The treatment interventions and targets of cancer cachexia research during the past decade: a systematic review of the literature

Introduction

Cachexia is a multifactorial syndrome, characterized by an ongoing loss of skeletal muscle mass (with or without loss of fat mass), leading to progressive functional impairment [1]. This condition has been strongly associated with cancer, and has been noted to occur in up to 80% of cases, depending on the cancer type [2]. Cancer cachexia has been described as the main contributor to more than 30% of cancer patients’ deaths [3], while this number is predicted to rise in the years to come [4]. Furthermore, cancer cachexia has been associated with negative effects on several aspects of patients’ quality of life, including depression, anxiety, physical function, role function, cognition, as well as emotional and social function [5].

The detrimental effects of cancer cachexia have sparked growing enthusiasm in the research community regarding interventions for disease prevention and treatment. Cancer cachexia is defined by a plethora of mediators, signaling and metabolic pathways [6,7]. Understanding these complex mechanisms can facilitate the development of management strategies for this muscle condition. Currently, the treatment arsenal for cancer cachexia consists of 3 broad categories, including pharmaceutical [8], nutritional [9], and exercise interventions [10]. However, only a limited number of these interventions have been approved as part of the management guidelines [11,12].

The pathways that regulate skeletal muscle homeostasis have been described in detail (Fig. 1) [13]. Experimental research into cancer cachexia has been rapidly evolving with a view to providing novel interventions that target these pathways of interest. Accurate documentation of results is considered of paramount importance, as a prelude to the implementation of innovative treatment strategies in clinical trials, and ultimately their introduction into clinical practice [14]. Therefore, this study aimed to delineate the broad landscape of cancer cachexia research, by comprehensively presenting the treatment interventions and corresponding targets of cancer cachexia during the past decade. Through this work we have attempted to construct a robust scientific base, so as to inform researchers regarding the recent advances in preclinical cachexia treatment, as well as to facilitate the application of this knowledge in refining future research protocols.

Figure 1 The anabolic and catabolic pathways that regulate skeletal muscle homeostasis. The dashed lines indicate inhibited pathways.

Figure from “Cancer cachexia: molecular mechanisms and treatment strategies”, by T. Setiawan et al., J Hematol Oncol, 2023;16:54, https://doi.org/10.1186/s13045-023-01454-0. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0/. No changes were made to the figure

GH, growth hormone; IGF1R, IGF1 receptor; IR, insulin receptor; BMP, bone morphogenetic protein; BMPRII, BMP receptor II; AR, androgen receptor; ActRIIb, activin type II receptor; AngII, angiotensin II; AT1R, type 1 angiotensin II receptors; IL-6R, interleukin 6 receptor; IL1bR, IL1b receptor; TNFaR, tumor necrosis alpha receptor; PIF, proteolysis-inducing factor; PIFR, proteolysis-inducing factor receptor; GR, glucocorticoid receptor; ROS, reactive oxygen species; UPS, ubiquitin (Ub)-proteasome system; ALS, autophagy-lysosome system.

Materials and methods

Results

The review flow chart is depicted in Fig. 2. A total of 3650 articles were screened in the form of title and abstract, following deduplication of the results that were generated from the Medline (n=1717) and Scopus (n=2710) database searches. After the initial title–abstract screening, a total of 297 articles were retrieved for full-text evaluation. Finally, 271 articles were considered eligible for our study. Details of the included studies classified by type of intervention can be found in Supplementary Table 2.

Figure 2 Review flow chart

Of these 271 studies, 176 pertained to pharmaceutical interventions with 100 corresponding targets (Fig. 3), 58 pertained to nutritional interventions with 60 corresponding targets (Fig. 4), and 37 pertained to exercise interventions with 60 corresponding targets (Fig. 5). Table 1 presents the interventions that showed positive results in animal models, organized per targeted pathways, during the last 10 years.

