IUPHAR ECR review: Cancer-related anorexia-cachexia in cancer patients: Pathophysiology and treatment.

Cancer-related anorexia-cachexia (CRAC) comprises one of the most common syndromes of advanced cancer patients. The prevalence of CRAC increases from 50% to 80% before death. CRAC is associated not only with impaired quality of life in patients and family members but also with shorter survival. The management of CRAC is a great challenge in clinical practice. There are no definite practice guidelines yet for the prevention and treatment of CRAC. A multimodal strategy is the most effective way to treat anorexia-cachexia. Numerous medications have been suggested and used in clinical trials, while others are still being studied on experimental animals. These medications include branched-chain amino acids, eicosapentaenoic acid, thalidomide, cytokine inhibitors, steroids, antiserotoninergic medications, and appetite stimulants. The benefits of supportive care interventions and the advancement of exciting new pharmacological medicines for anorexia-cachexia are becoming more widely recognized. Health care professionals need to be aware of the psychosocial and biological effects of anorexia-cachexia, even though knowledge of the underlying molecular causes of the disorder has advanced significantly.

Handgrip Strength Predicts Survival in Patients With Pancreatic Cancer.

OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is a common cancer with a poor prognosis and is associated with a high prevalence of cachexia, a metabolic syndrome of muscle wasting due to complex mechanisms. In addition to loss of muscle mass, cancer patients also experience functional deterioration. The aim of this study is to determine whether there is an association between muscle mass and function and clinical outcomes, particularly survival. METHODS: We performed a prospective cohort study including all patients with PDAC at Monash Health from March 2016 to December 2017. We conducted body composition analysis for myopenia and handgrip strength testing. We constructed Kaplan-Meier curves to estimate whether myopenia and low hand grip strength were associated with poorer survival. RESULTS: Myopenia was not associated with a significant difference in PDAC-specific survival (log-rank P = 0.60). However, low handgrip strength was associated with significantly worse PDAC-specific survival compared with other patients (log-rank hazard ratio, 1.88; 95% confidence interval, 1.15-3.09; P = 0.004). CONCLUSIONS: The relationship between survival in PDAC and handgrip strength, but not anatomical muscle mass, suggests that functional testing of strength may be important in prognostication of patients with PDAC, alongside existing tools such as the Eastern Cooperative Oncology Group performance status.

Skeletal muscle derived Musclin protects the heart during pathological overload.

Cachexia is associated with poor prognosis in chronic heart failure patients, but the underlying mechanisms of cachexia triggered disease progression remain poorly understood. Here, we investigate whether the dysregulation of myokine expression from wasting skeletal muscle exaggerates heart failure. RNA sequencing from wasting skeletal muscles of mice with heart failure reveals a reduced expression of Ostn, which encodes the secreted myokine Musclin, previously implicated in the enhancement of natriuretic peptide signaling. By generating skeletal muscle specific Ostn knock-out and overexpressing mice, we demonstrate that reduced skeletal muscle Musclin levels exaggerate, while its overexpression in muscle attenuates cardiac dysfunction and myocardial fibrosis during pressure overload. Mechanistically, Musclin enhances the abundance of C-type natriuretic peptide (CNP), thereby promoting cardiomyocyte contractility through protein kinase A and inhibiting fibroblast activation through protein kinase G signaling. Because we also find reduced OSTN expression in skeletal muscle of heart failure patients, augmentation of Musclin might serve as therapeutic strategy.

Moderate Intensity Endurance and Resistance Exercise Attenuates Cachexia in Tumor-bearing Mice.

BACKGROUND/AIM: Cancer cachexia encompasses several deleterious physiological alterations associated with functional impairments, poor quality of life, and increased mortality. The aim of this study was to examine the effects of chronic moderate intensity exercise training on markers of cachexia. MATERIALS AND METHODS: Balb/c mice were randomly assigned to sedentary (SED) or exercise (EX) groups and EX mice were further randomly assigned to one of three exercise modalities (aerobic, resistance, combined). RESULTS: Cachexia was induced in SED animals inoculated with C26 cells, as evidenced by significant changes in numerous markers. All cachexia-related perturbations were significantly attenuated in EX versus SED animals. Systemic inflammation was significantly decreased in all EX groups, as evident by a normalization of spleen mass and plasma IL-6. CONCLUSION: Multiple moderate intensity exercise modalities can provide significant benefits in cachectic mice, and this may be due, at least in part, to decreased systemic inflammation.

