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Tumour exosome integrins determine organotropic metastasis

机译：肿瘤外泌体整合素决定嗜有机性转移

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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.
机译：自斯蒂芬·佩吉特（Stephen Paget）1889年提出假说以来，转移性嗜有机性一直是癌症的最大谜团之一。在这里，我们证明了来自小鼠和人类的肺，肝和脑嗜性肿瘤细胞的外泌体优先与驻留细胞在其预测的目的地融合，即肺成纤维细胞和上皮细胞，肝库普弗细胞和脑内皮细胞。我们显示，器官特异性细胞摄取的肿瘤来源的外来体准备转移前的利基。用来自肺部模型的外来体进行治疗可重定向骨系肿瘤细胞的转移。外泌体蛋白质组学揭示了独特的整合素表达模式，其中外泌体整合素alpha（6）beta（4）和alpha（6）beta（1）与肺转移相关，而外泌体整合素alpha（v）beta（5）与肝转移。靶向整联蛋白alpha（6）beta（4）和alpha（v）beta（5）减少了外来体摄取，以及肺和肝转移。我们证明驻地细胞的外泌体整合素摄取激活Src磷酸化和促炎性S100基因表达。最后，我们的临床数据表明，外泌体整合素可用于预测器官特异性转移。

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  • 来源
    《Nature》 |2015年第7578期|329-335|共7页
  • 作者

    Hoshino Ayuko; Costa-Silva Bruno; Shen Tang-Long; Rodrigues Goncalo; Hashimoto Ayako; Mark Milica Tesic; Molina Henrik; Kohsaka Shinji; Di Giannatale Angela; Ceder Sophia; Singh Swarnima; Williams Caitlin; Soplop Nadine; Uryu Kunihiro; Pharmer Lindsay; King Tari; Bojmar Linda; Davies Alexander E.; Ararso Yonathan; Zhang Tuo; Zhang Haiying; Hernandez Jonathan; Weiss Joshua M.; Dumont-Cole Vanessa D.; Kramer Kimberly; Wexler Leonard H.; Narendran Aru; Schwartz Gary K.; Healey John H.; Sandstrom Per; Labori Knut Jorgen; Kure Elin H.; Grandgenett Paul M.; Hollingsworth Michael A.; de Sousa Maria; Kaur Sukhwinder; Jain Maneesh; Mallya Kavita; Batra Surinder K.; Jarnagin William R.; Brady Mary S.; Fodstad Oystein; Muller Volkmar; Pantel Klaus; Minn Andy J.; Bissell Mina J.; Garcia Benjamin A.; Kang Yibin; Rajasekhar Vinagolu K.; Ghajar Cyrus M.; Matei Irina; Peinado Hector; Bromberg Jacqueline; Lyden David;

  • 作者单位

    Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Pediat,Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA|Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Cell & Dev Biol,Childrens Canc & Blood Fdn L, New York, NY 10021 USA;

    Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Pediat,Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA|Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Cell & Dev Biol,Childrens Canc & Blood Fdn L, New York, NY 10021 USA;

    Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Pediat,Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA|Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Cell & Dev Biol,Childrens Canc & Blood Fdn L, New York, NY 10021 USA|Natl Taiwan Univ, Dept Plant Pathol & Microbiol, Taipei 10617, Taiwan|Natl Taiwan Univ, Ctr Biotechnol, Taipei 10617, Taiwan;

    Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Pediat,Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA|Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Cell & Dev Biol,Childrens Canc & Blood Fdn L, New York, NY 10021 USA|Univ Porto, Abel Salazar Biomed Sci Inst, Grad Program Areas Basic & Appl Biol, P-4099003 Oporto, Portugal;

    Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Pediat,Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA|Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Cell & Dev Biol,Childrens Canc & Blood Fdn L, New York, NY 10021 USA|Univ Tokyo, Dept Obstet & Gynecol, Fac Med, Tokyo 1138655, Japan;

    Rockefeller Univ, Prote Resource Ctr, New York, NY 10065 USA;

    Rockefeller Univ, Prote Resource Ctr, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA;

    Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Pediat,Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA|Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Cell & Dev Biol,Childrens Canc & Blood Fdn L, New York, NY 10021 USA;

    Karolinska Inst, Dept Pathol & Oncol, S-17176 Stockholm, Sweden;

    Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Pediat,Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA|Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Cell & Dev Biol,Childrens Canc & Blood Fdn L, New York, NY 10021 USA;

    Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Pediat,Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA|Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Cell & Dev Biol,Childrens Canc & Blood Fdn L, New York, NY 10021 USA;

    Rockefeller Univ, EMRC, New York, NY 10065 USA;

    Rockefeller Univ, EMRC, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Dept Surg, Breast Serv, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Dept Surg, Breast Serv, New York, NY 10065 USA;

    Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Pediat,Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA|Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Cell & Dev Biol,Childrens Canc & Blood Fdn L, New York, NY 10021 USA|Linkoping Univ, Fac Hlth Sci, Dept Surg, Cty Council Ostergotland, S-58185 Linkoping, Sweden|Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, S-58185 Linkoping, Sweden;

    Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA;

    Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Pediat,Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA|Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Cell & Dev Biol,Childrens Canc & Blood Fdn L, New York, NY 10021 USA;

    Weill Cornell Med, Genom Resources Core Facil, New York, NY 10021 USA;

    Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Pediat,Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA|Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Cell & Dev Biol,Childrens Canc & Blood Fdn L, New York, NY 10021 USA;

    Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Pediat,Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA|Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Cell & Dev Biol,Childrens Canc & Blood Fdn L, New York, NY 10021 USA|Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA;

    Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Pediat,Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA|Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Cell & Dev Biol,Childrens Canc & Blood Fdn L, New York, NY 10021 USA;

    Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA;

    Alberta Childrens Prov Gen Hosp, Div Pediat Oncol, Calgary, AB T3B 6A8, Canada;

    Columbia Univ, Sch Med, Div Hematol Oncol, New York, NY 10032 USA;

    Mem Sloan Kettering Canc Ctr, Dept Surg, Orthopaed Serv, New York, NY 10065 USA;

    Linkoping Univ, Fac Hlth Sci, Dept Surg, Cty Council Ostergotland, S-58185 Linkoping, Sweden|Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, S-58185 Linkoping, Sweden;

    Oslo Univ Hosp, Dept Hepatopancreatobiliary Surg, N-0424 Oslo, Norway;

    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, N-0424 Oslo, Norway;

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

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

    Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Pediat,Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA|Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Cell & Dev Biol,Childrens Canc & Blood Fdn L, New York, NY 10021 USA|Univ Porto, Abel Salazar Biomed Sci Inst, Grad Program Areas Basic & Appl Biol, P-4099003 Oporto, Portugal;

    Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, Omaha, NE 68198 USA;

    Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, Omaha, NE 68198 USA;

    Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, Omaha, NE 68198 USA;

    Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, Omaha, NE 68198 USA;

    Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA;

    Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Pediat,Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA|Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Cell & Dev Biol,Childrens Canc & Blood Fdn L, New York, NY 10021 USA|Mem Sloan Kettering Canc Ctr, Dept Surg, Gastr & Mixed Tumor Serv, New York, NY 10065 USA;

    Oslo Univ Hosp, Norwegian Radium Hosp, Dept Tumor Biol, N-0424 Oslo, Norway|Univ Oslo, Inst Clin Med, Fac Med, N-0318 Oslo, Norway;

    Univ Med Ctr, Dept Gynecol, D-20246 Hamburg, Germany;

    Univ Med Ctr Hamburg Eppendorf, Dept Tumor Biol, D-20246 Hamburg, Germany;

    Univ Penn, Abramson Family Canc Res Inst, Dept Radiat Oncol, Philadelphia, PA 19104 USA;

    Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA;

    Univ Penn, Perelman Sch Med, Dept Biochem & Biophys, Philadelphia, PA 19104 USA;

    Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA|Rutgers Canc Inst New Jersey, New Brunswick, NJ 08903 USA;

    Mem Sloan Kettering Canc Ctr, Dept Med, Breast Med Serv, New York, NY 10065 USA;

    Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA;

    Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Pediat,Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA|Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Cell & Dev Biol,Childrens Canc & Blood Fdn L, New York, NY 10021 USA;

    Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Pediat,Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA|Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Cell & Dev Biol,Childrens Canc & Blood Fdn L, New York, NY 10021 USA|Spanish Natl Canc Res Ctr CNIO, Dept Mol Oncol, Microenvironm & Metastasis Lab, Madrid 28029, Spain;

    Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA|Weill Cornell Med, Dept Med, New York, NY 10021 USA;

    Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Pediat,Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA|Weill Cornell Med, Meyer Canc Ctr, Drukier Inst Childrens Hlth, Dept Cell & Dev Biol,Childrens Canc & Blood Fdn L, New York, NY 10021 USA|Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA;

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