf, Dept Tumor Biol, D-20246 Hamburg, Germany

[30] Univ Penn, Abramson Family Canc Res Inst, Dept Radiat Oncol, Philadelphia, PA 19104 USA

[31] Univ Penn, Perelman Sch Med, Dept Biochem & Biophys, Philadelphia, PA 19104 USA

[32] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA

[33] Rutgers Canc Inst New Jersey, New Brunswick, NJ 08903 USA

[34] Mem Sloan Kettering Canc Ctr, Dept Med, Breast Med Serv, New York, NY 10065 USA

[35] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA

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

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

[38] Weill Cornell Med, Dept Med, New York, NY 10021 USA

来源：

NATURE | 2015年 / 527卷 / 7578期

基金：

美国国家卫生研究院;

关键词：

BREAST-CANCER METASTASIS; BONE METASTASES; IN-VIVO; CELLS; GROWTH; NICHE; MICROVESICLES; PROTEOMICS; PROTEINS; VESICLES;

D O I：

10.1038/nature15756

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 alpha(6)beta(4) and alpha(6)beta(1) were associated with lung metastasis, while exosomal integrin alpha(v)beta(5) was linked to liver metastasis. Targeting the integrins alpha(6)beta(4) and alpha(v)beta(5) 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.

引用

页码：329 / +

页数：19

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