Management of Cancer Cachexia: Attempting to Develop New Pharmacological Agents for New Effective Therapeutic Options

Abstract

Cancer cachexia (CC) is a multifactorial syndrome characterized by systemic inflammation, uncontrolled weight loss and dramatic metabolic alterations. This includes myofibrillar protein breakdown, increased lipolysis, insulin resistance, elevated energy expediture, and reduced food intake, hence impairing the patient's response to anti-cancer therapies and quality of life. While a decade ago the syndrome was considered incurable, over the most recent years much efforts have been put into the study of such disease, leading to the development of potential therapeutic strategies. Several important improvements have been reached in the management of CC from both the diagnostic-prognostic and the pharmacological viewpoint. However, given the heterogeneity of the disease, it is impossible to rely only on single variables to properly treat patients presenting this metabolic syndrome. Moreover, the cachexia symptoms are strictly dependent on the type of tumor, stage and the specific patient's response to cancer therapy. Thus, the attempt to translate experimentally effective therapies into the clinical practice results in a great challenge. For this reason, it is of crucial importance to further improve our understanding on the interplay of molecular mechanisms implicated in the onset and progression of CC, giving the opportunity to develop new effective, safe pharmacological treatments. In this review we outline the recent knowledge regarding cachexia mediators and pathways involved in skeletal muscle (SM) and adipose tissue (AT) loss, mainly from the experimental cachexia standpoint, then retracing the unimodal treatment options that have been developed to the present day.

Keywords: animal models; cachexia mediators; cancer cachexia; clinical trials; muscle tissue and adipose tissue loss; therapeutic strategies.

Figure 1

Notorious molecular mechanisms underlying skeletal muscle wasting during cancer cachexia. Atrophy of skeletal muscle in cancer cachexia is due to aberrant activation of specific signaling pathways, consequent to the binding of factors secreted by the tumor, the stroma or the immune system to their cognate receptors. Most of such signaling pathways converge toward activation of selective transcription factors, causing their nuclear translocation and binding to promoters of cachexigenic genes. These include genes encoding cytokines [e.g., tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6)], inflammation-related receptors [e.g., toll-like receptor 4 (TLR4) and TLR7], myokines [e.g., myostatin (Mstn)], muscle-specific E3 ubiquitin ligases and autophagy-related proteins. Such events potentiate inflammatory processes at the local level and cause the breakdown of myofibrillar proteins, impairing the contractile function of skeletal muscles. Several cachexia-inducing factors are known to exert their cachectigenic effect by acting synergistically, as in the case of TNFα and interferon gamma (INFγ). To the contrary, downregulation occurring in the insulin (Ins) and insulin growth-like factor (IGF) signaling determines a decrease in mTOR-dependent protein synthesis, due to upstream downregulation of RAC serine/threonine-protein kinase (AKT) activity. In normal conditions, AKT functions also as a negative regulator of forkhead box protein O1 (FoxO1) and FoxO3 transcription factors, preventing their nuclear translocation. Thus, consequent to AKT downregulation under cachectic conditions, both these FoxOs localize into the myonucleus and induce transcription of autophagy components and muscle-specific E3 ubiquitin ligases. Peroxisome-proliferator-activated receptor-gamma co-activator 1-alpha (PGC1α), overexpressed during cancer cachexia, is known to inhibit FoxO3 binding to the DNA and cause enhance expression of genes involved in energy metabolism and mitochondrial biogenesis. Upregulated nodes are colored in pink and connected with other nodes through continuous edges. Downregulated nodes are colored in azure and connected with other nodes through dash-dot edges. Dashed edges represent connections between transcriptional/co-transcriptional factors and gene expression. ActA, activin A; ActIIR, activin type 2 receptor; ALK4, activin receptor type-1B; C/EBP, CCAAT/enhancer binding protein; c-Jun, proto-oncogene c-Jun; Gp130, glycoprotein 130; Hsp, heat shock protein; IL-1a, interleukin 1 alpha; IL-1R1, interleukin 1 receptor 1; IL-6R, IL-6 receptor; INFGR, INFγ receptor; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; LIF, leukemia inhibitory factor; LIFR, LIF receptor; miR, microRNA; mTORC1, mammalian target of rapamycin complex 1; MyD88, myeloid differentiation factor 88; NF-kB, nuclear transcription factor kappa B; p38, p38 mitogen-activated protein kinase; PI3K, Phosphoinositide 3-kinase; SMAD, small mother against decapentaplegic; STAT3, signal transducer and activator of transcription 3; sXBP1, spliced isoform X-box-binding protein 1; TNFR, tumor necrosis factor receptor; TNFRSF12A, TNF Receptor Superfamily Member 12A; TSC2, tuberous sclerosis complex 2; TWEAK, TNF-related weak inducer of apoptosis; UCP, uncoupling protein.

Figure 2

Molecular mechanisms driving adipose tissue loss and remodeling during cancer cachexia. Similarly to the case of skeletal muscle wasting, the combination of abnormally activated pathways including β-adrenergic signaling, cytokine- and toll-like receptor (TLR)-mediated inflammation, and parathyroid-related peptide (PTHrP) stimulation, leads to enhanced lipolysis and thermogenesis of the AT in cancer cachexia. In particular, binding of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα) to their respective membrane receptors induce high phosphorylation levels of enzymes involved in catabolism of triglycerides, i.e., adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), implying higher rates of their enzyme activity. Interaction between zinc-α2-glycoprotein (ZAG) and beta-3 adrenergic receptor is known to induce even stronger lipolytic effects than those mediated by IL-6 and TNFα, partly due to induction of expression of lipolytic genes (including G proteins of the type Gαs) and suppression of expression of Gαs, an inhibitor of β-adrenergic signaling. Moreover, ZAG promotes phosphorylation of perilipin-1, which results in wider exposition of lipid droplets to the catabolic action of ATGL, HSL, and monoglyceride lipase (MGL). A role in enhanced lipolysis during cancer cachexia has been demonstrated also for TLR4, although precise mechanisms remained largely elusive. Meanwhile, such pattern recognition receptor seems to exert an important role during cachexia-driven white adipose tissue browning, along with IL-6 and PTHrP, promoting expression of thermogenic genes, such as uncoupling protein 1 (UCP1), and favoring mitochondrial biogenesis. In the present illustration, the process of browning proceeds from the left to the right side of the figure, with the left side presenting bigger lipid droplets and almost mitochondria, while the right side presenting a large number of small, sparse lipid droplets and mitochondria. Upregulated nodes are colored in pink and connected with other nodes through continuous edges. Non-deregulated nodes are represented as semi-transparent nodes. Dashed edges represent connections between transcriptional/co-transcriptional factors and gene expression. ADCY, adenylate cyclases; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; DAG, diglyceride; FA, fatty acid; gp130, glycoprotein-130 IL-6R, IL-6 receptor; JAK, Janus kinase; MAG, monoglyceride; MAPK, mitogen-activated protein kinase; PTHR, parathyroid receptor; STAT, signal transducer and activator of transcription; TAG, triglyceride; TNFR, tumor necrosis factor receptor.