Understanding tumor anabolism and patient catabolism in cancer-associated cachexia

Abstract

Cachexia is a multifactorial paraneoplastic syndrome commonly associated with advanced stages of cancer. Cachexia is responsible for poor responses to antitumoral treatment and death in close to one-third of affected patients. There is still an incomplete understanding of the metabolic dysregulation induced by a tumor that leads to the appearance and persistence of cachexia. Furthermore, cachexia is irreversible, and there are currently no guidelines for its diagnosis or treatments for it. In this review, we aim to discuss the current knowledge about cancer-associated cachexia, starting with generalities about cancer as the generator of this syndrome, then analyzing the characteristics of cachexia at the biochemical and metabolic levels in both the tumor and the patient, and finally discussing current therapeutic approaches to treating cancer-associated cachexia.

Keywords: Cachexia; biochemistry; cancer; metabolism.

Figure 1

Elements of cancer-associated cachexia. Neoplasia generates cachexia through the chronic presence of systemic inflammation, which is associated with muscle and adipose wasting as well as anorexia. Anorexia can also be promoted by the gastrointestinal obstruction caused by the physical presence of the tumor mass. Together, these aberrations lead to weight loss and, irremediably, to cachexia.

Figure 2

The effects of chronic systemic inflammation are strong promoters of cancer-induced cachexia. A permanent and uncontrolled inflammatory environment has multiple effects on the host at different levels in the pathogenesis of cachexia. LIF is a recognized inducer of myotube atrophy that damages myocytes. CNTF inhibits the gene expression of neuropeptide Y, a potent appetite stimulant in the arcuate nucleus of the brain. VEGF, PGE₂, MMP-9 and an acidic environment are associated with tumoral angiogenesis. Furthermore, a reduction in the pH of the tumor microenvironment stimulates the expulsion of acetate from malignant cells, which promotes histone acetylation aberrations within the tumor mass. Both IFN-γ and TNF-α block myosin heavy chain mRNA production to minimize the myogenesis process. Moreover, TNF-α-induced NF-κB functions as an alternative route to impede myogenesis via the blockade of myoD. Lipolysis is indirectly allowed through the NF-κB-mediated inhibition of perilipins. TNF-α also induces oxidative stress in muscle, which degrades muscle proteins. The upregulation of IL-6 is associated with inhibition of PGC-1α, which makes systemic cells susceptible to reactive oxygen species damage secondary to a reduction in mitochondrial biogenesis. IL-6 and CRP are promoters of weight loss. Abbreviations: LIF: leukemia inhibitory factor; CNTF: ciliary neurotrophic factor; pH: potential of hydrogen; VEGF: vascular endothelial growth factor; MMP-9: metalloproteinase 9; PGE₂: prostaglandin E₂; IFN-γ: interferon-γ; TNF-α: tumor necrosis factor α; NF-κB: nuclear factor kappa beta; myoD: myogenic differentiation I; PGC-1α: peroxisome proliferator-activated receptor gamma co-activator 1-α; IL-6: interleukin 6; CRP: C-reactive protein; ROS: reactive oxygen species.

Figure 3

Biochemical and metabolic changes within the tumor. Tumor cells are organized as an anabolically active group that continuously interchanges molecules with the environment. A. Usually, as the tumor progresses, its cells secrete lactate as an anaerobic product of energy metabolism. Lactate, in turn, reduces the pH of the surroundings to promote a change in the phenotype of infiltrating macrophages from M1 to M2. M2 macrophages, together with myeloid-derived suppressor cells, are associated with tolerogenic functions that enable the tumor to evade the immune action. Lactate is also mobilized to the liver with the employment of the high vascularization of the microenvironment to produce glucose via the Cori cycle, which then can return to the tumor in an endless loop. At the same time, malignant cells release acetate from lysines within histones as a protective mechanism against the acidic pH. B. At the cellular level, the neoplasm develops point mutations in the genome, such as mutations that induce the Ras-Akt-mTOR pathway, to increase glycolysis within the cell. The continuous activation of glycolysis, together with the Akt-induced ACLY enzyme, led to citrate generation within the mitochondria to fuel the Krebs cycle. Malate, through the malic enzyme, increases the pyruvate concentration. Both citrate and pyruvate are transformed into acetyl-coenzyme A, which can either be employed as an acetate group donor for the DNA acetylation process or can be extruded from the cell to the microenvironment to function as a regulator of intracellular pH. Enhanced glycolysis can also be promoted via the upregulation of hexokinase II and by the high glucose concentration secondary to the HIF-1α-mediated increase in glucose transporters. HIF-1α is also related to the transcription of glutamine transporters at the cellular membrane; along with adipophilin, it induces the formation of lipid droplets in close contact with the mitochondria. These lipid droplets contain a high amount of fatty acids secondary to the high expression of fatty acid synthase by SREBPs. Fatty acids are assembled into triacylglycerides, which are lysed by the hormone-sensitive lipase to provide energy to the tumor cell. The translocation of glutamine transporters into the cellular membrane promotes an increase in intracellular glutamine, which is transformed into glutamate via the upregulation of glutaminase, which produces ammonia as a waste product. Ammonia, in turn, is a signal for autophagy that the cancer cell employs to secure a continuous pool of energy and biomolecules for its anabolic processes. Inside the mitochondria, isocitrate dehydrogenase is transformed into an aberrant form of α-ketoglutarate termed 2-hydroxyglutarate. This reaction can be promoted by the anaplerotic reaction of glutamate, which is introduced as α-ketoglutarate by either GDH or ALT enzymes, depending on the presence of low or high glucose metabolism within the cell, respectively. Glutamate, with the help of NADPH, is associated with the generation of glutathione, which is the most potent antioxidant that safeguards the malignant cell from reactive oxygen species-mediated death. Abbreviations: FASN: fatty acid synthase; HIF-1α: hypoxia-inducible factor-1α; GLS: glutaminase; NH4+: ammonia; SREBP: sterol regulatory element-binding protein; HSL: hormone-sensitive lipase; IDH: isocitrate dehydrogenase; 2-HG: 2-hydroxyglutarate; ATP: adenosine triphosphate; GDH: glutamate dehydrogenase; ALT: alanine transaminase; NADPH: nicotinamide adenine dinucleotide phosphate; ACLY: ATP-citrate lyase; acetyl-CoA: acetyl-coenzyme A; HK2: hexokinase II; ME: malic enzyme; α-KG: α-ketoglutarate.

