Differential effects of IL6 and activin A in the development of cancer-associated cachexia

Justin L. Chen, Kelly L. Walton, Hongwei Qian, Timothy D. Colgan, Adam Hagg, Matthew J. Watt, Craig A. Harrison, Paul Gregorevic

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)5372-5382
Number of pages11
JournalCancer Research
Volume76
Issue number18
DOIs
Publication statusPublished - 15 Sep 2016

Cite this

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title = "Differential effects of IL6 and activin A in the development of cancer-associated cachexia",
abstract = "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.",
author = "Chen, {Justin L.} and Walton, {Kelly L.} and Hongwei Qian and Colgan, {Timothy D.} and Adam Hagg and Watt, {Matthew J.} and Harrison, {Craig A.} and Paul Gregorevic",
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Differential effects of IL6 and activin A in the development of cancer-associated cachexia. / Chen, Justin L.; Walton, Kelly L.; Qian, Hongwei; Colgan, Timothy D.; Hagg, Adam; Watt, Matthew J.; Harrison, Craig A.; Gregorevic, Paul.

In: Cancer Research, Vol. 76, No. 18, 15.09.2016, p. 5372-5382.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Walton, Kelly L.

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AU - Colgan, Timothy D.

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AU - Watt, Matthew J.

AU - Harrison, Craig A.

AU - Gregorevic, Paul

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