transforming-growth-factor-beta and Cachexia

Cachexia is a metabolic syndrome consisting of massive loss of muscle mass and function that has a severe impact on the quality of life and survival of cancer patients. Up to 20% of lung cancer patients and up to 80% of pancreatic cancer patients are diagnosed with cachexia, leading to death in 20% of them. The main drivers of cachexia are cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), macrophage inhibitory cytokine 1 (MIC-1/GDF15) and transforming growth factor-beta (TGF-β). Besides its double-edged role as a tumor suppressor and activator, TGF-β causes muscle loss through myostatin-based signaling, involved in the reduction in protein synthesis and enhanced protein degradation. Additionally, TGF-β induces inhibin and activin, causing weight loss and muscle depletion, while MIC-1/GDF15, a member of the TGF-β superfamily, leads to anorexia and so, indirectly, to muscle wasting, acting on the hypothalamus center. Against this background, the blockade of TGF-β is tested as a potential mechanism to revert cachexia, and antibodies against TGF-β reduced weight and muscle loss in murine models of pancreatic cancer. This article reviews the role of the TGF-β pathway and to a minor extent of other molecules including microRNA in cancer onset and progression with a special focus on their involvement in cachexia, to enlighten whether TGF-β and such other players could be potential targets for therapy.

Topics: Animals; Cachexia; Humans; Mice; Pancreatic Neoplasms; Quality of Life; Transforming Growth Factor beta; Transforming Growth Factors

Myostatin is a protein belonging to the myokine class, the family of transforming growth factors β (TGF-β). The review article, based on the analysis of literature data, shows the key role of myostatin in the development of senile sarcopenia and cachexia in various pathological conditions, such as cancer, chronic heart failure, chronic renal failure, COPD, etc. The article discusses the structure of myostatin, provides a detailed diagram of the synthesis and activation of myostatin, the ways of implementing the mechanism of action as a negative regulator of muscle growth and differentiation in these pathological conditions. The main physiological properties and clinical significance are highlighted. Exogenous and endogenous factors regulating myostatin expression and possible mechanisms of their action are considered.. Миостатин — белок, принадлежащий к классу миокинов, семейству трансформирующих факторов роста β (TGF-β). В обзорной статье, анализирующей литературные данные, показана ключевая роль миостатина в развитии старческой саркопении и кахексии при различных патологических состояниях, таких как рак, ХСН, ХБП, ХОБЛ и др. В статье рассматривается структура миостатина, подробная схема синтеза и его активации, механизм действия как негативного регулятора роста и дифференцировки мышц при этих патологических состояниях. Выделены основные физиологические свойства и клиническое значение. Рассмотрены экзогенные и эндогенные факторы, регулирующие экспрессию миостатина, и возможные механизмы их действия.

Topics: Cachexia; Cell Differentiation; Humans; Muscle, Skeletal; Myostatin; Sarcopenia; Transforming Growth Factor beta

To provide an overview and describe the mode of action of miRNAs recently implicated in muscle atrophy, and discuss the challenges to explore their potential as putative therapeutic targets in cachexia.. Recent work showed differentially expressed miRNAs in skeletal muscle of patients with cachexia-associated diseases. Studies using experimental models revealed miRNA regulation of the anabolic IGF-1 and catabolic TGF- β/myostatin pathways, and downstream protein synthesis and proteolysis signaling in control of muscle mass.. Cachexia is a complex metabolic condition associated with progressive body weight loss, wasting of skeletal muscle mass and decrease in muscle strength. MiRNAs play a central role in post-transcriptional gene regulation by targeting mRNAs, thereby coordinating and fine-tuning many cellular processes. MiRNA expression profiling studies of muscle biopsies have revealed differentially expressed miRNAs in patients with low muscle mass or cachexia. Evaluation in experimental models has revealed muscle atrophy, inhibition of protein synthesis and activation of proteolysis in response to modulation of specific miRNAs, termed 'atromiRs' in this review. These exciting findings call for further studies aimed at exploring the conservation of differentially expressed miRNAs across diseases accompanied by cachexia, identification of miRNA clusters and targets involved in muscle atrophy, and probing whether these miRNAs might be potential therapeutic targets for cachexia.

Topics: Animals; Cachexia; Gene Expression Regulation; Humans; Insulin-Like Growth Factor I; MicroRNAs; Muscle, Skeletal; Muscular Atrophy; Myostatin; Signal Transduction; Transforming Growth Factor beta

To review recent finding on MIC-1/GDF15 and re-evaluate it as a potential target for the therapy of anorexia/cachexia syndromes.. MIC-1/GDF15 consistently induces anorexia/cachexia in animal models. Its actions on brainstem feeding centers leads to anorexia, inducing prolonged undernutrition and consequent loss of both lean and fat mass. Epidemiological studies by multiple groups have linked substantially elevated serum levels of this cytokine to anorexia/cachexia syndromes in diverse diseases such as cancer, chronic renal and cardiac failure, and chronic obstructive lung disease. These elevated serum levels are similar to those required to induce this syndrome in animals. Recent identifications of its previously elusive receptor as GFRAL, has enhanced understanding of its biology and suggests that modulating the MIC-1/GDF15-GFRAL pathway may be a therapeutic target for anorexia/cachexia syndrome.. Inhibiting MIC-1/GDF15 or its receptor GFRAL are high-value potential targets for treatment of anorexia/cachexia syndrome in patients whose elevated serum levels may justify its use.

Topics: Animals; Anorexia; Cachexia; Glial Cell Line-Derived Neurotrophic Factor; Growth Differentiation Factor 15; Humans; Neoplasms; Syndrome; Transforming Growth Factor beta

Skeletal muscle possesses remarkable ability to change its size and force-producing capacity in response to physiological stimuli. Impairment of the cellular processes that govern these attributes also affects muscle mass and function in pathological conditions. Myostatin, a member of the TGF-β family, has been identified as a key regulator of muscle development, and adaptation in adulthood. In muscle, myostatin binds to its type I (ALK4/5) and type II (ActRIIA/B) receptors to initiate Smad2/3 signalling and the regulation of target genes that co-ordinate the balance between protein synthesis and degradation. Interestingly, evidence is emerging that other TGF-β proteins act in concert with myostatin to regulate the growth and remodelling of skeletal muscle. Consequently, dysregulation of TGF-β proteins and their associated signalling components is increasingly being implicated in muscle wasting associated with chronic illness, ageing, and inactivity. The growing understanding of TGF-β biology in muscle, and its potential to advance the development of therapeutics for muscle-related conditions is reviewed here.

