A wasted early warning. Stower Hannah Nature medicine 10.1038/s41591-018-0153-0
    Fatty acid metabolism-the first trigger for cachexia? Sassoon David A Nature medicine 10.1038/nm.4121
    Early Weight Loss during Chemoradiotherapy Has a Detrimental Impact on Outcome in NSCLC. Sanders Karin J C,Hendriks Lizza E,Troost Esther G C,Bootsma Gerben P,Houben Ruud M A,Schols Annemie M W J,Dingemans Anne-Marie C Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer OBJECTIVES:The aim of this study was to assess the effect of early weight loss before the onset of radiation esophagitis on overall survival (OS) in patients with non-small cell lung cancer treated with concurrent chemoradiotherapy. METHODS:Characteristics (e.g., patient weight, radiation esophagitis score, sex, World Health Organization performance status, chemotherapy dose, nodal status, and gross tumor volume) of 151 patients who received concurrent chemoradiotherapy (in 2006-2013) were retrospectively correlated with OS. Early weight loss was defined as weight loss of more than 5% between the start and third week of radiotherapy in patients whose weight was stable before treatment initiation. RESULTS:In 17% of the patients early weight loss was observed. Median OS (95% confidence interval [CI]) was significantly shorter in the early weight loss group (OS = 13.0 months, 95% CI: 2.0-24.0) versus in the non-early weight loss group (OS = 23.0 months, 95% CI: 14.7-31.3) (hazard ratio [HR] = 1.8, 95% CI: 1.12-2.96, p = 0.017). On multivariate analysis sex (HR = 2.1, 95% CI: 1.33-3.29, p = 0.001), World Health Organization performance status (HR = 1.9, 95% CI: 1.20-2.97, p = 0.006), nodal status (HR = 2.9, 95% CI: 1.38-6.01, p = 0.005), and early weight loss (HR = 1.9, 95% CI: 1.10-3.19, p = 0.022) were associated with OS. CONCLUSIONS:Early weight loss in patients with non-small cell lung cancer was found to be associated with worse prognosis. These data warrant further investigation into the efficacy of tailored intervention to prevent early weight loss. 10.1016/j.jtho.2016.02.013
    An AMP-activated protein kinase-stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice. Rohm Maria,Schäfer Michaela,Laurent Victor,Üstünel Bilgen Ekim,Niopek Katharina,Algire Carolyn,Hautzinger Oksana,Sijmonsma Tjeerd P,Zota Annika,Medrikova Dasa,Pellegata Natalia S,Ryden Mikael,Kulyte Agné,Dahlman Ingrid,Arner Peter,Petrovic Natasa,Cannon Barbara,Amri Ez-Zoubir,Kemp Bruce E,Steinberg Gregory R,Janovska Petra,Kopecky Jan,Wolfrum Christian,Blüher Matthias,Berriel Diaz Mauricio,Herzig Stephan Nature medicine Cachexia represents a fatal energy-wasting syndrome in a large number of patients with cancer that mostly results in a pathological loss of skeletal muscle and adipose tissue. Here we show that tumor cell exposure and tumor growth in mice triggered a futile energy-wasting cycle in cultured white adipocytes and white adipose tissue (WAT), respectively. Although uncoupling protein 1 (Ucp1)-dependent thermogenesis was dispensable for tumor-induced body wasting, WAT from cachectic mice and tumor-cell-supernatant-treated adipocytes were consistently characterized by the simultaneous induction of both lipolytic and lipogenic pathways. Paradoxically, this was accompanied by an inactivated AMP-activated protein kinase (Ampk), which is normally activated in peripheral tissues during states of low cellular energy. Ampk inactivation correlated with its degradation and with upregulation of the Ampk-interacting protein Cidea. Therefore, we developed an Ampk-stabilizing peptide, ACIP, which was able to ameliorate WAT wasting in vitro and in vivo by shielding the Cidea-targeted interaction surface on Ampk. Thus, our data establish the Ucp1-independent remodeling of adipocyte lipid homeostasis as a key event in tumor-induced WAT wasting, and we propose the ACIP-dependent preservation of Ampk integrity in the WAT as a concept in future therapies for cachexia. 10.1038/nm.4171
