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Targeting of Fn14 prevents cancer-induced cachexia and prolongs survival


Abstract

The cytokine TWEAK and its cognate receptor Fn14 are members of the TNF/TNFR superfamily and are upregulated in tumors. We found that Fn14, when expressed in tumors, causes cachexia and that antibodies against Fn14 dramatically extended lifespan by inhibiting tumor-induced weight loss although having only moderate inhibitory effects on tumor growth. Anti-Fn14 antibodies prevented tumor-induced inflammation and loss of fat and muscle mass. Fn14 signaling in the tumor, rather than host, is responsible for inducing this cachexia because tumors in Fn14- and TWEAK-deficient hosts developed cachexia that was comparable to that of wild-type mice. These results extend the role of Fn14 in wound repair and muscle development to involvement in the etiology of cachexia and indicate that Fn14 antibodies may be a promising approach to treat cachexia, thereby extending lifespan and improving quality of life for cancer patients.

Abstract

The cytokine TWEAK and its cognate receptor Fn14 are members of the TNF/TNFR superfamily and are upregulated in tumors. We found that Fn14, when expressed in tumors, causes cachexia and that antibodies against Fn14 dramatically extended lifespan by inhibiting tumor-induced weight loss although having only moderate inhibitory effects on tumor growth. Anti-Fn14 antibodies prevented tumor-induced inflammation and loss of fat and muscle mass. Fn14 signaling in the tumor, rather than host, is responsible for inducing this cachexia because tumors in Fn14- and TWEAK-deficient hosts developed cachexia that was comparable to that of wild-type mice. These results extend the role of Fn14 in wound repair and muscle development to involvement in the etiology of cachexia and indicate that Fn14 antibodies may be a promising approach to treat cachexia, thereby extending lifespan and improving quality of life for cancer patients.

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24 citations in Web of Science®
21 citations in Scopus®
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Contributors:Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia., Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Melbourne, VIC 3010, Australia., Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia., Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland., Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia; The Walter and Eliza Hall Institute, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of M, The Walter and Eliza Hall Institute, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3050, Australia., Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland., Olivia Newton-John Cancer Research Institute, Melbourne, VIC 3084, Australia; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia., Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia., Broad Institute, MIT and Harvard, Cambridge, MA 02142, USA., Department of Immunology, Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA.
Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:10 September 2015
Deposited On:07 Jan 2016 10:12
Last Modified:08 Dec 2017 16:36
Publisher:Cell Press (Elsevier)
ISSN:0092-8674
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.cell.2015.08.031
PubMed ID:26359988

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