Topics: Adaptation, Physiological; Animals; Cachexia; Homeostasis; Humans; Marfan Syndrome; Muscle Development; Muscular Dystrophies; Regeneration; Sarcopenia; Signal Transduction; Transforming Growth Factor beta

There are a variety of pathophysiologic conditions that are known to induce skeletal muscle atrophy. However, muscle wasting can occur through multiple distinct signaling pathways with differential sensitivity between selective skeletal muscle fiber subtypes. This review summarizes some of the underlying molecular mechanisms responsible for fiber-specific muscle mass regulation.. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha protects slow-twitch oxidative fibers from denervation/immobilization (disuse)-induced muscle atrophies. Nutrient-related muscle atrophies, such as those induced by cancer cachexia, sepsis, chronic heart failure, or diabetes, are largely restricted to fast-twitch glycolytic fibers, of which the underlying mechanism is usually related to abnormality of protein degradation, including proteasomal and lysosomal pathways. In contrast, nuclear factor kappaB activation apparently serves a dual function by inducing both fast-twitch fiber atrophy and slow-twitch fiber degeneration.. Fast-twitch glycolytic fibers are more vulnerable than slow-twitch oxidative fibers under a variety of atrophic conditions related to signaling transduction of Forkhead box O family, autophagy inhibition, transforming growth factor beta family, and nuclear factor-kappaB. The resistance of oxidative fibers may result from the protection of peroxisome proliferator-activated receptor gamma coactivator 1-alpha.

Topics: Animals; Cachexia; Chronic Disease; Diabetes Mellitus; Disease Models, Animal; Forkhead Box Protein O1; Forkhead Transcription Factors; Glycolysis; Heart Diseases; Humans; Muscle Fibers, Fast-Twitch; Muscle Fibers, Slow-Twitch; Muscular Atrophy; Muscular Diseases; NF-kappa B; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Sepsis; Signal Transduction; Transcription Factors; Transforming Growth Factor beta

Members of the transforming growth factor β (TGF-β) family regulate fundamental physiological process, such as cell growth, differentiation and apoptosis. As a result, defects in this pathway have been linked to uncontrolled proliferation and cancer progression. Here we explore the signal transduction mechanism of TGF-β focusing on therapeutic intervention in human diseases. Like TGF-β, another member of the TGF-β superfamily, activin has been proven to play an important role in maintenance of tissue homeostasis and dysregulation leads to disease. Several studies showed elevated levels of activin are responsible for the development of gonadal tumours and a cachexia-like weight loss syndrome. Discussing the recent advances in approaches developed to antagonise the activin pathway and the encouraging results obtained in animal models, this review presents a therapeutic rationale for targeting the activin pathway in conditions such as cachexia, neuromuscular and/or musculoskeletal disorders.

Topics: Activins; Animals; Antineoplastic Agents; Cachexia; Cell Proliferation; Humans; Musculoskeletal Diseases; Neoplasm Proteins; Neoplasms, Gonadal Tissue; Neuromuscular Diseases; Signal Transduction; Transforming Growth Factor beta

To discuss the mechanisms of muscle loss during cachexia.. Cachexia can be defined as a wasting of lean body mass that cannot be reversed nutrionally, indicating a dysregulation in the pathways maintaining body composition. In skeletal muscle, during cachexia, there is an upregulation of protein degradation. A search for transcriptional markers of muscle atrophy led to the discovery of the E3 ubiquitin ligases MuRF1 and MAFbx (also called Atrogin-1). These genes are upregulated in multiple models of atrophy and cachexia. They target particular protein substrates for degradation via the ubiquitin/proteasome pathway. The insulin-like growth factor-1 can block the transcriptional upregulation of MuRF1 and MAFbx via the phosphatidylinositol-3 kinase/Akt/Foxo pathway. MuRF1's substrates include several components of the sarcomeric thick filament, including myosin heavy chain. Thus, by blocking MuRF1, insulin-like growth factor-1 prevents the breakdown of the thick filament, particularly myosin heavy chain, which is asymmetrically lost in settings of cortisol-linked skeletal muscle atrophy. Insulin-like growth factor-1/phosphatidylinositol-3 kinase/Akt signaling also dominantly inhibits the effects of myostatin, which is a member of the transforming growth factor-[beta] family of proteins. Deletion or inhibition of myostatin causes a significant increase in skeletal muscle size. Recently, myostatin has been shown to act both by inhibiting gene activation associated with differentiation, even when applied to postdifferentiated myotubes, and by blocking the phosphatidylinositol-3 kinase/Akt pathway.. These findings will help to define strategies to treat cachexia.

Topics: Cachexia; Forkhead Box Protein O1; Forkhead Transcription Factors; Gene Expression Regulation; Hydrocortisone; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Myosin Heavy Chains; Organ Size; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Transforming Growth Factor beta; Ubiquitin-Protein Ligases

To describe the most relevant recent observations concerning the molecular mechanisms behind myostatin-induced muscle wasting.. The main theme of this review is to summarize the biology and function of myostatin. Myostatin is a secreted growth factor that negatively regulates muscle growth. While inactivation of myostatin leads to muscle growth in vivo, excess levels of myostatin induces cachectic-like muscle wasting. Molecular analyses reveal that excess levels of myostatin induce Atrogin-1 expression by reducing Akt phosphorylation and thereby increasing FoxO1 activity. Recent findings have further speculated that myostatin may also play a role in cardiac cachexia.. As myostatin is a potent inducer of muscle wasting, antagonists to myostatin have been speculated to have great therapeutic value in alleviating muscle wasting. Indeed, myostatin peptide antagonists and antibodies have shown great promise in containing muscle loss in animal models of muscle wasting. Given the beneficial effects of myostatin antagonists in animal models, clinical trials are underway with myostatin antibodies, peptibodies and soluble receptor. Therefore, this review article on the role of myostatin in muscle wasting is highly relevant to current themes in muscle biology.