    Insulin resistance and body composition in cancer patients. Dev R,Bruera E,Dalal S Annals of oncology : official journal of the European Society for Medical Oncology Cancer cachexia, weight loss with altered body composition, is a multifactorial syndrome propagated by symptoms that impair caloric intake, tumor byproducts, chronic inflammation, altered metabolism, and hormonal abnormalities. Cachexia is associated with reduced performance status, decreased tolerance to chemotherapy, and increased mortality in cancer patients. Insulin resistance as a consequence of tumor byproducts, chronic inflammation, and endocrine dysfunction has been associated with weight loss in cancer patients. Insulin resistance in cancer patients is characterized by increased hepatic glucose production and gluconeogenesis, and unlike type 2 diabetes, normal fasting glucose with high, normal or low levels of insulin. Cancer cachexia results in altered body composition with the loss of lean muscle mass with or without the loss of adipose tissue. Alteration in visceral adiposity, accumulation of intramuscular adipose tissue, and secretion of adipocytokines from adipose cells may play a role in promoting the metabolic derangements associated with cachexia including a proinflammatory environment and insulin resistance. Increased production of ghrelin, testosterone deficiency, and low vitamin D levels may also contribute to altered metabolism of glucose. Cancer cachexia cannot be easily reversed by standard nutritional interventions and identifying and treating cachexia at the earliest stage of development is advocated. Experts advocate for multimodal therapy to address symptoms that impact caloric intake, reduce chronic inflammation, and treat metabolic and endocrine derangements, which propagate the loss of weight. Treatment of insulin resistance may be a critical component of multimodal therapy for cancer cachexia and more research is needed. 10.1093/annonc/mdx815
    Phases of Metabolic and Soft Tissue Changes in Months Preceding a Diagnosis of Pancreatic Ductal Adenocarcinoma. Sah Raghuwansh P,Sharma Ayush,Nagpal Sajan,Patlolla Sri Harsha,Sharma Anil,Kandlakunta Harika,Anani Vincent,Angom Ramcharan Singh,Kamboj Amrit K,Ahmed Nazir,Mohapatra Sonmoon,Vivekanandhan Sneha,Philbrick Kenneth A,Weston Alexander,Takahashi Naoki,Kirkland James,Javeed Naureen,Matveyenko Aleksey,Levy Michael J,Mukhopadhyay Debabrata,Chari Suresh T Gastroenterology BACKGROUND & AIMS:Identifying metabolic abnormalities that occur before pancreatic ductal adenocarcinoma (PDAC) diagnosis could increase chances for early detection. We collected data on changes in metabolic parameters (glucose, serum lipids, triglycerides; total, low-density, and high-density cholesterol; and total body weight) and soft tissues (abdominal subcutaneous fat [SAT], adipose tissue, visceral adipose tissue [VAT], and muscle) from patients 5 years before the received a diagnosis of PDAC. METHODS:We collected data from 219 patients with a diagnosis of PDAC (patients) and 657 healthy individuals (controls) from the Rochester Epidemiology Project, from 2000 through 2015. We compared metabolic profiles of patients with those of age- and sex-matched controls, constructing temporal profiles of fasting blood glucose, serum lipids including triglycerides, cholesterol profiles, and body weight and temperature for 60 months before the diagnosis of PDAC (index date). To construct the temporal profile of soft tissue changes, we collected computed tomography scans from 68 patients, comparing baseline (>18 months before diagnosis) areas of SAT, VAT, and muscle at L2/L3 vertebra with those of later scans until time of diagnosis. SAT and VAT, isolated from healthy individuals, were exposed to exosomes isolated from PDAC cell lines and analyzed by RNA sequencing. SAT was collected from KRASG12D P53 mice with PDACs, C57/BL6 (control) mice, and 5 patients and analyzed by histology and immunohistochemistry. RESULTS:There were no significant differences in metabolic or soft tissue features of patients vs controls until 30 months before PDAC diagnosis. In the 30 to 18 months before PDAC diagnosis (phase 1, hyperglycemia), a significant proportion of patients developed