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Exosomes containing ErbB2/CRK induce vascular growth in premetastatic niches and promote metastasis of bladder cancer

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Title: Exosomes containing ErbB2/CRK induce vascular growth in premetastatic niches and promote metastasis of bladder cancer
Authors: Yoshida, Kazuhiko Browse this author →KAKEN DB
Tsuda, Masumi Browse this author →KAKEN DB
Matsumoto, Ryuji Browse this author →KAKEN DB
Semba, Shingo Browse this author →KAKEN DB
Wang, Lei Browse this author →KAKEN DB
Sugino, Hirokazu Browse this author
Tanino, Mishie Browse this author →KAKEN DB
Kondo, Tsunenori Browse this author
Tanabe, Kazunari Browse this author →KAKEN DB
Tanaka, Shinya Browse this author →KAKEN DB
Keywords: bladder cancer
CRK
ErbB2
exosome
metastasis
Issue Date: Jul-2019
Publisher: John Wiley & Sons
Journal Title: Cancer science
Volume: 110
Issue: 7
Start Page: 2119
End Page: 2132
Publisher DOI: 10.1111/cas.14080
PMID: 31141251
Abstract: Locally advanced and metastatic invasive bladder cancer (BC) has a poor prognosis, and no advanced therapies beyond cisplatin-based combination chemotherapy have been developed. Therefore, it is an urgent issue to elucidate the underlying mechanisms of tumor progression and metastasis of invasive BC for the development of new therapeutic strategies. Here, we clarified a novel role of exosomes containing ErbB2 and CRK in a formation of premetastatic niches and subsequent metastases. CRK adaptors were overexpressed in invasive UM-UC-3 BC cells. In an orthotopic xenograft model, metastases to lung, liver, and bone of UM-UC-3 cells were completely abolished by CRK elimination. Mass spectrometry analysis identified that ErbB2 was contained in UM-UC-3-derived exosomes in a CRK-dependent manner; the exosomes significantly increased proliferation and invasion properties of low-grade 5637 BC cells and HUVECs through FAK and PI3K/AKT signaling pathways. In athymic mice educated with UM-UC-3-derived exosomes, i.v. implanted UM-UC-3 cells were trapped with surrounding PKH67-labeled exosomes in lung and led to development of lung metastasis with disordered vascular proliferation. In contrast, exosomes derived from CRK-depleted BC cells failed to induce these malignant features. Taken together, we showed that CRK adaptors elevated the expression of ErbB2/3 in BC cells, and these tyrosine kinase/adaptor units were transferred from host BC cells to metastatic recipient cells by exosomes, leading to vascular leakiness and proliferation and contributing to the formation of distant metastasis. Thus, CRK intervention with ErbB2/3 blockade might be a potent therapeutic strategy for patients with ErbB2 overexpressing advanced and metastatic BC.
Rights: https://creativecommons.org/licenses/by-nc/4.0/
Type: article
URI: http://hdl.handle.net/2115/75931
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
国際連携研究教育局 : GI-CoRE (Global Institution for Collaborative Research and Education : GI-CoRE) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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