Topics: Animals; Antibodies, Monoclonal; Cachexia; Cell Size; Gene Expression Regulation; Humans; Muscle Development; Muscular Atrophy; Muscular Diseases; Myostatin; Transforming Growth Factor beta

Wasting, or cachexia, is a significant, debilitating, and potentially life-threatening complication of HIV infection. It is associated with reduced strength and functional ability, reduced ability to withstand opportunistic infections, and increased risk of mortality. Although the incidence of HIV-associated wasting may have declined since the introduction of highly active antiretroviral therapy (HAART), it continues to be a concern in this patient population.. This paper reviews available data on the etiology and clinical impact of HIV-associated wasting, the role of the growth hormone/insulin-like growth factor-I axis in the pathophysiology of this condition, and the rationale for its treatment with recombinant human growth hormone (rhGH).. MEDLINE was searched for articles published in English through August 2007 using the terms HIV, wasting (and related terms), and growth hormone. Preference was given to clinical studies (including randomized clinical studies), meta-analyses, and guidelines. Review articles were evaluated and the bibliographies examined for additional relevant articles. The analysis was restricted to studies conducted in developed countries.. Alterations in the growth hormone/insulin like growth factor-I axis have been observed in patients with HIV-associated wasting, including elevated levels of the former and reduced levels of insulin-like growth factor I. In randomized, placebo-controlled studies, rhGH significantly improved lean body mass by approximately 3 kg compared with placebo (P < 0.001) and total body weight by approximately 3 kg (P < 0.001), and was associated with significant improvements in physical endurance and quality of life (P < 0.001). Common adverse events with rhGH therapy include blood glucose elevations, arthralgia (36.4%), myalgia (30.4%), and peripheral edema (26.1%), but these usually respond to dose reduction or drug discontinuation.. Physicians should be alert to the possibility of wasting in HIV-infected patients receiving HAART and should consider treatment to improve patients' stamina and quality of life. The evidence supports a role for rhGH in the treatment of patients with HIV-associated wasting. Regular blood glucose monitoring is advised when treating wasting with rhGH.

Topics: Adolescent; Adult; Antiretroviral Therapy, Highly Active; Body Composition; Cachexia; Child; Cytokines; Energy Metabolism; Growth Hormone; HIV Infections; HIV Wasting Syndrome; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Muscular Diseases; Myostatin; Proteins; Recombinant Proteins; Risk Factors; Signal Transduction; Testosterone; Transforming Growth Factor beta

The presence of sufficient skeletal muscle is of paramount importance for body function. Cachexia can be defined as a wasting syndrome describing the progressive loss of both adipose and skeletal muscle tissue in concert with severe injury, chronic or end-stage malignant and infectious diseases. Generally, cachexia predisposes to poor prognosis, co-morbidities and death. One signaling pathway possibly involved in muscle atrophy and cachexia is the myostatin cascade. This transforming growth factor-beta superfamily member myostatin is a strong candidate for regulating muscle mass, and is shown to inhibit muscle growth in different in vivo mammalian models. Overall, the modulation of the myostatin pathway seems interesting from the perspective of both pathology and sports medicine. Hence, myostatin signaling components and post-translational modulators are possible targets of pharmacological and other treatments against muscle loss, thus potentially contributing to the understanding and mitigation of muscle atrophies associated with inactivity, senescence and disease.

Topics: Animals; Cachexia; Humans; Muscle, Skeletal; Muscular Atrophy; Myostatin; Signal Transduction; Transforming Growth Factor beta

Cachexia causes weight loss and increased mortality. It affects more than 5 million persons in the United States. Other causes of weight loss include anorexia, sarcopenia, and dehydration. The pathophysiology of cachexia is reviewed in this article. The major cause appears to be cytokine excess. Other potential mediators include testosterone and insulin-like growth factor I deficiency, excess myostatin, and excess glucocorticoids. Numerous diseases can result in cachexia, each by a slightly different mechanism. Both nutritional support and orexigenic agents play a role in the management of cachexia.

Topics: Aging; Anorexia; Arthritis, Rheumatoid; Cachexia; Chronic Disease; Cytokines; Glucocorticoids; HIV Wasting Syndrome; Humans; Insulin-Like Growth Factor I; Kidney Failure, Chronic; Myostatin; Neoplasms; Pulmonary Disease, Chronic Obstructive; Testosterone; Transforming Growth Factor beta; Weight Loss

Topics: Animals; Cachexia; Growth Inhibitors; Humans; Interferon-gamma; Interleukin-1; Interleukin-6; Leukemia Inhibitory Factor; Lymphokines; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Patients with gastrointestinal (GI) cancer are exposed to cachexia, which is highly correlated with chemotherapy-induced side effects. Research suggests that specific immunonutrients could prevent such toxicities.. The primary objective of this phase III study was to evaluate the efficacy of glutamine and transforming growth factor-β2 (TGF-β2) in the prevention of grade 3-4 non-hematological toxicities induced by chemotherapy in patients with GI cancer.. We designed a double-blind, randomized, controlled and multicenter trial stratified according to center, type of chemotherapy, presence of cachexia, and age. Patients were randomized to receive either Clinutren Protect(®) (CP) or a control isocaloric diet (without TGF-β2 or glutamine).. Between November 2007 and October 2011, 210 patients were enrolled in the study, of which 201 were included in the intention-to-treat analysis. Grade 3-4 non-hematological toxicities were not significantly different between the CP and control groups when evaluated by univariate and multivariate analyses. Likewise, no difference was observed regarding grade 3-4 hematological toxicities or reasons for treatment interruption.. This randomized study does not support the hypothesis that oral glutamine and TGF-β2 supplementation is effective to reduce grade 3 or 4 non-hematological toxicities induced by chemotherapy in patients with GI neoplasm.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cachexia; Dietary Supplements; Double-Blind Method; Female; Fluorouracil; Gastrointestinal Diseases; Gastrointestinal Neoplasms; Glutamine; Humans; Male; Middle Aged; Platinum Compounds; Transforming Growth Factor beta