hyperglycemia, compared with controls, without soft tissue changes. In the 18 to 6 months before PDAC diagnosis (phase 2, pre-cachexia), patients had significant increases in hyperglycemia and decreases in serum lipids, body weight, and SAT, with preserved VAT and muscle. In the 6 to 0 months before PDAC diagnosis (phase 3, cachexia), a significant proportion of patients had hyperglycemia compared with controls, and patients had significant reductions in all serum lipids, SAT, VAT, and muscle. We believe the patients had browning of SAT, based on increases in body temperature, starting 18 months before PDAC diagnosis. We observed expression of uncoupling protein 1 (UCP1) in SAT exposed to PDAC exosomes, SAT from mice with PDACs, and SAT from all 5 patients but only 1 of 4 controls. CONCLUSIONS:We identified 3 phases of metabolic and soft tissue changes that precede a diagnosis of PDAC. Loss of SAT starts 18 months before PDAC identification, and is likely due to browning. Overexpression of UCP1 in SAT might be a biomarker of early-stage PDAC, but further studies are needed. 10.1053/j.gastro.2019.01.039
    ZIP4 Promotes Muscle Wasting and Cachexia in Mice With Orthotopic Pancreatic Tumors by Stimulating RAB27B-Regulated Release of Extracellular Vesicles From Cancer Cells. Yang Jingxuan,Zhang Zicheng,Zhang Yuqing,Ni Xiaoling,Zhang Guohua,Cui Xiaobo,Liu Mingyang,Xu Can,Zhang Qiang,Zhu Huiyun,Yan Jie,Zhu Vivian F,Luo Yusheng,Hagan John P,Li Zhaoshen,Fang Jing,Jatoi Aminah,Fernandez-Zapico Martin E,Zheng Lei,Edil Barish H,Bronze Michael S,Houchen Courtney W,Li Yi-Ping,Li Min Gastroenterology BACKGROUND & AIMS:Cachexia, which includes muscle wasting, is a frequent complication of pancreatic cancer. There are no therapies that reduce cachexia and increase patient survival, so it is important to learn more about its mechanisms. The zinc transporter ZIP4 promotes growth and metastasis of pancreatic tumors. We investigated its effects on muscle catabolism via extracellular vesicle (EV)-mediated stimulation of mitogen-activated protein kinase 14 (p38 MAPK). METHODS:We studied nude mice with orthotopic tumors grown from human pancreatic cancer cell lines (AsPC-1 and BxPC-3); tumors were removed 8 days after cell injection and analyzed by histology. Mouse survival was analyzed by Kaplan-Meier curves. ZIP4 was knocked down in AsPC-1 and BxPC-3 cells with small hairpin RNAs; cells with empty vectors were used as controls. Muscle tissues were collected from mice and analyzed by histology and immunohistochemistry. Conditioned media from cell lines and 3-dimensional spheroid/organoid cultures of cancer cells were applied to C2C12 myotubes. The myotubes and the media were analyzed by immunoblots, enzyme-linked immunosorbent assays, and immunofluorescence microscopy. EVs were isolated from conditioned media and analyzed by immunoblots. RESULTS:Mice with orthotopic tumors grown from pancreatic cancer cells with knockdown of ZIP4 survived longer and lost less body weight and muscle mass than mice with control tumors. Conditioned media from cancer cells activated p38 MAPK, induced expression of F-box protein 32 and UBR2 in C2C12 myotubes, and also led to loss of myofibrillar protein myosin heavy chain and myotube thinning. Knockdown of ZIP4 in cancer cells reduced these effects. ZIP4 knockdown also reduced pancreatic cancer cell release of heat shock protein (HSP) 70 and HSP90, which are associated with EVs, by decreasing CREB-regulated expression of RAB27B. CONCLUSIONS:ZIP4 promotes growth of orthotopic pancreatic tumors in mice and loss of muscle mass by activating CREB-regulated expression of RAB27B, required for release of EVs from pancreatic cancer cells. These EVs activate p38 MAPK and induce expression of F-box protein 32 and UBR2 in myotubes, leading to loss of myofibrillar myosin heavy chain and myotube thinning. Strategies to disrupt these pathways might be developed to reduce pancreatic cancer progression and accompanying cachexia. 10.1053/j.gastro.2018.10.026
    Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus. Campos Carlos A,Bowen Anna J,Han Sung,Wisse Brent E,Palmiter Richard D,Schwartz Michael W Nature neuroscience Anorexia is a common manifestation of chronic diseases, including cancer. Here we investigate the contribution to cancer anorexia made by calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) that transmit anorexic signals. We show that CGRP neurons are activated in mice implanted with Lewis lung carcinoma cells. Inactivation of CGRP neurons before tumor implantation prevents anorexia and loss of lean mass, and their inhibition after symptom onset reverses anorexia. CGRP neurons are also activated in Apc mice, which develop intestinal cancer and lose weight despite the absence of reduced food intake. Inactivation of CGRP neurons in Apc mice permits hyperphagia that counteracts weight loss, revealing a role for these neurons in a 'nonanorexic' cancer model. We also demonstrate that inactivation of CGRP neurons prevents lethargy, anxiety and malaise associated with cancer. These findings establish CGRP neurons as key mediators of cancer-induced appetite suppression and associated behavioral changes. 10.1038/nn.4574
    A TGF-β pathway associated with cancer cachexia. Guttridge Denis C Nature medicine 10.1038/nm.3988
    PTH/PTHrP Receptor Mediates Cachexia in Models of Kidney Failure and Cancer. Kir Serkan,Komaba Hirotaka,Garcia Ana P,Economopoulos Konstantinos P,Liu Wei,Lanske Beate,Hodin Richard A,Spiegelman Bruce M Cell metabolism Cachexia is a wasting syndrome associated with elevated basal energy expenditure and loss of adipose and muscle tissues. It accompanies many chronic diseases including renal failure and cancer and is an important risk factor for mortality. Our recent work demonstrated that tumor-derived PTHrP drives adipose tissue browning and cachexia. Here, we show that PTH is involved in stimulating a thermogenic gene program in 5/6 nephrectomized mice that suffer from cachexia. Fat-specific knockout of PTHR blocked adipose browning and wasting. Surprisingly, loss of PTHR in fat tissue also preserved muscle mass and improved muscle strength. Similarly, PTHR knockout mice were resistant to cachexia driven by tumors. Our results demonstrate that PTHrP and PTH mediate wasting through a common mechanism involving PTHR, and there exists an unexpected crosstalk mechanism between wasting of fat tissue and skeletal muscle. Targeting the PTH/PTHrP pathway may have therapeutic uses in humans with cachexia. 10.1016/j.cmet.2015.11.003
    Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Kir Serkan,White James P,Kleiner Sandra,Kazak Lawrence,Cohen Paul,Baracos Vickie E,Spiegelman Bruce M Nature Cachexia is a wasting disorder of adipose and skeletal muscle tissues that leads to profound weight loss and frailty. About half of all cancer patients suffer from cachexia, which impairs quality of life, limits cancer therapy and decreases survival. One key characteristic of cachexia is higher resting energy expenditure levels than in healthy individuals, which has been linked to greater thermogenesis by brown fat. How tumours induce brown fat activity is unknown. Here, using a Lewis lung carcinoma model of cancer cachexia, we show that tumour-derived parathyroid-hormone-related protein (PTHrP) has an important role in wasting, through driving the expression of genes involved in thermogenesis in adipose tissues. Neutralization of PTHrP in tumour-bearing mice blocked adipose tissue browning and the loss of muscle mass and strength. Our results demonstrate that PTHrP mediates energy wasting in fat tissues and contributes to the broader aspects of cancer cachexia. Thus, neutralization of PTHrP might hold promise for ameliorating cancer cachexia and improving patient survival. 10.1038/nature13528