Metabolomics as an Important Tool for Determining the Mechanisms of Human Skeletal Muscle Deconditioning.

Muscle deconditioning impairs both locomotor function and metabolic health, and is associated with reduced quality life and increased mortality rates. Despite an appreciation of the existence of phenomena such as muscle anabolic resistance, mitophagy, and insulin resistance with age and disease in humans, little is known about the mechanisms responsible for these negative traits. With the complexities surrounding these unknowns and the lack of progress to date in development of effective interventions, there is a need for alternative approaches. Metabolomics is the study of the full array of metabolites within cells or tissues, which collectively constitute the metabolome. As metabolomics allows for the assessment of the cellular metabolic state in response to physiological stimuli, any chronic change in the metabolome is likely to reflect adaptation in the physiological phenotype of an organism. This, therefore, provides a holistic and unbiased approach that could be applied to potentially uncover important novel facets in the pathophysiology of muscle decline in ageing and disease, as well as identifying prognostic markers of those at risk of decline. This review will aim to highlight the current knowledge and potential impact of metabolomics in the study of muscle mass loss and deconditioning in humans and will highlight key areas for future research.

Cardiac myocyte intrinsic contractility and calcium handling deficits underlie heart organ dysfunction in murine cancer cachexia.

Cachexia is a muscle wasting syndrome occurring in many advanced cancer patients. Cachexia significantly increases cancer morbidity and mortality. Cardiac atrophy and contractility deficits have been observed in patients and in animal models with cancer cachexia, which may contribute to cachexia pathophysiology. However, underlying contributors to decreased in vivo cardiac contractility are not well understood. In this study, we sought to distinguish heart-intrinsic changes from systemic factors contributing to cachexia-associated cardiac dysfunction. We hypothesized that isolated heart and cardiac myocyte functional deficits underlie in vivo contractile dysfunction. To test this hypothesis, isolated heart and cardiac myocyte function was measured in the colon-26 adenocarcinoma murine model of cachexia. Ex vivo perfused hearts from cachectic animals exhibited marked contraction and relaxation deficits during basal and pacing conditions. Isolated myocytes displayed significantly decreased peak contraction and relaxation rates, which was accompanied by decreased peak calcium and decay rates. This study uncovers significant organ and cellular-level functional deficits in cachectic hearts outside of the catabolic in vivo environment, which is explained in part by impaired calcium cycling. These data provide insight into physiological mechanisms of cardiomyopathy in cachexia, which is critical for the ultimate development of effective treatments for patients.

An Oatp transporter-mediated steroid sink promotes tumor-induced cachexia in Drosophila.

Cancer cachexia is associated with many types of tumors and is characterized by a combination of anorexia, loss of body weight, catabolic alterations, and systemic inflammation. We developed a tumor model in Drosophila larvae that causies cachexia-like syndrome, and we found that cachectic larvae show reduced levels of the circulating steroid ecdysone (Ec). Artificially importing Ec in the tumor through the use of the EcI/Oatp74D importer aggravated cachexia, whereas feeding animals with Ec rescued cachectic defects. This suggests that a steroid sink induced by the tumor promotes catabolic alterations in healthy tissues. We found that Oatp33Eb, a member of the Oatp transporter family, is specifically induced in tumors promoting cachexia. The overexpression of Oatp33Eb in noncachectic tumors induced cachexia, whereas its inhibition in cachectic tumors restored circulating Ec and reversed cachectic alterations. Oatp transporters are induced in several types of hormone-dependent tumors, and this result suggests that a similar sink effect could modify hormonal balance in cachectic cancer patients.