Topics: Animals; Cachexia; Early Growth Response Transcription Factors; Humans; Kruppel-Like Transcription Factors; Mice; Muscle, Skeletal; Muscular Atrophy; Pancreatic Neoplasms; Transforming Growth Factor beta

In this study, we found that in the adipose tissue of wildtype animals, insulin and TGF-β signalling converge via a BMP antagonist short gastrulation (sog) to regulate ECM remodelling. In tumour bearing animals, Sog also modulates TGF-β signalling to regulate ECM accumulation in the fat body. TGF-β signalling causes ECM retention in the fat body and subsequently depletes muscles of fat body-derived ECM proteins. Activation of insulin signalling, inhibition of TGF-β signalling, or modulation of ECM levels via SPARC, Rab10 or Collagen IV in the fat body, is able to rescue tissue wasting in the presence of tumour. Together, our study highlights the importance of adipose ECM remodelling in the context of cancer cachexia.

Topics: Adipose Tissue; Animals; Cachexia; Drosophila; Fat Body; Insulin; Neoplasms; Transforming Growth Factor beta

Pancreatic cancer has the highest prevalence of cancer-associated cachexia among all cancers. ZIP4 promotes pancreatic cancer progression by regulating oncogenic miR-373, and perturbation of circular RNAs (circRNAs) is associated with cancer aggressiveness. This study aimed to identify circRNAs involved in ZIP4/miR-373-driven cancer growth and cachexia and decipher the underlying mechanism.. Differentially expressed circRNAs and potential targets of microRNA were identified through in silico analysis. The RNA interactions were determined by means of biotinylated microRNA pulldown, RNA immunoprecipitation, and luciferase reporter assays. The function of circRNA in ZIP4-miR-373 signaling axis were examined in human pancreatic cancer cells, 3-dimensional spheroids and organoids, mouse models, and clinical specimens. Mouse skeletal muscles were analyzed by means of histology.. We identified circANAPC7 as a sponge for miR-373, which inhibited tumor growth and muscle wasting in vitro and in vivo. Mechanistic studies showed that PHLPP2 is a downstream target of ZIP4/miR-373. CircANAPC7 functions through PHLPP2-mediated dephosphorylation of AKT, thus suppressing cancer cell proliferation by down-regulating cyclin D1 and inhibiting muscle wasting via decreasing the secretion of transforming growth factor-β through STAT5. We further demonstrated that PHLPP2 induced dephosphorylation of CREB, a zinc-dependent transcription factor activated by ZIP4, thereby forming a CREB-miR-373-PHLPP2 feed-forward loop to regulate tumor progression and cancer cachexia.. This study identified circANAPC7 as a novel tumor suppressor, which functions through the CREB-miR-373-PHLPP2 axis, leading to AKT dephosphorylation, and cyclin D1 and transforming growth factor-β down-regulation to suppress tumor growth and muscle wasting in pancreatic cancer.

Topics: Animals; Cachexia; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Humans; Mice; MicroRNAs; Muscles; Pancreatic Neoplasms; Phosphoprotein Phosphatases; Proto-Oncogene Proteins c-akt; RNA, Circular; Transforming Growth Factor beta

Rheumatoid arthritis targets numerous organs in patients, including the skeletal muscle, resulting in rheumatoid cachexia. In the muscle niche, satellite cells, macrophages, and myofibroblasts may be affected and the factors they release altered. This study aimed to assess these cell types, cytokines, and growth factors and their relationships to muscle fiber size and number in a rodent collagen-induced arthritis (CIA) model, in order to identify new therapeutic targets. Fiber cross-sectional area (CSA) was 57% lower in CIA than controls (p < 0.0001), thus smaller but more fibers visible per field of view. Immunostaining indicated the increased presence of satellite cells, macrophages, myofibroblasts, and myonuclei per field of view in CIA (p < 0.01), but this finding was not maintained when taking fiber number into consideration. Western blots of gastrocnemius samples indicated that tumor necrosis factor-α was significantly elevated (p < 0.01) while interleukin-10 (IL-10) was decreased (p < 0.05) in CIA. This effect was maintained (and heightened for IL-10) when expressed per fiber number. Myogenic regulatory factors (MyoD and myogenin), transforming growth factor-β and inhibitor of differentiation were significantly elevated in CIA muscle and levels correlated significantly with CSA. Several of these factors remained elevated, but bone morphogenetic protein-7 decreased when considering fiber number per area. In conclusion, CIA-muscle demonstrated a good regenerative response. Myoblast numbers per fiber were not elevated, suggesting their activity results from the persistent inflammatory signaling which also significantly hampered maintenance of muscle fiber size. A clearer picture of signaling events at cellular level in arthritis muscle may be derived from expressing data per fiber.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Bone Morphogenetic Protein 7; Cachexia; Cytokines; Inflammation; Interleukin-10; Macrophages; Muscle, Skeletal; MyoD Protein; Myofibroblasts; Myogenin; Rats; Regeneration; Satellite Cells, Skeletal Muscle; Transforming Growth Factor beta