    Autophagy is required for glucose homeostasis and lung tumor maintenance. Karsli-Uzunbas Gizem,Guo Jessie Yanxiang,Price Sandy,Teng Xin,Laddha Saurabh V,Khor Sinan,Kalaany Nada Y,Jacks Tyler,Chan Chang S,Rabinowitz Joshua D,White Eileen Cancer discovery UNLABELLED:Macroautophagy (autophagy hereafter) recycles intracellular components to sustain mitochondrial metabolism that promotes the growth, stress tolerance, and malignancy of lung cancers, suggesting that autophagy inhibition may have antitumor activity. To assess the functional significance of autophagy in both normal and tumor tissue, we conditionally deleted the essential autophagy gene, autophagy related 7 (Atg7), throughout adult mice. Here, we report that systemic ATG7 ablation caused susceptibility to infection and neurodegeneration that limited survival to 2 to 3 months. Moreover, upon fasting, autophagy-deficient mice suffered fatal hypoglycemia. Prior autophagy ablation did not alter the efficiency of non-small cell lung cancer (NSCLC) initiation by activation of oncogenic Kras(G12D) and deletion of the Trp53 tumor suppressor. Acute autophagy ablation in mice with preexisting NSCLC, however, blocked tumor growth, promoted tumor cell death, and generated more benign disease (oncocytomas). This antitumor activity occurred before destruction of normal tissues, suggesting that acute autophagy inhibition may be therapeutically beneficial in cancer. SIGNIFICANCE:We systemically ablated cellular self-cannibalization by autophagy in adult mice and determined that it is dispensable for short-term survival, but required to prevent fatal hypoglycemia and cachexia during fasting, delineating a new role for autophagy in metabolism. Importantly, acute, systemic autophagy ablation was selectively destructive to established tumors compared with normal tissues, thereby providing the preclinical evidence that strategies to inhibit autophagy may be therapeutically advantageous for RAS-driven cancers. 10.1158/2159-8290.CD-14-0363
    Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity. Flint Thomas R,Janowitz Tobias,Connell Claire M,Roberts Edward W,Denton Alice E,Coll Anthony P,Jodrell Duncan I,Fearon Douglas T Cell metabolism In patients with cancer, the wasting syndrome, cachexia, is associated with caloric deficiency. Here, we describe tumor-induced alterations of the host metabolic response to caloric deficiency that cause intratumoral immune suppression. In pre-cachectic mice with transplanted colorectal cancer or autochthonous pancreatic ductal adenocarcinoma (PDA), we find that IL-6 reduces the hepatic ketogenic potential through suppression of PPARalpha, the transcriptional master regulator of ketogenesis. When these mice are challenged with caloric deficiency, the resulting relative hypoketonemia triggers a marked rise in glucocorticoid levels. Multiple intratumoral immune pathways are suppressed by this hormonal stress response. Moreover, administering corticosterone to elevate plasma corticosterone to a level that is lower than that occurring in cachectic mice abolishes the response of mouse PDA to an immunotherapy that has advanced to clinical trials. Therefore, tumor-induced IL-6 impairs the ketogenic response to reduced caloric intake, resulting in a systemic metabolic stress response that blocks anti-cancer immunotherapy. 10.1016/j.cmet.2016.10.010
    Targeting of Fn14 Prevents Cancer-Induced Cachexia and Prolongs Survival. Johnston Amelia J,Murphy Kate T,Jenkinson Laura,Laine David,Emmrich Kerstin,Faou Pierre,Weston Ross,Jayatilleke Krishnath M,Schloegel Jessie,Talbo Gert,Casey Joanne L,Levina Vita,Wong W Wei-Lynn,Dillon Helen,Sahay Tushar,Hoogenraad Joan,Anderton Holly,Hall Cathrine,Schneider Pascal,Tanzer Maria,Foley Michael,Scott Andrew M,Gregorevic Paul,Liu Spring Yingchun,Burkly Linda C,Lynch Gordon S,Silke John,Hoogenraad Nicholas J Cell The cytokine TWEAK and its cognate receptor Fn14 are members of the TNF/TNFR superfamily and are upregulated in tumors. We found that Fn14, when expressed in tumors, causes cachexia and that antibodies against Fn14 dramatically extended lifespan by inhibiting tumor-induced weight loss although having only moderate inhibitory effects on tumor growth. Anti-Fn14 antibodies prevented tumor-induced inflammation and loss of fat and muscle mass. Fn14 signaling in the tumor, rather than host, is responsible for inducing this cachexia because tumors in Fn14- and TWEAK-deficient hosts developed cachexia that was comparable to that of wild-type mice. These results extend the role of Fn14 in wound repair and muscle development to involvement in the etiology of cachexia and indicate that Fn14 antibodies may be a promising approach to treat cachexia, thereby extending lifespan and improving quality of life for cancer patients. 10.1016/j.cell.2015.08.031