IGF-1 and IGFBP-3 in Inflammatory Cachexia.

Inflammation induces a wide response of the neuroendocrine system, which leads to modifications in all the endocrine axes. The hypothalamic-growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis is deeply affected by inflammation, its response being characterized by GH resistance and a decrease in circulating levels of IGF-1. The endocrine and metabolic responses to inflammation allow the organism to survive. However, in chronic inflammatory conditions, the inhibition of the hypothalamic-GH-IGF-1 axis contributes to the catabolic process, with skeletal muscle atrophy and cachexia. Here, we review the changes in pituitary GH secretion, IGF-1, and IGF-1 binding protein-3 (IGFBP-3), as well as the mechanism that mediated those responses. The contribution of GH and IGF-1 to muscle wasting during inflammation has also been analyzed.

Curcumin and Resveratrol Improve Muscle Function and Structure through Attenuation of Proteolytic Markers in Experimental Cancer-Induced Cachexia.

Muscle wasting and cachexia are prominent comorbidities in cancer. Treatment with polyphenolic compounds may partly revert muscle wasting. We hypothesized that treatment with curcumin or resveratrol in cancer cachectic mice may improve muscle phenotype and total body weight through attenuation of several proteolytic and signaling mechanisms in limb muscles. In gastrocnemius and soleus muscles of cancer cachectic mice (LP07 adenocarcinoma cells, N = 10/group): (1) LC-induced cachexia, (2) LC-cachexia+curcumin, and (3) LC-cachexia + resveratrol, muscle structure and damage (including blood troponin I), sirtuin-1, proteolytic markers, and signaling pathways (NF-κB and FoxO3) were explored (immunohistochemistry and immunoblotting). Compared to nontreated cachectic mice, in LC-cachexia + curcumin and LC-cachexia + resveratrol groups, body and muscle weights (gastrocnemius), limb muscle strength, muscle damage, and myofiber cross-sectional area improved, and in both muscles, sirtuin-1 increased, while proteolysis (troponin I), proteolytic markers, and signaling pathways were attenuated. Curcumin and resveratrol elicited beneficial effects on fast- and slow-twitch limb muscle phenotypes in cachectic mice through sirtuin-1 activation, attenuation of atrophy signaling pathways, and proteolysis in cancer cachectic mice. These findings have future therapeutic implications as these natural compounds, separately or in combination, may be used in clinical settings of muscle mass loss and dysfunction including cancer cachexia.

Cancer Cachexia: Its Mechanism and Clinical Significance.

The term "cachexia" is derived from the Greek words kakos (bad) and hexis (habit). Cachexia is a malnutrition associated with chronic diseases such as cancer, chronic heart failure, chronic renal failure, and autoimmune diseases, and is characterized by decreased skeletal muscle mass. Cancer cachexia is quite common in patients with advanced cancer. Weight loss is also a characteristic symptom of cancer cachexia, along with decreased skeletal muscle mass. As nutritional supplementation alone cannot improve cachexia, cytokines and tumor-derived substances have been attracting attention as its relevant factors. Cancer cachexia can be also associated with reduced chemotherapeutic effects, increased side effects and treatment interruptions, and even poorer survival. In 2011, a consensus definition of cachexia has been proposed, and the number of relevant research reports has increased significantly. However, the pathogenesis of cachexia is not fully understood, and there are currently few regulatory-approved standard treatments for cachexia. The main reason for this is that multiple etiologies are involved in the development of cachexia. In this review, we will outline the current status of cachexia, the mechanisms of which have been elucidated in recent years, especially from the perspective of advanced cancer.

Diet and Exercise Interventions in Patients With Pancreatic Cancer: A Scoping Review.