Figure 3 Targets of pharmaceutical interventions for cancer cachexia. Data stem from 176 studies on pharmaceutical interventions. Up and down arrows demonstrate upregulation/activation and downregulation/inhibition, respectively

Figure 4 Targets of nutritional interventions for cancer cachexia. Data stem from 58 studies on nutritional/supplement interventions. Up and down arrows demonstrate upregulation/activation and downregulation/inhibition, respectively

Figure 5 Targets of physical activity interventions for cancer cachexia. Data stem from 37 studies on exercise interventions. Up and down arrows demonstrate upregulation/activation and downregulation/inhibition, respectively

Table 1 The interventions used for the most common targets of cancer cachexia throughout the past decade

Discussion

The rapidly evolving landscape of cancer cachexia research has uncovered a plethora of disease targets and corresponding treatment interventions. In this review, a systematic assessment of the literature allowed for a comprehensive presentation of the cancer cachexia advances throughout the past decade. The arsenal of therapeutic strategies consists of pharmaceutical, nutritional and exercise interventions. The knowledge of the available intervention–target couplings can inform evidence-based decision making with a view to the design of future study protocols.

The ubiquitin proteasome system (UPS) has served as one of the most utilized targets for cancer cachexia treatments. The UPS is the main protein degradation system in eukaryotic cells, marking myofibrillar proteins and other short-lived proteins with polyubiquitin chains and transferring them to the 26S proteasome for degradation [16-18]. Activation of the UPS in skeletal muscle leads to the degradation of structural and contractile proteins, resulting in atrophy and decreased muscle function [19]. Accumulating evidence highlights the critical role of dysregulated ubiquitin ligases in processes associated with the initiation and progression of cancer [20], while UPS inhibitors have been continuously gaining ground as a part of the arsenal for cancer therapy. Several studies have now proposed that one of the most essential factors involved in the induction of muscle wasting in cancer cachexia is upregulation of the UPS pathway [21,22].

The function of the UPS is enabled by an enzymatic cascade, which consists of the ubiquitin-activating enzyme (UAE or E1), the ubiquitin-conjugating enzyme (UBC or E2), and the ubiquitin ligase (E3) [18,23]. The E3 ligase muscle-specific RING finger protein-1 (MuRF1) and muscular atrophy fbox-1 protein (MAFbx/Atrogin-1) constitute the 2 key ligases that identify muscle proteins, in order to be degraded by the UPS in skeletal muscle [24]. MuRF1 and Atrogin-1 are regulated by a variety of signaling pathways, including NF-κB, interleukin (IL)-6, and the p38 MAPK pathway [25,26]. Since MURF1 and Atrogin-1 directly control protein degradations that lead to cachexia, it has been suggested that their inhibition has the potential to preserve protein levels and maintain muscle mass without unwanted side-effects [27]. Indeed, through our systematic review of the literature, we have found that MURF1 and Atrogin-1, as well as corresponding regulatory signaling pathways such as IL-6, NF-κB and MAPK, have all been consistently used as targets of therapeutic modalities employed in cancer cachexia research.

Apart from the UPS, another signaling pathway that serves as an essential contributor to skeletal muscle degradation is the autophagy lysosomal pathway. Autophagy is a crucial process, which serves in the selective elimination of damaged organelles and degradation of misfolded proteins [28]. Acting as sensors, mTOR and AMP-activated protein kinase (AMPK) are pivotal regulators of autophagy, crucial for maintaining cellular energy balance [29,30]. The role of autophagy in mediating skeletal muscle wasting and cachexia progression has garnered increasing interest [21,22]. Accumulating evidence indicates a significant upregulation of autophagy during cancer cachexia [31]. FOXO3, identified as the main transcription factor inducing autophagy, regulates the expression of key autophagy genes such as LC3 and Bnip3 [32]. Activation of FOXO3 stimulates autophagic lysosomal pathways by attenuating the IGF1/PI3K/AKT signaling pathway via mTOR and transcriptional-dependent mechanisms [32]. Additionally, oxidative stress has been linked to the induction of ATG7 expression in the autophagic lysosomal pathway, which was associated with the p38 MAPK pathway in another study [26].

In general, increased oxidative stress contributes to mechanisms that favor protein breakdown over protein synthesis through increased ubiquitin proteasome activity, mitochondrial dysfunction and dysregulation of autophagy, thus making it a potential target for cachexia treatment [33]. Damage to mitochondria by pro-oxidant species triggers a cascade of events, including increased production of reactive oxygen species and induction of mitophagy, ultimately impacting mitochondrial abundance in muscle tissue [34,35]. Given that mitochondria play a crucial role in producing the energy required for muscle contraction, disruptions in their equilibrium detrimentally affect muscle function. Notably, studies have reported alterations in the mitochondrial ultrastructure in the skeletal muscle of Lewis lung carcinoma and colon-26 carcinoma hosts, which can be attributed to mitochondrial dysfunction [36]. Furthermore, there is evidence of heightened mitophagy activity in cachectic skeletal muscle [37]. These structural changes often coincide with reductions in oxidative capacity, as indicated by alterations in the activity of key enzymes such as succinate dehydrogenase and pyruvate dehydrogenase, both vital for the tricarboxylic acid cycle. Additionally, the modulation of pyruvate dehydrogenase kinase-4, which is involved in regulating cellular energy metabolism, contributes to these metabolic shifts [38]. Collectively, these alterations drive a transition from oxidative to glycolytic muscle fiber composition in cachectic tumor hosts compared to healthy controls, playing a role in the accumulation of intramuscular fat observed in cachectic mice [39].

Aside from these catabolic mechanisms, the anabolic pathways that are responsible for muscle growth stimulation, as well as the accumulation of proteins and organelles in the cytoplasm, should not be neglected. The mechanistic target of rapamycin (mTOR) serves as a pivotal factor in growth regulation and functions as a key regulator of nutrient and stress responses [40]. It comprises mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2): mTORC1 primarily oversees anabolic processes, including protein synthesis, ribosomal and mitochondrial biogenesis, while mTORC2 is involved in maintaining glucose and lipid homeostasis [40]. mTORC1 plays a critical role in metabolic balance by activating 4E-BP1, which subsequently triggers the expression of FGF21 and enhances the translation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), thus promoting mitochondrial biogenesis and oxidative function [40,41]. Studies indicate that in cancer cachexia, increased IL-6 levels suppress mTORC1 activation by stimulating AMPK [42]. Additionally, activation of the mTOR pathway via insulin-like growth factor-1 (IGF1) is diminished in tumor-bearing mice with cancer cachexia [43]. Insulin and IGF1 initiate a phosphorylation cascade involving key regulators crucial for skeletal muscle growth, differentiation and homeostasis [44]. In the context of cancer cachexia, insulin resistance is associated with reduced glucose tolerance and insulin sensitivity, leading to decreased glucose uptake [45]. Insulin resistance correlates with diminished phosphorylation of P13K and Akt, which normally inhibits the release of FoxO and caspase-3, thus allowing for increased proteolytic activity [46].

Through this review, we additionally demonstrate the potential of nonpharmacological interventions to regulate a plethora of signaling pathways for cancer cachexia, highlighting that interest in these targets should not be monopolized by drug treatments. Exercise interventions have already been reported to positively affect and control systemic inflammation, induce protein synthesis when Akt/mTORC1 signaling is disrupted, or during systemic IL-6 overexpression, by improving mTORC1 signaling, promote the expression of several mitochondrial proteins, such as PGC-1α, mitochondrial transcription factor A and nuclear respiratory factor. This can lead to improved muscle oxidative capacity, and can also regulate hypogonadism by influencing circulating sex hormones and promoting androgen receptor expression [42,47]. Nutritional support in cancer cachexia targets the restoration of energy balance and prevention of net protein breakdown, all while avoiding stimulation of tumor growth or interference with anti-tumor treatments [48]. Achieving a net positive protein balance involves selecting nutrients that counteract catabolic signals and promote anabolic pathways [49]. Towards fostering an anabolic environment, it is essential to ensure adequate caloric intake and nutrient composition, since without sufficient nutrient availability, even the most potent anabolic signals may fail to maintain muscle mass or induce muscle growth [50].

The main drawback of this study was the broad scope of the review, which resulted in a high number of screened and consequently included articles. We attempted to solve this matter by limiting our search to include only studies from the last decade. To avoid critical loss of information, we also screened the reference lists of included studies, as well as the reference list of cachexia-related recently published reviews. Moreover, in view of the large number quantity of data, we chose to focus specifically on presenting intervention–target relationships.

In this study, we presented the therapeutic interventions and targets of cancer cachexia research throughout the last decade. Moving forward, research should aim towards refining the already available treatment strategies, while also attempting to address the gaps in the literature. Utilization and assessment of combined treatment strategies, as well as comparative research protocols, are essential requirements for future studies.