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  Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis

Strilic, B., Yang, L., Albarran Juarez, J. A., Wachsmuth, L., Han, K., Mueller, U. C., et al. (2016). Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis. NATURE, 536(7615), 215-+. doi:10.1038/nature19076.

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Genre: Journal Article

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 Creators:
Strilic, Boris1, Author              
Yang, Lida1, Author              
Albarran Juarez, Julian Alberto1, Author              
Wachsmuth, Laurens, Author
Han, Kang, Author
Mueller, Ulrike C., Author
Pasparakis, Manolis, Author
Offermanns, Stefan1, Author              
Affiliations:
1Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591696              

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Free keywords: AMYLOID PRECURSOR PROTEIN; LUNG METASTASIS; MIGRATION; DR6; INFLAMMATION; ACTIVATION; INSIGHTSScience & Technology - Other Topics;
 Abstract: Metastasis is the leading cause of cancer-related death in humans. It is a complex multistep process during which individual tumour cells spread primarily through the circulatory system to colonize distant organs(1-3). Once in the circulation, tumour cells remain vulnerable, and their metastatic potential largely depends on a rapid and efficient way to escape from the blood stream by passing the endothelial barrier(4-9). Evidence has been provided that tumour cell extravasation resembles leukocyte transendothelial migration(7-9). However, it remains unclear how tumour cells interact with endothelial cells during extravasation and how these processes are regulated on a molecular level. Here we show that human and murine tumour cells induce programmed necrosis (necroptosis) of endothelial cells, which promotes tumour cell extravasation and metastasis. Treatment of mice with the receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-inhibitor necrostatin-1 or endothelial-cell-specific deletion of RIPK3 reduced tumour-cell-induced endothelial necroptosis, tumour cell extravasation and metastasis. In contrast, pharmacological caspase inhibition or endothelial-cell-specific loss of caspase-8 promoted these processes. We furthermore show in vitro and in vivo that tumour-cell-induced endothelial necroptosis leading to extravasation and metastasis requires amyloid precursor protein expressed by tumour cells and its receptor, death receptor 6 (DR6), on endothelial cells as the primary mediators of these effects. Our data identify a new mechanism underlying tumour cell extravasation and metastasis, and suggest endothelial DR6-mediated necroptotic signalling pathways as targets for anti-metastatic therapies.

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Language(s): eng - English
 Dates: 2016
 Publication Status: Published in print
 Pages: 20
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000381472100037
DOI: 10.1038/nature19076
 Degree: -

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Title: NATURE
Source Genre: Journal
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Publ. Info: MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND : NATURE PUBLISHING GROUP
Pages: - Volume / Issue: 536 (7615) Sequence Number: - Start / End Page: 215 - + Identifier: ISSN: 0028-0836