ABSTRACT: Diet and exercise interventions may help reverse malnutrition and muscle wasting common in pancreatic cancer. We performed a scoping review to identify the knowledge gaps surrounding diet and exercise interventions. We searched PubMed, Scopus, Cumulative Index to Nursing and Allied Health Literature, Embase, ProQuest Theses and Dissertations, and Google Scholar using the umbrella terms of "pancreatic cancer," "diet/nutrition," and "exercise." Included were articles reporting on ambulatory adults with diagnosed pancreatic cancer. Excluded were studies examining prevention and/or risk, animal, or cell lines. Of the 15,708 articles identified, only 62 met the final inclusion criteria. Almost half of the articles were randomized controlled studies (n = 27). Most studies were from the United States (n = 20). The majority examined dietary interventions (n = 41), with 20 assessing the use of omega-3 fatty acids. Exercise interventions were reported in 13 studies, with 8 examining a diet and exercise intervention. Most studies were small and varied greatly in terms of study design, intervention, and outcomes. We identified 7 research gaps that should be addressed in future studies. This scoping review highlights the limited research examining the effect of diet and exercise interventions in ambulatory patients with pancreatic cancer.

Tumors modulate fenestrated vascular beds and host endocrine status.

Allograft and xenograft transplantation into a mouse host is frequently utilized to study cancer biology, tumor behavior, and response to treatment. Preclinical studies employing these models often focus solely upon the intra-tumoral effects of a given treatment, without consideration of systemic toxicity or tumor-host interaction, nor whether this latter relationship could modulate the toxicologic response to therapy. Here it is demonstrated that the implantation and growth of a range of human- and mouse-derived cell lines leads to structural vascular and, potentially, functional changes within peripheral endocrine tissues, a process that could conceivably ameliorate the severity of anti-angiogenic-induced fenestrated vessel attenuation. Observations suggest a multifactorial process, which may involve host- and tumor-derived cytokines/growth factors, and the liberation of myeloid-derived suppressor cells. Further investigation revealed a structurally comparable response to the administration of exogenous estrogen. These findings, in addition to providing insight into the development of clinical anti-angiogenic "adaptation," may be of significance within the "cancer-cachexia" and cancer-related anemia syndromes in man.

Biomarkers for Cancer Cachexia: A Mini Review.

Cancer cachexia is a common condition in many cancer patients, particularly those with advanced disease. Cancer cachexia patients are generally less tolerant to chemotherapies and radiotherapies, largely limiting their treatment options. While the search for treatments of this condition are ongoing, standards for the efficacy of treatments have yet to be developed. Current diagnostic criteria for cancer cachexia are primarily based on loss of body mass and muscle function. However, these criteria are rather limiting, and in time, when weight loss is noticeable, it may be too late for treatment. Consequently, biomarkers for cancer cachexia would be valuable adjuncts to current diagnostic criteria, and for assessing potential treatments. Using high throughput methods such as "omics approaches", a plethora of potential biomarkers have been identified. This article reviews and summarizes current studies of biomarkers for cancer cachexia.

Diet-related interventions for cancer-associated cachexia.

PURPOSE: Cancer-associated cachexia is a common condition in patients with advanced cancer, and is associated with extreme and involuntary weight loss and irreversible muscle wasting. Despite its high morbidity and mortality, there is no known treatment to reverse its effects. Thus, there is increasing interest in whether diet and exercise can assist in the minimization of cancer-associated cachexia. METHODS: We reviewed the literature on the impact of dietary patterns, dietary components, and exercise on the progress and severity of cancer cachexia. RESULTS: Although most studies have produced inconclusive or controversial findings, some promising studies using animal models and early human clinical trials suggest that dietary and physical therapy interventions may alleviate cancer-associated cachexia. Moreover, many studies suggest that controlling diet and exercise nevertheless improved the quality of life (QoL) for cancer patients with cachexia. CONCLUSION: Ongoing studies will continue to examine whether different forms of multimodal therapy-combinations of cancer treatment, dietary regimens, anti-inflammatory therapy, and physical therapy-are effective methods to improve outcomes in advanced cancer patients with cachexia. Moreover, future studies should examine the effects of such interventions on long-term QoL and establish nutritional guidelines for the management of cancer-associated cachexia.

Rheumatoid cachexia: the underappreciated role of myoblast, macrophage and fibroblast interplay in the skeletal muscle niche.

