Inter-tissue communication in cancer cachexia

During the past decade, skeletal muscle has been identified as a secretory organ. Accordingly, we have suggested that cytokines and other peptides that are produced, expressed and released by muscle fibres and exert either autocrine, paracrine or endocrine effects should be classified as myokines. The finding that the muscle secretome consists of several hundred secreted peptides provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs, such as adipose tissue, liver, pancreas, bones and brain. However, some myokines exert their effects within the muscle itself. Thus, myostatin, LIF, IL-6 and IL-7 are involved in muscle hypertrophy and myogenesis, whereas BDNF and IL-6 are involved in AMPK-mediated fat oxidation. IL-6 also appears to have systemic effects on the liver, adipose tissue and the immune system, and mediates crosstalk between intestinal L cells and pancreatic islets. Other myokines include the osteogenic factors IGF-1 and FGF-2; FSTL-1, which improves the endothelial function of the vascular system; and the PGC-1α-dependent myokine irisin, which drives brown-fat-like development. Studies in the past few years suggest the existence of yet unidentified factors, secreted from muscle cells, which may influence cancer cell growth and pancreas function. Many proteins produced by skeletal muscle are dependent upon contraction; therefore, physical inactivity probably leads to an altered myokine response, which could provide a potential mechanism for the association between sedentary behaviour and many chronic diseases.

Disease progression in cancer is dependent on the complex interaction between the tumor and the host inflammatory response. There is substantial evidence in advanced cancer that host factors, such as weight loss, poor performance status and the host systemic inflammatory response, are linked, and the latter is an important tumor-stage-independent predictor of outcome. Indeed, the systemic inflammatory response, as evidenced by an elevated level of C-reactive protein, is now included in the definition of cancer cachexia. This review examines the role of the systemic inflammatory response in predicting survival in patients with primary operable cancer. Approximately 80 studies have evaluated the role of the systemic inflammatory response using biochemical or hematological markers, such as elevated C-reactive protein levels, hypoalbuminemia or increased white cell, neutrophil and platelet counts. Combinations of such factors have been used to derive simple inflammation-based prognostic scores, such as the Glasgow Prognostic Score, the neutrophil:lymphocyte ratio and the platelet:lymphocyte ratio. This review demonstrates that there is now good evidence that preoperative measures of the systemic inflammatory response predict cancer survival, independent of tumor stage, in primary operable cancer. The evidence is particularly robust in colorectal (including liver metastases), gastro-esophageal and renal cancers. As described in this article, measurement of the systemic inflammatory response is simple, reliable and can be clinically incorporated into current staging algorithms. This will provide the clinician with a better prediction of outcome, and therefore better treatment allocation in patients with primary operable cancer. Furthermore, systemic inflammation-based markers and prognostic scores not only identify patients at risk, but also provide well-defined therapeutic targets for future clinical trials.

Muscle wasting and cachexia have long been postulated to be key determinants of cancer-related death, but there has been no direct experimental evidence to substantiate this hypothesis. Here, we show that in several cancer cachexia models, pharmacological blockade of ActRIIB pathway not only prevents further muscle wasting but also completely reverses prior loss of skeletal muscle and cancer-induced cardiac atrophy. This treatment dramatically prolongs survival, even of animals in which tumor growth is not inhibited and fat loss and production of proinflammatory cytokines are not reduced. ActRIIB pathway blockade abolished the activation of the ubiquitin-proteasome system and the induction of atrophy-specific ubiquitin ligases in muscles and also markedly stimulated muscle stem cell growth. These findings establish a crucial link between activation of the ActRIIB pathway and the development of cancer cachexia. Thus ActRIIB antagonism is a promising new approach for treating cancer cachexia, whose inhibition per se prolongs survival. Copyright 2010 Elsevier Inc. All rights reserved.