Mechanisms of metabolic dysfunction in cancer-associated cachexia

Abstract

Metabolic dysfunction contributes to the clinical deterioration observed in advanced cancer patients and is characterized by weight loss, skeletal muscle wasting, and atrophy of the adipose tissue. This systemic syndrome, termed cancer-associated cachexia (CAC), is a major cause of morbidity and mortality. While once attributed solely to decreased food intake, the present description of cancer cachexia is a disorder of multiorgan energy imbalance. Here we review the molecules and pathways responsible for metabolic dysfunction in CAC and the ideas that led to the current understanding.

Keywords: cancer-associated cachexia (CAC); metabolic failure; skeletal muscle atrophy; white adipose tissue (WAT) browning.

Figure 1.

Multilevel cancer pathophysiology at a glance. Schematic representation of the evolution of cancer from a single transformed cell to a systemic disease. At the “cell” level, the transformed cell (purple) is characterized by the presence of genome instability and mutations, sustained proliferative signaling, avoidance of growth suppressors, replicative immortality, resistance to cell death, and deregulated cellular energetics. At the “tissue” level, the proliferation of the tumor mass is associated with induction of angiogenesis, activation of invasion, promotion of inflammation, and avoidance of immune destruction—all hallmarks of cancer as described in Hanahan and Weinberg (2011). At the “organism” level, the developing cancer induces changes in distant organs, including metastasis, metabolic failure, and cancer cachexia, which is not included in the hallmarks of cancer. Cancer cells are shown in purple, “normal” cells are indicated in blue, immune cells are shown in green, and blood vessels are indicated in red. The arrow at the “cell” level points to the conversion from a normal cell to a cancer cell, whereas the arrow pointing to the “organism” depicts a growing tumor (purple).

Figure 2.

Timeline of discoveries in cancer cachexia. In 1951, the first systemic manifestation of cancer was described in rats. In 1962, it was observed that injection of tumor preparations in mice was sufficient to induce fat atrophy. In 1983 and 1985, the first candidate molecules were identified. Seminal publications in 1993 and 2001 described a role for the ubiquitin pathway and myostatin in skeletal muscle atrophy. It was not until some years ago that an international consensus on the diagnostic criteria of CAC was reached. Promising results have been reported in late 2015 from the first phase III clinical trial targeting CAC with the ghrelin receptor agonist anamorelin (https://www.iaslc.org/news/results-phase-iii-trials-anamorelin-advanced-non-small-cell-lung-cancer-patients-cachexia).

Figure 3.

Mechanisms and consequences of WAT browning in cancer cachexia. At the “cell” level, beige adipocytes are induced in WAT by a combination of signaling pathways, including β-adrenergic stimulation, inflammation mediated by IL-6, and the presence of parathyroid-related peptide (PTHrP); as a result, UCP1 levels and mitochondrial content are increased. At the “tissue” level, CAC is associated with the appearance of islets of beige adipocytes in WAT, surrounded by white adipocytes of reduced size due to ongoing lipolysis. WAT browning and lipolysis result in decreased energy storage and increased production of heat. In the context of obesity, WAT browning is beneficial, while in cancer patients, it is detrimental.

Figure 4.

Conceptual evolution of the understanding of cancer cachexia. The scheme depicts the way we envision multifactorial cancer cachexia in 2015, involving reciprocal compounding interactions between the tumor and the organism, which result in inflammatory and metabolic changes distant from the pathological sites of tumor growth. This way is very different from the unidirectional way that “cancer aggression” was viewed decades ago (Costa 1977).