Differential Effects of IL6 and Activin A in the Development of Cancer-Associated Cachexia.
Cachexia is a life-threatening wasting syndrome lacking effective treatment, which arises in many cancer patients. Although ostensibly induced by multiple tumor-produced cytokines (tumorkines), their functional contribution to initiation and progression of this syndrome has proven difficult to determine. In this study, we used adeno-associated viral vectors to elevate circulating levels of the tumorkines IL6 and/or activin A in animals in the absence of tumors as a tactic to evaluate hypothesized roles in cachexia development. Mice with elevated levels of IL6 exhibited 8.1% weight loss after 9 weeks, whereas mice with elevated levels of activin A lost 11% of their body weight. Co-elevation of both tumorkines to levels approximating those observed in cancer cachexia models induced a more rapid and profound body weight loss of 15.4%. Analysis of body composition revealed that activin A primarily triggered loss of lean mass, whereas IL6 was a major mediator of fat loss. Histologic and transcriptional analysis of affected organs/tissues (skeletal muscle, fat, and liver) identified interactions between the activin A and IL6 signaling pathways. For example, IL6 exacerbated the detrimental effects of activin A in skeletal muscle, whereas activin A curbed the IL6-induced acute-phase response in liver. This study presents a useful model to deconstruct cachexia, opening a pathway to determining which tumorkines are best targeted to slow/reverse this devastating condition in cancer patients. Cancer Res; 76(18); 5372-82. ©2016 AACR.
Hudson Institute of Medical Research, Clayton, Australia. Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
Justin L
JL
Chen
Hudson Institute of Medical Research, Clayton, Australia.
Kelly L
KL
Walton
Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
Hongwei
H
Qian
Baker IDI Heart and Diabetes Institute, Melbourne, Australia. Department of Physiology, The University of Melbourne, Melbourne, Australia.
Timothy D
TD
Colgan
Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
Adam
A
Hagg
The Obesity and Metabolism Program of the Biomedicine Discovery Institute, Monash University, Clayton, Australia. Department of Physiology, Monash University, Clayton, Australia.
Matthew J
MJ
Watt
Hudson Institute of Medical Research, Clayton, Australia. Department of Physiology, Monash University, Clayton, Australia. Department of Molecular and Translational Sciences, Monash University, Clayton, Australia.
Craig A
CA
Harrison
Baker IDI Heart and Diabetes Institute, Melbourne, Australia. Department of Physiology, The University of Melbourne, Melbourne, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia. Department of Neurology, The University of Washington School of Medicine, Seattle, Washington. paul.gregorevic@bakeridi.edu.au.
Paul
P
Gregorevic
D028341:Activins / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002100:Cachexia / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000150:complications; D016133:Polymerase Chain Reaction
D015850:Interleukin-6; C422405:activin A; C577686:interleukin-6, mouse; D028341:Activins