Cachexia is a paraneoplastic syndrome related with poor prognosis. The tumour micro-environment contributes to systemic inflammation and increased oxidative stress as well as to fibrosis. The aim of the present study was to characterise the inflammatory circulating factors and tumour micro-environment profile, as potentially contributing to tumour fibrosis in cachectic cancer patients.. 74 patients (weight stable cancer n = 31; cachectic cancer n = 43) diagnosed with colorectal cancer were recruited, and tumour biopsies were collected during surgery. Multiplex assay was performed to study inflammatory cytokines and growth factors. Immunohistochemistry analysis was carried out to study extracellular matrix components.. Higher protein expression of inflammatory cytokines and growth factors such as epidermal growth factor, granulocyte-macrophage colony-stimulating factor, interferon-α, and interleukin (IL)-8 was observed in the tumour and serum of cachectic cancer patients in comparison with weight-stable counterparts. Also, IL-8 was positively correlated with weight loss in cachectic patients (P = 0.04; r = 0.627). Immunohistochemistry staining showed intense collagen deposition (P = 0.0006) and increased presence of α-smooth muscle actin (P < 0.0001) in tumours of cachectic cancer patients, characterizing fibrosis. In addition, higher transforming growth factor (TGF)-β1, TGF-β2, and TGF-β3 expression (P = 0.003, P = 0.05, and P = 0.047, respectively) was found in the tumour of cachectic patients, parallel to p38 mitogen-activated protein kinase alteration. Hypoxia-inducible factor-1α mRNA content was significantly increased in the tumour of cachectic patients, when compared with weight-stable group (P = 0.005).. Our results demonstrate TGF-β pathway activation in the tumour in cachexia, through the (non-canonical) mitogen-activated protein kinase pathway. The results show that during cachexia, intratumoural inflammatory response contributes to the onset of fibrosis. Tumour remodelling, probably by TGF-β-induced transdifferentiation of fibroblasts to myofibroblasts, induces unbalanced inflammatory cytokine profile, angiogenesis, and elevation of extracellular matrix components (EMC). We speculate that these changes may affect tumour aggressiveness and present consequences in peripheral organs.

Topics: Aged; Biomarkers; Biopsy; Body Composition; Body Mass Index; Cachexia; Cells, Cultured; Cytokines; Female; Fibroblasts; Fibrosis; Gene Expression; Humans; Hypoxia; Immunohistochemistry; Male; Middle Aged; Neoplasms; Oxidative Stress; Signal Transduction; Transforming Growth Factor beta; Tumor Microenvironment

Patients with metastatic cancer experience a severe loss of skeletal muscle mass and function known as cachexia. Cachexia is associated with poor prognosis and accelerated death in patients with cancer, yet its underlying mechanisms remain poorly understood. Here, we identify the metal-ion transporter ZRT- and IRT-like protein 14 (ZIP14) as a critical mediator of cancer-induced cachexia. ZIP14 is upregulated in cachectic muscles of mice and in patients with metastatic cancer and can be induced by TNF-α and TGF-β cytokines. Strikingly, germline ablation or muscle-specific depletion of Zip14 markedly reduces muscle atrophy in metastatic cancer models. We find that ZIP14-mediated zinc uptake in muscle progenitor cells represses the expression of MyoD and Mef2c and blocks muscle-cell differentiation. Importantly, ZIP14-mediated zinc accumulation in differentiated muscle cells induces myosin heavy chain loss. These results highlight a previously unrecognized role for altered zinc homeostasis in metastatic cancer-induced muscle wasting and implicate ZIP14 as a therapeutic target for its treatment.

Topics: Animals; Cachexia; Cation Transport Proteins; Cell Differentiation; Cell Line; Cytokines; Disease Models, Animal; Humans; Mice, Inbred C57BL; Muscle, Skeletal; Myosin Heavy Chains; Neoplasm Metastasis; Neoplasms; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Up-Regulation; Zinc

Macrophage inhibitory cytokine-1/growth differentiation factor 15 (MIC-1/GDF15) is a divergent transforming growth factor (TGFβ) superfamily cytokine implicated in biological and disease processes including metabolism, cancer, and chronic inflammation, but whose receptor has remained elusive. Four laboratories have recently identified GFRAL, an orphan receptor of the glial-derived neurotrophic factor (GDNF) receptor α family, as the receptor for MIC-1/GDF15, signaling though the coreceptor Ret. These data identify a new systemic to central nervous system (CNS) circuit that regulates metabolism in response to stress and which could be targeted to treat both severe obesity and anorexia/cachexia syndrome.

Topics: Animals; Cachexia; Central Nervous System; Glial Cell Line-Derived Neurotrophic Factor Receptors; Growth Differentiation Factor 15; Humans; Inflammation; Obesity; Orphan Nuclear Receptors; Proto-Oncogene Proteins c-ret; Transforming Growth Factor beta

Cancer cachexia is a multifactorial syndrome that dramatically decreases survival. Loss of white adipose tissue (WAT) is one of the key characteristics of cachexia. WAT wasting is paralleled by microarchitectural remodeling in cachectic cancer patients. Fibrosis results from uncontrolled ECM synthesis, a process in which, transforming growth factor-beta (TGFβ) plays a pivotal role. So far, the mechanisms involved in adipose tissue (AT) re-arrangement, and the role of TGFβ in inducing AT remodeling in weight-losing cancer patients are poorly understood. This study examined the modulation of ECM components mediated by TGFβ pathway in fibrotic AT obtained from cachectic gastrointestinal cancer patients.. After signing the informed consent form, patients were enrolled into the following groups: cancer cachexia (CC, n = 21), weight-stable cancer (WSC, n = 17), and control (n = 21). The total amount of collagen and elastic fibers in the subcutaneous AT was assessed by histological analysis and by immunohistochemistry. TGFβ isoforms expression was analyzed by Multiplex assay and by immunohistochemistry. Alpha-smooth muscle actin (αSMA), fibroblast-specific protein (FSP1), Smad3 and 4 were quantified by qPCR and/or by immunohistochemistry. Interleukin (IL) 2, IL5, IL8, IL13 and IL17 content, cytokines known to be associated with fibrosis, was measured by Multiplex assay.. There was an accumulation of collagen and elastic fibers in the AT of CC, as compared with WSC and controls. Collagens type I, III, VI, and fibronectin expression was enhanced in the tissue of CC, compared with both WSC and control. The pronounced expression of αSMA in the surrounding of adipocytes, and the increased mRNA content for FSP1 (20-fold) indicate the presence of activated myofibroblasts; particularly in CC. TGFβ1 and TGFβ3 levels were up-regulated by cachexia in AT, as well in the isolated adipocytes. Smad3 and Smad4 labeling was found to be more evident in the fibrotic areas of CC adipose tissue.. Cancer cachexia promotes the development of AT fibrosis, in association with altered TGFβ signaling, compromising AT organization and function.

