Induction Of Cancer Cachexia By Inflammatory Molecules In Directed Complementation Tumor Models

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Cancer cachexia is a complex multi-factorial syndrome characterized by anorexia, body weight loss that is primarily due to the loss of skeletal muscle and adipose tissue, as well as systemic inflammation. It affects the majority of advanced cancer patients, being the cause of death in 20% to 40% of the cases. Although inflammation is recognized as an important component of cancer cachexia, the role of individual cytokines is poorly understood. Our analyses of inflammatory markers in two independent human cancer cachexia plasma collections identified several cytokines (GDF-15, Activin-A, IL-6 and IL-8) that are consistently upregulated in cancer cachexia patients. To examine the ability of these cytokines to induce cancer cachexia, we utilized an inducible breast cancer model as the background in which to create a panel of genetically-engineered mouse tumor models that overexpress targets of interests, namely GDF15, Activin A and IL-6. Such complemented tumor models present a unique preclinical opportunity for dissecting the role of candidate markers in vivo, in part because they were generated on a genetically homogeneous background, allowing the role of each individual target to be identified and differentiated. Mice bearing tumors that overexpress each inflammatory marker were characterized for phenotypic manifestation of cachexia. Mice bearing tumors that overexpress GDF15 (or MIC-1, macrophage inhibitory cytokine-1) developed severe cachexia with a rapid onset of body weight loss as well as changes in body composition. Overexpression of Activin A or IL-6 induced partial body weight loss with a milder cachexia phenotype at concentrations significantly higher that seen in cachexic human patients, while mice bearing control tumors without the engineered expression of an inflammatory cytokine showed no detectable changes in either body weight or body composition. These results indicate that the elevated expression of GDF-15 and to a lesser extent Activin A, and IL-6 can result in the development of cancer cachexia and may represent attractive therapeutic targets. Citation Format: Qing Liu, Lorena Lerner, Zakir Siddiquee, Lucia Huang, Ruojie Wang, Nianjun Tao, Brian Krieger, Isabel Chiu, Jeno Gyuris. Induction of cancer cachexia by inflammatory molecules in directed complementation tumor models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1441. doi:10.1158/1538-7445.AM2014-1441