Figure 4

Muscle cells are direct targets in cachexia. At the muscle level, an increase in proteolysis-inducing factor is related to a reduction in protein synthesis. This effect is potentiated by the secretion of Th1 cytokines, such as TNF-α, which minimize myogenesis, promote mitochondrial damage with concomitant muscle cell wasting, induce the release of diverse catecholamines that increase the metabolic rate at rest, and provoke direct muscle wasting by the release of cortisol, which activates the muscle-specific ubiquitin ligases MuRF1 and MAFbx/atrogin-1 mediated by the transcription factor FoxO. In particular, the upregulation of FoxO1 increases myostatin, which blocks muscle hypertrophy in the subject. Furthermore, the inhibition of the myoD transcription factor is accompanied by a reduction in the differentiation of satellite cells, which are precursors of new myocytes under healthy conditions. Abbreviations: PIF: proteolysis-inducing factor; FoxO: Forkhead box O proteins; MuRF1: muscle RING finger 1 ubiquitin ligase; MAFbx: muscle atrophy F-box ubiquitin ligase; myoD: myogenic differentiation I.

Figure 5

Adipose tissue undergoes browning transition and lipolysis during the progression of cachexia. Systemic inflammation causes an increase in pro-inflammatory cytokines that have an impact on adipose tissue. TNF-α impedes three pathways associated with adipose metabolism. First, by the inhibition of the adipogenic transcription factors PPAR-γ and C/EBPα, the adipogenesis process is stopped. Second, lipoprotein lipase fails to take up fatty acids to construct complex lipids within the adipocyte. Finally, perilipins are unable to prevent hormone-sensitive lipase from inducing lipolysis in the adipose tissue. On the other hand, the high abundance of IL-6 stimulates the expression of uncoupling proteins, which in turn are related to the browning transition in adipocytes and, thus, a permanent thermogenic state. The browning transition is also associated with an increase in the skeletal muscle transcription factor myoD. Furthermore, lipolysis can be stimulated through different routes. IL-6, together with the browning transition and the ZAG protein, directly induces lipolysis. Th1 cytokines are related to the secretion of catecholamines into circulation, which upregulates both hormone-sensitive lipase and adipose triglyceride lipase. Both enzymes generate lipolysis. Together, these processes stimulate adipose wasting via a reduction in adipocyte volume. Abbreviations: TNF-α: tumor necrosis factor α; PPAR-γ: peroxisome proliferator-activated receptor-gamma; C/EBP: CCAAT/enhancer-binding protein; LPL: lipoprotein lipase; HSL: hormone-sensitive lipase; IL-6: interleukin 6; UCPs: uncoupling proteins; ZAG: zinc-α2-glycoprotein; myoD: myogenic differentiation I.

Figure 6

Cancer-associated cachexia stimulates anorexia and weight loss. A pro-inflammatory systemic environment is a direct promoter of insulin resistance, and high circulating levels of insulin cause the POMC neurons at the arcuate nucleus of the hypothalamus to become activated. IL-6 also induces corticotrophin-releasing factor, which, together with ciliary neurotrophic factor and leptin, decreases neuropeptide Y levels. The upregulation of POMC and the downregulation of neuropeptide Y are linked to early satiety in the patient and therefore to reduced food ingestion, which leads to weight loss. The latter is related to an increase in adiponectin levels, which concomitantly augments POMC neuronal activity. This response creates a loop of early satiety and weight loss, and it is potentiated by chronic systemic inflammation. Abbreviations: IL-6: interleukin 6; CRF: corticotrophin-releasing factor; POMC: proopiomelanocortin; NPY: neuropeptide Y; CNTF: ciliary neurotrophic factor.