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Tumour exosome integrins determine organotropic metastasis.

ABSTRACT: 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 ?6?4 and ?6?1 were associated with lung metastasis, while exosomal integrin ?v?5 was linked to liver metastasis. Targeting the integrins ?6?4 and ?v?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.

SUBMITTER: Hoshino A

PROVIDER: S-EPMC4788391 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Tumour exosome integrins determine organotropic metastasis.

Hoshino Ayuko A Costa-Silva Bruno B Shen Tang-Long TL Rodrigues Goncalo G Hashimoto Ayako A Tesic Mark Milica M Molina Henrik H Kohsaka Shinji S Di Giannatale Angela A Ceder Sophia S Singh Swarnima S Williams Caitlin C Soplop Nadine N Uryu Kunihiro K Pharmer Lindsay L King Tari T Bojmar Linda L Davies Alexander E AE Ararso Yonathan Y Zhang Tuo T Zhang Haiying H Hernandez Jonathan J Weiss Joshua M JM Dumont-Cole Vanessa D VD Kramer Kimberly K Wexler Leonard H LH Narendran Aru A Schwartz Gary K GK Healey John H JH Sandstrom Per P Labori Knut Jørgen KJ Kure Elin H EH Grandgenett Paul M PM Hollingsworth Michael A MA de Sousa Maria M Kaur Sukhwinder S Jain Maneesh M Mallya Kavita K Batra Surinder K SK Jarnagin William R WR Brady Mary S MS Fodstad Oystein O Muller Volkmar V Pantel Klaus K Minn Andy J AJ Bissell Mina J MJ Garcia Benjamin A BA Kang Yibin Y Rajasekhar Vinagolu K VK Ghajar Cyrus M CM Matei Irina I Peinado Hector H Bromberg Jacqueline J Lyden David D

Nature 20151028 7578

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 wit ...[more]

PMID: 26524530

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Project description:TGFβ1 is the most pleiotropic of all known cytokines and thus, to avoid uncontrolled TGFβ-activated processes, its activity is tightly regulated. Studies in fibrosis have led to the discovery that αv integrins are the major regulators of the local activation of latent TGFβ in our tissues. Since all cells can express one or more types of αv integrins, this raises the possibility that, in the complex milieu of a developing cancer, multiple cell types including both cancer cells and stromal cells activate TGFβ. In normal tissues, TGFβ1 is a tumour suppressor through its ability to suppress epithelial cell division, whereas in cancer, in which tumour cells develop genetic escape mechanisms to become resistant to TGFβ growth suppression, TGFβ signalling creates a tumour-permissive environment by activating fibroblast-to-myofibroblast transition, by promoting angiogenesis, by suppressing immune cell populations and by promoting the secretion of both matrix proteins and proteases. In addition, TGFβ drives epithelial-to-mesenchymal transition (EMT) increasing the potential for metastasis. Since αv integrins activate TGFβ, they almost certainly drive TGFβ-dependent cancer progression. In this review, we discuss the data that are helping to develop this hypothesis and describe the evidence that αv integrins regulate the TGFβ promotion of cancer. Graphical Abstract Mechanisms of integrin-mediated transforming growth factor beta (TGFβ) activation and its effect on stromal processes. 1 Matrix-bound latent LAP-TGFβ1 binds αv integrins expressed by epithelial cells or fibroblasts (LAP latency-associated peptide). TGFβ1 becomes exposed. 2 Active TGFβ1 binds the TGFβ receptor in an autocrine or paracrine fashion. 3 TGFβ1 signalling increases integrin expression, LAP-TGFβ1 secretion and trans-differentiation of fibroblasts into contractile cells that secrete collagens and collagen cross-linking proteins. By contracting the matrix, latent TGFβ1 is stretched making the activation of latent TGFβ1 easier and creating a continuous cycle of TGFβ1 signalling. TGFβ1 promotes cancer progression by promoting angiogenesis, immune suppression and epithelial-to-mesenchymal transition (EMT).

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Tumour exosome integrins determine organotropic metastasis.

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Tumour exosome integrins determine organotropic metastasis.

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