Topics: Actins; Adipose Tissue; Adult; Aged; Cachexia; Calcium-Binding Proteins; Female; Fibrosis; Gene Expression; Humans; Male; Middle Aged; Neoplasms; Protein Isoforms; S100 Calcium-Binding Protein A4; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

The phenotype and severity of cancer cachexia differ among tumor types and metastatic site in individual patients. In this study, we evaluated if differences in tumor microenvironment would affect the development of cancer cachexia in a murine model, and demonstrated that body weight, adipose tissue and gastrocnemius muscle decreased in tumor-bearing mice. Interestingly, a reduction in heart weight was observed in the intraperitoneal tumor group but not in the subcutaneous group. We evaluated 23 circulating cytokines and members of the TGF-β family, and found that levels of IL-6, TNF-α and activin A increased in both groups of tumor-bearing mice. Eotaxin and G-CSF levels in the intraperitoneal tumor group were higher than in the subcutaneous group. Atrogin 1 and MuRF1 mRNA expressions in the gastrocnemius muscle increased significantly in both groups of tumor-bearing mice, however, in the myocardium, expression of these mRNAs increased in the intraperitoneal group but not in subcutaneous group. Based on these results, we believe that differences in microenvironment where tumor cells develop can affect the progression and phenotype of cancer cachexia through alterations in various circulating factors derived from the tumor microenvironment.

Topics: Activins; Animals; Cachexia; Cell Line, Tumor; Disease Models, Animal; Interleukin-6; Male; Mice; Mice, Inbred BALB C; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Myocardium; RNA, Messenger; SKP Cullin F-Box Protein Ligases; Transforming Growth Factor beta; Tripartite Motif Proteins; Tumor Microenvironment; Tumor Necrosis Factor-alpha; Ubiquitin-Protein Ligases

Cancer cachexia is a debilitating condition characterized by a combination of anorexia, muscle wasting, weight loss, and malnutrition. This condition affects an overwhelming majority of patients with pancreatic cancer and is a primary cause of cancer-related death. However, few, if any, effective therapies exist for both treatment and prevention of this syndrome. In order to develop novel therapeutic strategies for pancreatic cancer cachexia, appropriate animal models are necessary. In this study, we developed and validated a syngeneic, metastatic, murine model of pancreatic cancer cachexia. Using our model, we investigated the ability of transforming growth factor beta (TGF-β) blockade to mitigate the metabolic changes associated with cachexia. We found that TGF-β inhibition using the anti-TGF-β antibody 1D11.16.8 significantly improved overall mortality, weight loss, fat mass, lean body mass, bone mineral density, and skeletal muscle proteolysis in mice harboring advanced pancreatic cancer. Other immunotherapeutic strategies we employed were not effective. Collectively, we validated a simplified but useful model of pancreatic cancer cachexia to investigate immunologic treatment strategies. In addition, we showed that TGF-β inhibition can decrease the metabolic changes associated with cancer cachexia and improve overall survival.

Topics: Animals; Antibodies; Body Composition; Cachexia; Cell Line, Tumor; Disease Models, Animal; Immunotherapy; Male; Mice; Mice, Inbred C57BL; Muscular Atrophy; Neoplasm Metastasis; Pancreatic Neoplasms; Survival Analysis; Transforming Growth Factor beta

Topics: Animals; Bone Neoplasms; Bone Resorption; Cachexia; Calcium; Humans; Mice; Muscle Weakness; Muscle, Skeletal; NADPH Oxidases; Neoplasms; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta; Troponin

Topics: Activin Receptors, Type II; Activins; Animals; Cachexia; Disease Models, Animal; Humans; Mice; Muscle, Skeletal; Neoplasms; Signal Transduction; Transforming Growth Factor beta

Myostatin belongs to the transforming growth factor-beta superfamily and negatively regulates skeletal muscle mass. Its deletion induces muscle overgrowth, while, on the contrary, its overexpression or systemic administration cause muscle atrophy. The present study was aimed at investigating whether muscle depletion as occurring in an experimental model of cancer cachexia, the rat bearing the Yoshida AH-130 hepatoma, is associated with modulations of myostatin signalling and whether the cytokine tumour necrosis factor-alpha may be relevant in this regard.. Protein levels of myostatin, follistatin (myostatin endogenous inhibitor) and the activin receptor type IIB have been evaluated in the gastrocnemius of tumour-bearing rats by Western blotting. Circulating myostatin and follistatin in tumour hosts were evaluated by immunoprecipitation, while the DNA-binding activity of the SMAD transcription factors was determined by electrophoretic-mobility shift assay.. In day 4 tumour hosts muscle myostatin levels were comparable to controls, yet follistatin was reduced, and SMAD DNA-binding activity was enhanced. At day 7, both myostatin and follistatin increased in tumour bearers, while SMAD DNA-binding activity was unchanged. To investigate whether tumour necrosis factor-alpha contributed to induce such changes, rats were administered pentoxifylline, an inhibitor of tumour necrosis factor-alpha synthesis that partially corrects muscle depletion in tumour-bearing rats. The drug reduced both myostatin expression and SMAD DNA-binding activity in day 4 tumour hosts and up-regulated follistatin at day 7.. These observations suggest that myostatin pathway should be regarded as a potential therapeutic target in cancer cachexia.

Topics: Analysis of Variance; Animals; Blotting, Western; Cachexia; Disease Models, Animal; Male; Muscle, Skeletal; Muscular Atrophy; Myostatin; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Myostatin is a recently described negative regulator of skeletal muscle mass. This paper hypothesizes a role for this system in cardiac cachexia and insulin resistance and osteoporosis associated with advanced heart failure.

