Cachexia, progressive wasting of adipose tissue and skeletal muscle, is a devastating condition afflicting about half of all cancer patients. Disproportionate loss of muscle protein despite adequate food intake results in reduced ambulation, diminished quality of life, poor response to therapy, and ultimately death. Indeed, cachexia itself causes the deaths of roughly 25% of all cancer patients. Pathological muscle wasting appears to result from suppression of hypertrophic pathways including the insulin-like growth factor pathway, and activation of catabolism largely through skeletal muscle specific ubiquitin ligases. Both tumor-derived factors and host-derived cytokines such as TNF, interferon-gamma and Interleukins (IL)-1 and IL-6 appear to mediate cancer cachexia. In normal development and adulthood, muscle growth is suppressed by the muscle-specific factor myostatin. We show that IL-6 and myostatin both induced myotube wasting in vitro and profound wasting of muscle and adipose tissue in vivo. Analysis of signaling pathways and gene expression demonstrated induction of the STAT3 pathway and downstream target genes by both IL-6 and myostatin. IL-6 and myostatin markedly induced genes predicted to inhibit the IGF pathway and promote proteolysis. Consistent with a role in cachexia, STAT3 was activated in five mouse models of muscle wasting due to cancer or prolonged sepsis. Moreover, STAT3 activation was sufficient to induce wasting in normal skeletal muscle, while STAT3 inhibition blocked IL-6-induced wasting. Thus STAT3 represents a novel therapeutic target for potential treatment of muscle wasting in cachexia due to cancer, sepsis, burn, AIDS, organ failure or other chronic disease. The objectives of this project are to define the role of the STAT3 pathway on muscle growth and wasting, to identify the downstream effectors leading to wasting, and to target the STAT3 pathway for potential muscle preservation in cancer cachexia.
The specific aims are to 1) dissect the molecular pathways from IL-6 and myostatin signaling through STAT3 to muscle wasting using C2C12 myofiber cultures; 2) define the contribution of STAT3 and downstream targets SOCS3 and TC-PTP/PTPN2 in muscle growth regulation and wasting using gene transfer in intact mouse skeletal muscle, and 3) determine the role of skeletal muscle SOCS3 expression in muscle growth regulation and wasting using transgenic mice. These studies are an essential step towards understanding the pathological basis of cancer cachexia and will contribute to development of therapies aimed at preserving muscle mass and improving and prolonging life.

Public Health Relevance

Muscle wasting in cancer and other chronic diseases contributes to decreased quality of life, reduced response to therapy and mortality. We have identified a new molecular pathway leading to muscle wasting. Understanding the molecular workings of that pathway is essential to develop muscle preserving therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA122596-03
Application #
8310587
Study Section
Special Emphasis Panel (ZRG1-MOSS-K (03))
Program Officer
Spalholz, Barbara A
Project Start
2010-07-02
Project End
2015-04-30
Budget Start
2011-08-01
Budget End
2012-04-30
Support Year
3
Fiscal Year
2011
Total Cost
$160,828
Indirect Cost
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Mace, Thomas A; Shakya, Reena; Pitarresi, Jason R et al. (2018) IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut 67:320-332
Milgrom, Daniel P; Koniaris, Leonidas G; Valsangkar, Nakul P et al. (2018) An Assessment of the Academic Impact of Shock Society Members. Shock 49:508-513
Kays, Joshua K; Shahda, Safi; Stanley, Melissa et al. (2018) Three cachexia phenotypes and the impact of fat-only loss on survival in FOLFIRINOX therapy for pancreatic cancer. J Cachexia Sarcopenia Muscle 9:673-684
Talbert, Erin E; Lewis, Heather L; Farren, Matthew R et al. (2018) Circulating monocyte chemoattractant protein-1 (MCP-1) is associated with cachexia in treatment-naïve pancreatic cancer patients. J Cachexia Sarcopenia Muscle 9:358-368
Jin, Xiaoling; Zimmers, Teresa A; Jiang, Yanlin et al. (2018) Meloxicam increases epidermal growth factor receptor expression improving survival after hepatic resection in diet-induced obese mice. Surgery 163:1264-1271
Pin, Fabrizio; Barreto, Rafael; Kitase, Yukiko et al. (2018) Growth of ovarian cancer xenografts causes loss of muscle and bone mass: a new model for the study of cancer cachexia. J Cachexia Sarcopenia Muscle 9:685-700
Wang, Ruizhong; Bhat-Nakshatri, Poornima; Padua, Maria B et al. (2017) Pharmacological Dual Inhibition of Tumor and Tumor-Induced Functional Limitations in a Transgenic Model of Breast Cancer. Mol Cancer Ther 16:2747-2758
Milgrom, Daniel P; Lad, Neha L; Koniaris, Leonidas G et al. (2017) Bone Pain and Muscle Weakness in Cancer Patients. Curr Osteoporos Rep 15:76-87
Sato, Amy Y; Richardson, Danielle; Cregor, Meloney et al. (2017) Glucocorticoids Induce Bone and Muscle Atrophy by Tissue-Specific Mechanisms Upstream of E3 Ubiquitin Ligases. Endocrinology 158:664-677
Bell, Teresa M; Valsangkar, Nakul; Joshi, Mugdha et al. (2017) The Role of PhD Faculty in Advancing Research in Departments of Surgery. Ann Surg 265:111-115

Showing the most recent 10 out of 34 publications