    Cancer cachexia induces morphological and inflammatory changes in the intestinal mucosa. Costa Raquel G F,Caro Paula L,de Matos-Neto Emídio M,Lima Joanna D C C,Radloff Katrin,Alves Michele J,Camargo Rodolfo G,Pessoa Ana Flávia M,Simoes Estefania,Gama Patrícia,Cara Denise C,da Silva Aloísio S F,O Pereira Welbert,Maximiano Linda F,de Alcântara Paulo S M,Otoch José P,Trinchieri Giorgio,Laviano Alessandro,Muscaritoli Maurizio,Seelaender Marília Journal of cachexia, sarcopenia and muscle BACKGROUND:Cachexia is a multifactorial and multiorgan syndrome associated with cancer and other chronic diseases and characterized by severe involuntary body weight loss, disrupted metabolism, inflammation, anorexia, fatigue, and diminished quality of life. This syndrome affects around 50% of patients with colon cancer and is directly responsible for the death of at least 20% of all cancer patients. Systemic inflammation has been recently proposed to underline most of cachexia-related symptoms. Nevertheless, the exact mechanisms leading to the initiation of systemic inflammation have not yet been unveiled, as patients bearing the same tumour and disease stage may or may not present cachexia. We hypothesize a role for gut barrier disruption, which may elicit persistent immune activation in the host. To address this hypothesis, we analysed the healthy colon tissue, adjacent to the tumour. METHODS:Blood and rectosigmoid colon samples (20 cm distal to tumour margin) obtained during surgery, from cachectic (CC = 25) or weight stable (WSC = 20) colon cancer patients, who signed the informed consent form, were submitted to morphological (light microscopy), immunological (immunohistochemistry and flow cytometry), and molecular (quantification of inflammatory factors by Luminex® xMAP) analyses. RESULTS:There was no statistical difference in gender and age between groups. The content of plasma interleukin 6 (IL-6) and IL-8 was augmented in cachectic patients relative to those with stable weight (P = 0.047 and P = 0.009, respectively). The number of lymphocytic aggregates/field in the gut mucosa was higher in CC than in WSC (P = 0.019), in addition to those of the lamina propria (LP) eosinophils (P < 0.001) and fibroblasts (P < 0.001). The area occupied by goblet cells in the colon mucosa was decreased in CC (P = 0.016). The M1M2 macrophages percentage was increased in the colon of CC, in relation to WSC (P = 0.042). Protein expression of IL-7, IL-13, and transforming growth factor beta 3 in the colon was significantly increased in CC, compared with WSC (P = 0.02, P = 0.048, and P = 0.048, respectively), and a trend towards a higher content of granulocyte-colony stimulating factor in CC was also observed (P = 0.061). The results suggest an increased recruitment of immune cells to the colonic mucosa in CC, as compared with WSC, in a fashion that resembles repair response following injury, with higher tissue content of IL-13 and transforming growth factor beta 3. CONCLUSIONS:The changes in the intestinal mucosa cellularity, along with modified cytokine expression in cachexia, indicate that gut barrier alterations are associated with the syndrome. 10.1002/jcsm.12449
