Understanding cachexia as a cancer metabolism syndrome

Abstract

Metabolic reprogramming occurs in tumors to foster cancer cell proliferation, survival and metastasis, but as well at a systemic level affecting the whole organism, eventually leading to cancer cachexia. Indeed, as cancer cells rely on external sources of nitrogen and carbon skeleton to grow, systemic metabolic deregulation promoting tissue wasting and metabolites mobilization ultimately supports tumor growth. Cachectic patients experience a wide range of symptoms affecting several organ functions such as muscle, liver, brain, immune system and heart, collectively decreasing patients' quality of life and worsening their prognosis. Moreover, cachexia is estimated to be the direct cause of at least 20% of cancer deaths. The main aspect of cachexia syndrome is the unstoppable skeletal muscle and fat storage wasting, even with an adequate caloric intake, resulting in nutrient mobilization - both directly as lipid and amino acids and indirectly as glucose derived from the exploitation of liver gluconeogenesis - that reaches the tumor through the bloodstream. From a metabolic standpoint, cachectic host develops a wide range of dysfunctions, from increased insulin and IGF-1 resistance to induction of mitochondrial uncoupling proteins and fat tissue browning resulting in an increased energy expenditure and heat generation, even at rest. For a long time, cachexia has been merely considered an epiphenomenon of end-stage tumors. However, in specific tumor types, such as pancreatic cancers, it is now clear that patients present markers of tissue wasting at a stage in which tumor is not yet clinically detectable, and that host amino acid supply is required for tumor growth. Indeed, tumor cells actively promote tissue wasting by secreting specific factors such as parathyroid hormone-related protein and micro RNAs. Understanding the molecular and metabolic mediators of cachexia will not only advance therapeutic approaches against cancer, but also improve patients' quality of life.

Figure 1

The simplified scheme represents the major organs commonly affected during cachexia progression and how they fuel tumor growth. In brief, tumor tissue and the co-opted immune system secrete specific factors, thus promoting skeletal muscle wasting and lipolysis. Pro-inflammatory cytokines contribute to develop anorexia and insulin resistance, ultimately worsening skeletal muscle wasting. Gastrointestinal tract tumors and bone metastasis can promote further cachexia by causing endotoxemia and transforming growth factor beta release, respectively. (Adapted from Servier Medical Art, www.servier.com).