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: Amelia J Johnston, Kate T Murphy, Laura Jenkinson, David Laine, Kerstin Emmrich, Pierre Faou, Ross Weston, Krishnath M Jayatilleke, Jessie Schloegel, Gert Talbo, Joanne L Casey, Vita Levina, W Wei-Lynn Wong, Helen Dillon, Tushar Sahay, Joan Hoogenraad, Holly Anderton, Cathrine Hall, Pascal Schneider, Maria Tanzer, Michael Foley, Andrew M Scott, Paul Gregorevic, Spring Yingchun Liu, Linda C Burkly, Gordon S Lynch, John Silke, Nicholas J Hoogenraad
• Journal: Cell (Cell) Vol. 162 Issue 6 Pg. 1365-78 (Sep 10 2015) ISSN: 1097-4172 [Electronic] United States
• PMID: 26359988 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• Cytokine TWEAK
• Receptors, Tumor Necrosis Factor
• TNFRSF12A protein, human
• TWEAK Receptor
• Tnfrsf12a protein, mouse
• Tnfsf12 protein, mouse
• Tumor Necrosis Factors

Topics

• Amino Acid Sequence
• Animals
• Antibodies, Monoclonal (administration & dosage)
• Atrophy (drug therapy)
• Cachexia (drug therapy, pathology)
• Cell Death
• Colonic Neoplasms (drug therapy)
• Cytokine TWEAK
• Female
• Humans
• Lung Neoplasms (drug therapy)
• Mice
• Mice, Inbred BALB C
• Molecular Sequence Data
• Muscle Development
• Neoplasms (metabolism, pathology)
• Receptors, Tumor Necrosis Factor (antagonists & inhibitors, chemistry, metabolism)
• Sequence Alignment
• Signal Transduction
• TWEAK Receptor
• Tumor Necrosis Factors (metabolism)