Although rheumatoid arthritis affects 1% of the global population, the role of rheumatoid cachexia, which occurs in up to a third of patients, is relatively neglected as research focus, despite its significant contribution to decreased quality of life in patients. A better understanding of the cellular and molecular processes involved in rheumatoid cachexia, as well as its potential treatment, is dependent on elucidation of the intricate interactions of the cells involved, such as myoblasts, fibroblasts and macrophages. Persistent RA-associated inflammation results in a relative depletion of the capacity for regeneration and repair in the satellite cell niche. The repair that does proceed is suboptimal due to dysregulated communication from the other cellular role players in this multi-cellular environment. This includes the incomplete switch in macrophage phenotype resulting in a lingering pro-inflammatory state within the tissues, as well as fibroblast-associated dysregulation of the dynamic control of the extracellular matrix. Additional to this endogenous dysregulation, some treatment strategies for RA may exacerbate muscle wasting and no multi-cell investigation has been done in this context. This review summarizes the most recent literature characterising clinical RA cachexia and links these features to the roles of and complex communication between multiple cellular contributors in the muscle niche, highlighting the importance of a targeted approach to therapeutic intervention.

Targeting the Activin Receptor Signaling to Counteract the Multi-Systemic Complications of Cancer and Its Treatments.

Muscle wasting, i.e., cachexia, frequently occurs in cancer and associates with poor prognosis and increased morbidity and mortality. Anticancer treatments have also been shown to contribute to sustainment or exacerbation of cachexia, thus affecting quality of life and overall survival in cancer patients. Pre-clinical studies have shown that blocking activin receptor type 2 (ACVR2) or its ligands and their downstream signaling can preserve muscle mass in rodents bearing experimental cancers, as well as in chemotherapy-treated animals. In tumor-bearing mice, the prevention of skeletal and respiratory muscle wasting was also associated with improved survival. However, the definitive proof that improved survival directly results from muscle preservation following blockade of ACVR2 signaling is still lacking, especially considering that concurrent beneficial effects in organs other than skeletal muscle have also been described in the presence of cancer or following chemotherapy treatments paired with counteraction of ACVR2 signaling. Hence, here, we aim to provide an up-to-date literature review on the multifaceted anti-cachectic effects of ACVR2 blockade in preclinical models of cancer, as well as in combination with anticancer treatments.

MC38 Tumors Induce Musculoskeletal Defects in Colorectal Cancer.

Colorectal cancer (CRC) is a leading cause of cancer-related death, and the prevalence of CRC in young adults is on the rise, making this a largescale clinical concern. Advanced CRC patients often present with liver metastases (LM) and an increased incidence of cachexia, i.e., musculoskeletal wasting. Despite its high incidence in CRC patients, cachexia remains an unresolved issue, and animal models for the study of CRC cachexia, in particular, metastatic CRC cachexia, remain limited; therefore, we aimed to establish a new model of metastatic CRC cachexia. C57BL/6 male mice (8 weeks old) were subcutaneously (MC38) or intrasplenically injected (mMC38) with MC38 murine CRC cells to disseminate LM, while experimental controls received saline (n = 5-8/group). The growth of subcutaneous MC38 tumors was accompanied by a reduction in skeletal muscle mass (-16%; quadriceps muscle), plantarflexion force (-22%) and extensor digitorum longus (EDL) contractility (-20%) compared to experimental controls. Meanwhile, the formation of MC38 LM (mMC38) led to heighted reductions in skeletal muscle mass (-30%; quadriceps), plantarflexion force (-28%) and EDL contractility (-35%) compared to sham-operated controls, suggesting exacerbated cachexia associated with LM. Moreover, both MC38 and mMC38 tumor hosts demonstrated a marked loss of bone indicated by reductions in trabecular (Tb.BV/TV: -49% in MC38, and -46% in mMC38) and cortical (C.BV/TV: -12% in MC38, and -8% in mMC38) bone. Cell culture experiments revealed that MC38 tumor-derived factors directly promote myotube wasting (-18%) and STAT3 phosphorylation (+5-fold), while the pharmacologic blockade of STAT3 signaling was sufficient to preserve myotube atrophy in the presence of MC38 cells (+21%). Overall, these results reinforce the notion that the formation of LM heightens cachexia in an experimental model of CRC.