Topics: Animals; Biomarkers; Body Mass Index; Cachexia; Cross-Sectional Studies; Disease Models, Animal; Heart Failure; Humans; Insulin Resistance; Mice; Myostatin; Osteoporosis; Sensitivity and Specificity; Severity of Illness Index; Transforming Growth Factor beta

Myostatin is a negative regulator of myogenesis, and inactivation of myostatin leads to muscle growth. Here we have used modified RNA oligonucleotides targeting the myostatin mRNA and examined the therapeutic potential in normal and cancer cachexia mouse models. We found that the RNA oligonucleotides could suppress the myostatin expression in vivo, leading to the increase in muscle growth both in normal and cachectic mice. We also established that the effect of myostatin inhibition caused by the RNA oligonucleotides may be through the MyoD pathway, as evidenced by a significant upregulation of MyoD expression. Taken together, these results demonstrate the feasibility using antisense strategy for the treatment of muscle wasting conditions.

Topics: Adenosine Triphosphatases; Administration, Oral; Animals; Base Sequence; Biomarkers; Blotting, Western; Cachexia; Female; Genetic Therapy; Injections, Intraperitoneal; Injections, Intravenous; Mice; Mice, Inbred BALB C; Models, Animal; Molecular Sequence Data; Muscle, Skeletal; Muscular Atrophy; MyoD Protein; Myostatin; Neoplasm Transplantation; Reverse Transcriptase Polymerase Chain Reaction; RNA, Antisense; RNA, Messenger; Transforming Growth Factor beta

Insulin-like growth factor (IGF)-I increases muscle mass while myostatin inhibits its development. Muscle wasting is common in patients with uremic cachexia and may be due to imbalance of this regulation. We had proposed a central mechanism involving leptin and melanocortin signaling in the pathogenesis of uremic cachexia since agouti-related peptide (AgRP), a melanocortin-4 receptor antagonist, reduced uremic cachexia. Here we found that injection of AgRP into the cerebral ventricles resulted in a gain of body mass and improved metabolic rate regulation in a mouse model of uremic cachexia. These salutary effects occurred independent of increased protein and calorie intake. Myostatin mRNA and protein concentrations were increased while those of IGF-I were decreased in the skeletal muscle of uremic mice. AgRP treatment partially corrected these uremia-induced changes. Suppressor of cytokine signaling-2 gene expression (SOCS2) was significantly increased in uremic animals and AgRP reduced this expression. We suggest that AgRP improves uremic cachexia and muscle wasting by a peripheral mechanism involving the balance between myostatin and IGF-I.

Topics: Agouti-Related Protein; Animals; Appetite Regulation; Cachexia; Chronic Disease; Gene Expression; Humans; Insulin-Like Growth Factor I; Leptin; Male; Melanocortins; Mice; Mice, Inbred C57BL; Muscular Atrophy; Myostatin; Nephrectomy; RNA, Messenger; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transforming Growth Factor beta; Uremia

Foxo-1, a member of the Foxo forkhead type transcription factors, is markedly upregulated in skeletal muscle in energy-deprived states such as fasting, cancer and severe diabetes. In this study, we target the Foxo-1 mRNA in a mouse skeletal myoblast cell line C2C12 and in vivo models of normal and cancer cachexia mice by a Foxo-1 specific RNA oligonucleotide. Our results demonstrate that the RNA oligonucleotide can reduce the expression of Foxo-1 in cells and in normal and cachectic mice, leading to an increase in skeletal muscle mass of the mice. In search for the possible downstream target genes of Foxo-1, we show that when Foxo-1 expression is blocked both in cells and in mice, the level of MyoD, a myogenic factor, is increased while a muscle negative regulator GDF-8 or myostatin is suppressed. Taken together, these results show that Foxo-1 pays a critical role in development of muscle atrophy, and suggest that Foxo-1 is a potential molecular target for treatment of muscle wasting conditions.

Topics: Animals; Cachexia; Cell Line, Tumor; Female; Forkhead Box Protein O1; Forkhead Transcription Factors; Gene Expression Regulation; Mice; Mice, Inbred BALB C; Muscle, Skeletal; Muscular Atrophy; Myoblasts; MyoD Protein; Myostatin; Neoplasms; Oligoribonucleotides, Antisense; Transforming Growth Factor beta

The pathogenesis of cancer anorexia-cachexia syndrome (CACS) is very complicated. In development of this syndrome play a role: metabolism of glucose, tumor necrosis factor (TNF), interleukin 1, interleukin 6, interferon a, interferon y, the oncological treatment and many other factors. Vascular endothelial growth factor (VEGF) is the most important proangiogenic factor. It promotes new vessels development, enhances vascular permeability and recruits monocytes. Many factors play a role in regulation of VEGF level. One of the most important is transforming growth factor beta (TGF-beta). Vascular endothelial growth factor and TGF-beta play a role in inflammation reaction too. The aim of this study was the evaluation of correlation between VEGF and TGF-beta in CACS in lung cancer.. We measured the serum level of VEGF and TGF-beta in 40 patients with lung cancer (20 with and 20 without CACS) and in control group. The serum level was measured by ELISA method.. The correlation between VEGF and TGF-beta was not statistically significant in patients with CACS (p = 0.67), but the statistical significance was in patients without CACS (p = 0.006) and in control group (p = 0.035).. Results suggest, that VEGF regulation in CACS may be more complicated.

Topics: Anorexia; Cachexia; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lung Neoplasms; Male; Middle Aged; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Myostatin, a transforming growth factor-beta (TGF-beta) super-family member, has been well characterized as a negative regulator of muscle growth and development. Myostatin has been implicated in several forms of muscle wasting including the severe cachexia observed as a result of conditions such as AIDS and liver cirrhosis. Here we show that Myostatin induces cachexia by a mechanism independent of NF-kappaB. Myostatin treatment resulted in a reduction in both myotube number and size in vitro, as well as a loss in body mass in vivo. Furthermore, the expression of the myogenic genes myoD and pax3 was reduced, while NF-kappaB (the p65 subunit) localization and expression remained unchanged. In addition, promoter analysis has confirmed Myostatin inhibition of myoD and pax3. An increase in the expression of genes involved in ubiquitin-mediated proteolysis is observed during many forms of muscle wasting. Hence we analyzed the effect of Myostatin treatment on proteolytic gene expression. The ubiquitin associated genes atrogin-1, MuRF-1, and E214k were upregulated following Myostatin treatment. We analyzed how Myostatin may be signaling to induce cachexia. Myostatin signaling reversed the IGF-1/PI3K/AKT hypertrophy pathway by inhibiting AKT phosphorylation thereby increasing the levels of active FoxO1, allowing for increased expression of atrophy-related genes. Therefore, our results suggest that Myostatin induces cachexia through an NF-kappaB-independent mechanism. Furthermore, increased Myostatin levels appear to antagonize hypertrophy signaling through regulation of the AKT-FoxO1 pathway.

