Differential Effects of IL6 and Activin A in the Development of Cancer-Associated Cachexia

Cancer Res. 2016 Sep 15;76(18):5372-82. doi: 10.1158/0008-5472.CAN-15-3152. Epub 2016 Jun 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins / metabolism*
  • Animals
  • Blotting, Western
  • Cachexia / metabolism*
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Interleukin-6 / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms / complications
  • Polymerase Chain Reaction


  • Interleukin-6
  • activin A
  • interleukin-6, mouse
  • Activins