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.

Unravelling the role of fatty acid metabolism in cancer through the FOXO3-FOXM1 axis

“…Another lipid and energy metabolism-related condition strongly associated with cancer is cachexia. It is depicted as involuntary weight loss that cannot be reversed by nutritional intervention (Tsoli and Robertson, 2013) and is observed in up to 80% of cancers (Porporato, 2016). Cachexia is characterized by skeletal muscle wasting and atrophy of the adipose tissue (Petruzzelli and Wagner, 2016), such that fat is lost more rapidly than lean tissues.…”

Bone mineral density and content are differentially impacted by aerobic and resistance training in the colon-26 mouse model of cancer cachexia

“…To address this unmet need, research has attempted to discern the principal causes and consequences of cachexia. Traditional emphasis has been placed on events specific to skeletal muscle mass and function; however, current frameworks describe a systemic condition in which multiple organs are reprogrammed or remodeled to generate the cachectic phenotype [5][6][7].…”

A U-Shaped Relationship between Fasting Plasma Glucose and Severity of Sleep Apnea

“…[20] On the other hand, low fasting glucose levels have been associated with cachexia in people with cancer or other degenerative diseases. [21] In these populations, individuals have a very low BMI, ectopic fat accumulation and extreme insulin resistance. Thus, one could hypothesize that insulin resistance may be associated with reasons others than body weight and/or BMI.…”