Topics: Animals; Atrophy; Cachexia; Cell Size; Cells, Cultured; CHO Cells; Cricetinae; Cricetulus; Forkhead Box Protein O1; Forkhead Transcription Factors; Gene Expression Regulation; Mice; Mice, Nude; Microarray Analysis; Models, Biological; Muscle Development; Muscle Fibers, Skeletal; Muscle Proteins; Myostatin; NF-kappa B; Protein Processing, Post-Translational; RNA, Messenger; SKP Cullin F-Box Protein Ligases; Transforming Growth Factor beta; Ubiquitin; Ubiquitin-Protein Ligases

The onset of cancer anorexia and the accompanying neurological symptoms and signs involve the general influence of cytokines on the brain. Using methylcholanthrene to induce tumors in Fischer 344 rats, we measured various specific components of the cytokine-induced anorectic reaction, including: (1) IL-1beta system components (ligand, signaling receptor, receptor accessory proteins, and receptor antagonist); (2) TNF-alpha; (3) TGF-beta1; and (4) IFN-gamma in the tumor tissue, the liver and the brain.. The data show that IL-1beta, TNF-alpha and IFN-gamma messenger RNA were detected in the tumor tissue of anorectic tumor-bearing rats. In brain regions, anorexia is associated with the upregulation of IL-1beta and its receptor mRNA. All other mRNA remained unchanged in the brain regions examined.. This suggests that IL-1beta and its receptor may play a significant role in this model of cancer-associated anorexia. In vivo, the characterization of cytokine components in the brain may provide data for potential pharmacological interventions to ameliorate the anorexia of disease.

Topics: Animals; Anorexia; Brain; Cachexia; Cytokines; Interferon-gamma; Interleukin-1; Liver; Male; Neoplasms; Rats; Rats, Inbred F344; RNA, Messenger; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Mice and cattle with genetic deficiencies in myostatin exhibit dramatic increases in skeletal muscle mass, suggesting that myostatin normally suppresses muscle growth. Whether this increased muscling results from prenatal or postnatal lack of myostatin activity is unknown. Here we show that myostatin circulates in the blood of adult mice in a latent form that can be activated by acid treatment. Systemic overexpression of myostatin in adult mice was found to induce profound muscle and fat loss analogous to that seen in human cachexia syndromes. These data indicate that myostatin acts systemically in adult animals and may be a useful pharmacologic target in clinical settings such as cachexia, where muscle growth is desired.

Topics: 3T3 Cells; Activins; Adipose Tissue; Animals; Body Weight; Cachexia; CHO Cells; Cricetinae; Eating; Female; Follistatin; Liver; Mice; Mice, Nude; Muscle Fibers, Skeletal; Muscle, Skeletal; Myostatin; Organ Size; Peptide Fragments; Recombinant Proteins; Transforming Growth Factor beta; Wasting Syndrome; Weight Loss

The aim of this study was to evaluate the correlations between tumor size and cachexia parameters including cytokine levels in serum. In transplantable colon 26 adenocarcinoma-bearing mice, parameters having negative correlations with tumor size were host weight changes, epididymal adipose tissue weight, glucose and interleukin 3 (IL-3) concentration in serum. Parameters having a positive correlation with tumor size were the number of circulating white blood cells and immunosuppressive acidic protein (IAP), interleukin 6 (IL-6) and transforming growth factor beta (TGF-beta) concentration in serum.

Topics: Adenocarcinoma; Animals; Blood Glucose; Cachexia; Colonic Neoplasms; Cytokines; Interleukin-3; Interleukin-6; Male; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Neoplasm Proteins; Transforming Growth Factor beta

While stimulating the growth of fibroblasts, transforming growth factor beta 1 (TGF-beta 1) inhibits the growth of various normal and malignant cell lines in vitro. We studied the effects of TGF-beta 1 in vivo. The level of TGF-beta 1 in serum was maximally elevated 2 h after injecting 1 muCi of 125I-TGF-beta 1 into the peritoneal cavity of nude mice. Five h after the i.p. administration of 10 micrograms of unlabeled TGF-beta 1, 20 ng/ml of TGF-beta-like material in serum were detected by a radioreceptor assay on A549 lung carcinoma cells. Trichloracetic acid-precipitable 125I-TGF-beta 1 was taken up by liver, spleen, lungs, kidneys, and tumor tissue but not by the brain. At doses exceeding 2 micrograms/day, TGF-beta 1 induced a generalized interstitial fibrosis and a cachexia, which was not mediated by elevated serum levels of tumor necrosis factor alpha as determined by Western blot analysis and enzyme-linked immunosorbent assay. A total of 200,000 cells of the estrogen receptor-negative human breast cancer line MDA-MB-231, which had been shown to be maximally growth inhibited in vitro by 40 pM TGF-beta 1 and to have high-affinity receptors (9, 11, 12), were injected into the mammary fat pad of each nude mouse. The duration of treatment was 16 days with ten animals in the control group and five animals in the treated groups. The dose ranged from 1 to 4 micrograms per animal daily. The treatment was started 24 h after the injection of the tumor cells. Tumor growth was not significantly affected at either nontoxic or toxic doses of TGF-beta 1. Thus, we have demonstrated that TGF-beta 1, apart from being a local growth factor, has systemic effects, such as cachexia and multiple fibrosis. Its role as an antitumor agent may be limited.

Topics: Animals; Breast Neoplasms; Cachexia; Cell Division; Fibrosis; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Organ Size; Transforming Growth Factor beta; Transplantation, Heterologous; Tumor Cells, Cultured