title: 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.
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia. Electronic address: a.johnston@latrobe.edu.au.
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Johnston
authors.affiliation: Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Melbourne, VIC 3010, Australia.
authors.forename: Kate T
authors.initials: KT
authors.lastname: Murphy
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Jenkinson
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Laine
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Emmrich
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
authors.forename: Pierre
authors.initials: P
authors.lastname: Faou
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
authors.forename: Ross
authors.initials: R
authors.lastname: Weston
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
authors.forename: Krishnath M
authors.initials: KM
authors.lastname: Jayatilleke
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
authors.forename: Jessie
authors.initials: J
authors.lastname: Schloegel
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
authors.forename: Gert
authors.initials: G
authors.lastname: Talbo
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Casey
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
authors.forename: Vita
authors.initials: V
authors.lastname: Levina
authors.affiliation: Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland.
authors.forename: W Wei-Lynn
authors.initials: WW
authors.lastname: Wong
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Dillon
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
authors.forename: Tushar
authors.initials: T
authors.lastname: Sahay
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
authors.forename: Joan
authors.initials: J
authors.lastname: Hoogenraad
authors.affiliation: 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 Melbourne, Melbourne, VIC 3050, Australia.
authors.forename: Holly
authors.initials: H
authors.lastname: Anderton
authors.affiliation: The Walter and Eliza Hall Institute, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3050, Australia.
authors.forename: Cathrine
authors.initials: C
authors.lastname: Hall
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.affiliation: The Walter and Eliza Hall Institute, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3050, Australia.
authors.forename: Maria
authors.initials: M
authors.lastname: Tanzer
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Foley
authors.affiliation: 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.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic
authors.affiliation: Broad Institute, MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Spring Yingchun
authors.initials: SY
authors.lastname: Liu
authors.affiliation: Department of Immunology, Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
authors.affiliation: Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Melbourne, VIC 3010, Australia.
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Lynch
authors.affiliation: 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 Melbourne, Melbourne, VIC 3050, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Silke
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia. Electronic address: n.hoogenraad@latrobe.edu.au.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Hoogenraad
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001284:Atrophy / Q000188:drug therapy; D002100:Cachexia / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death; D003110:Colonic Neoplasms / Q000188:drug therapy; D000074049:Cytokine TWEAK; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D024510:Muscle Development; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000074049:Cytokine TWEAK; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors