Tumor cell anabolism and host tissue catabolism-energetic inefficiency during cancer cachexia

Abstract

Cancer-associated cachexia (CC) is a pathological condition characterized by sarcopenia, adipose tissue depletion, and progressive weight loss. CC is driven by multiple factors such as anorexia, excessive catabolism, elevated energy expenditure by growing tumor mass, and inflammatory mediators released by cancer cells and surrounding tissues. In addition, endocrine system, systemic metabolism, and central nervous system (CNS) perturbations in combination with cachexia mediators elicit exponential elevation in catabolism and reduced anabolism in skeletal muscle, adipose tissue, and cardiac muscle. At the molecular level, mechanisms of CC include inflammation, reduced protein synthesis, and lipogenesis, elevated proteolysis and lipolysis along with aggravated toxicity and complications of chemotherapy. Furthermore, CC is remarkably associated with intolerance to anti-neoplastic therapy, poor prognosis, and increased mortality with no established standard therapy. In this context, we discuss the spatio-temporal changes occurring in the various stages of CC and highlight the imbalance of host metabolism. We provide how multiple factors such as proteasomal pathways, inflammatory mediators, lipid and protein catabolism, glucocorticoids, and in-depth mechanisms of interplay between inflammatory molecules and CNS can trigger and amplify the cachectic processes. Finally, we highlight current diagnostic approaches and promising therapeutic interventions for CC.

Keywords: Glycolysis; anabolism; anorexia; cachexia; catabolism; gluconeogenesis.

Figure 1.

Mechanism of cancer cachexia. Anabolic tumor tissue continuously demands glucose, amino acids, fatty acids, and other nutrients. The cytokine storm generated from the growing mass of tumors acts on host tissue leading to catabolism and cachexia. The figure was created in BioRender.com. (A color version of this figure is available in the online journal.)

Figure 2.

Molecular insight to cachexia and mechanism of cancer cachexia inhibition by various drugs. The figure was created in BioRender.com. (A color version of this figure is available in the online journal.)