Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Differential effects of interleukin-6 and activin A in the development of cancer-associated cachexia (#34)

Justin L Chen 1 2 3 , Kelly L Walton 2 3 , Hongwei Qian 1 , Timothy D Colgan 1 , Adam Hagg 1 , Matthew J Watt 3 , Craig A Harrison 2 3 , Paul Gregorevic 1 4
  1. Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia
  2. Hudson Institute of Medical Research, Clayton, VIC, Australia
  3. Monash University, Clayton, VIC, Australia
  4. University of Melbourne, Parkville, VIC, Australia

Cachexia in cancer patients is a life-threatening wasting condition without any effective treatment options. This syndrome is ostensibly induced by multiple tumour-derived factors, although the relative contribution of these ‘tumourkines’ to the initiation and progression of cachexia has proven difficult to determine. Here, we used adeno-associated viral vectors (AAVs) to raise the circulating levels of two recognised tumourkines, interleukin-6 (IL-6) and/or activin A, in the absence of tumour burden. In this approach, we characterised their respective contribution to the pathogenesis of cachexia. Mice with elevated levels of IL-6 demonstrated substantial weight loss after nine weeks (-8.1% or -3.0 ± 1.0 g), and greater weight loss was observed in mice with high circulating activin A (-11% or -4.0 ± 1.4 g). Co-elevation of both serum IL-6 and activin A to levels approximating those observed in cachexia models induced a more rapid and profound weight loss in mice (-15.4%; -5.9 ± 1.8 g). Body composition analysis indicated that activin A primarily drove the loss of body weight from decreases in lean mass, while IL-6 was the major mediator of fat loss. Histological and transcriptional analysis of affected organs/tissues (skeletal muscle, fat and liver) identified interactions between the activin A and IL-6 signalling pathways. For example, activin A curbed the IL-6-induced acute phase response in liver, whereas IL-6 exacerbated the detrimental effects of activin A in skeletal muscle. Our new approach provides the means to deconstruct cachexia and to identify the tumourkines best targeted to slow/reverse this devastating condition.