Soluble ST2 proteins in male cachectic patients with chronic heart failure.

BACKGROUND AND AIMS: Until now, there are lack of established clinical factors allowing management of chronic heart failure (CHF) patients being at risk of cardiac cachexia (CC). The changes in soluble protein ST2 (sST2) concentrations suggest a valuable and prognostic usefulness of this biomarker in monitoring patients with CHF, especially those who potentially are prompt to develop CC. The aim of this study was to assess the potential role of sST2 in male patients with CHF under cachexia condition. METHODS AND RESULT: 91 male patients were selected to the study group and underwent meticulous screening according to recent clinical guidelines in order to CHF and CC detection. Additionally all patients underwent assessment of body composition and sST2 testing. Patients were followed-up for 60 months. Plasma sST2 concentration was significantly increased in cachectic compared with non-cachectic patients (median: 27.40 ng/mL and 20.62 ng/mL; p < 0.001), however, in this group the EF% was reduced (mean: 34 ± 13.5% and 41 ± 14.5%; p = 0.029). Correlations between sST2 and CRP (R = 0.524; p < 0.001) and phase angle (PA) (R = -0.513; p < 0.001) were observed. CHF patients in whose the PA value ranged in Q1 (<3.06°) and sST2 concentration ranged in Q3 (>33.15 ng/mL) had higher risk of death (HR = 9.62 and 8.60, respectively). The death rate was the highest in cachectic group with the simultaneous presence of sST2-Q3 and PA-Q1 (87.5% of this group). They had almost 7-fold higher risk of death during follow-up period (HR = 6.89, p < 0.001). CONCLUSIONS: sST2 demonstrates potential utility in male patients with CHF under cachexia condition in prediction death rate.

Extracellular vesicles-released parathyroid hormone-related protein from Lewis lung carcinoma induces lipolysis and adipose tissue browning in cancer cachexia.

Cancer cachexia is a metabolic disorder characterized by skeletal muscle wasting and white adipose tissue browning. Specific functions of several hormones, growth factors, and cytokines derived from tumors can trigger cachexia. Moreover, adipose tissue lipolysis might explain weight loss that occurs owing to cachexia. Extracellular vesicles (EVs) are involved in intercellular communication. However, whether EVs participate in lipolysis induced by cancer cachexia has not been thoroughly investigated. Using Lewis lung carcinoma (LLC) cell culture, we tested whether LLC cell-derived EVs can induce lipolysis in 3T3-L1 adipocytes. EVs derived from LLC cells were isolated and characterized biochemically and biophysically. Western blotting and glycerol assay were used to study lipolysis. LLC cell-derived EVs induced lipolysis in vivo and vitro. EVs fused directly with target 3T3-L1 adipocytes and transferred parathyroid hormone-related protein (PTHrP), activating the PKA signaling pathway in 3T3-L1 adipocytes. Blocking PTHrP activity in LLC-EVs using a neutralizing antibody and by knocking down PTHR expression prevented lipolysis in adipocytes. Inhibiting the PKA signaling pathway also prevents the lipolytic effects of EVs. In vivo, suppression of LLC-EVs release by knocking down Rab27A alleviated white adipose tissue browning and lipolysis. Our data showed that LLC cell-derived EVs induced adipocyte lipolysis via the extracellular PTHrP-mediated PKA pathway. Our data demonstrate that LLC-EVs induce lipolysis in vitro and vivo by delivering PTHrP, which interacts with PTHR. The lipolytic effect of LLC-EVs was abrogated by PTHR knockdown and treatment with a neutralizing anti-PTHrP antibody. Together, these data show that LLC-EV-induced lipolysis is mediated by extracellular PTHrP. These findings suggest a novel mechanism of lipid droplet loss and identify a potential therapeutic strategy for cancer cachexia.