    The systemic activin response to pancreatic cancer: implications for effective cancer cachexia therapy. Zhong Xiaoling,Pons Marianne,Poirier Christophe,Jiang Yanlin,Liu Jianguo,Sandusky George E,Shahda Safi,Nakeeb Attila,Schmidt C Max,House Michael G,Ceppa Eugene P,Zyromski Nicholas J,Liu Yunlong,Jiang Guanglong,Couch Marion E,Koniaris Leonidas G,Zimmers Teresa A Journal of cachexia, sarcopenia and muscle BACKGROUND:Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy partly due to frequent, severe cachexia. Serum activin correlates with cachexia and mortality, while exogenous activin causes cachexia in mice. METHODS:Isoform-specific activin expression and activities were queried in human and murine tumours and PDAC models. Activin inhibition was by administration of soluble activin type IIB receptor (ACVR2B/Fc) and by use of skeletal muscle specific dominant negative ACVR2B expressing transgenic mice. Feed-forward activin expression and muscle wasting activity were tested in vivo and in vitro on myotubes. RESULTS:Murine PDAC tumour-derived cell lines expressed activin-βA but not activin-βB. Cachexia severity increased with activin expression. Orthotopic PDAC tumours expressed activins, induced activin expression by distant organs, and produced elevated serum activins. Soluble factors from PDAC elicited activin because conditioned medium from PDAC cells induced activin expression, activation of p38 MAP kinase, and atrophy of myotubes. The activin trap ACVR2B/Fc reduced tumour growth, prevented weight loss and muscle wasting, and prolonged survival in mice with orthotopic tumours made from activin-low cell lines. ACVR2B/Fc also reduced cachexia in mice with activin-high tumours. Activin inhibition did not affect activin expression in organs. Hypermuscular mice expressing dominant negative ACVR2B in muscle were protected for weight loss but not mortality when implanted with orthotopic tumours. Human tumours displayed staining for activin, and expression of the gene encoding activin-βA (INHBA) correlated with mortality in patients with PDAC, while INHBB and other related factors did not. CONCLUSIONS:Pancreatic adenocarcinoma tumours are a source of activin and elicit a systemic activin response in hosts. Human tumours express activins and related factors, while mortality correlates with tumour activin A expression. PDAC tumours also choreograph a systemic activin response that induces organ-specific and gene-specific expression of activin isoforms and muscle wasting. Systemic blockade of activin signalling could preserve muscle and prolong survival, while skeletal muscle-specific activin blockade was only protective for weight loss. Our findings suggest the potential and need for gene-specific and organ-specific interventions. Finally, development of more effective cancer cachexia therapy might require identifying agents that effectively and/or selectively inhibit autocrine vs. paracrine activin signalling. 10.1002/jcsm.12461
    Tumour-derived transforming growth factor-β signalling contributes to fibrosis in patients with cancer cachexia. Lima Joanna D C C,Simoes Estefania,de Castro Gabriela,Morais Mychel Raony P T,de Matos-Neto Emidio M,Alves Michele J,Pinto Nelson I,Figueredo Raquel G,Zorn Telma M T,Felipe-Silva Aloísio S,Tokeshi Flavio,Otoch José P,Alcantara Paulo,Cabral Fernanda J,Ferro Emer S,Laviano Alessandro,Seelaender Marilia Journal of cachexia, sarcopenia and muscle BACKGROUND: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. METHODS: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. RESULTS: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). CONCLUSIONS: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. 10.1002/jcsm.12441
    MyD88 signalling is critical in the development of pancreatic cancer cachexia. Zhu Xinxia,Burfeind Kevin G,Michaelis Katherine A,Braun Theodore P,Olson Brennan,Pelz Katherine R,Morgan Terry K,Marks Daniel L Journal of cachexia, sarcopenia and muscle BACKGROUND:Up to 80% of pancreatic cancer patients suffer from cachexia, a devastating condition that exacerbates underlying disease, reduces quality of life, and increases treatment complications and mortality. Tumour-induced inflammation is linked to this multifactorial wasting syndrome, but mechanisms and effective treatments remain elusive. Myeloid differentiation factor (MyD88), a key component of the innate immune system, plays a pivotal role in directing the inflammatory response to various insults. In this study, we tested whether MyD88 signalling is essential in the development of pancreatic cancer cachexia using a robust mouse tumour model. METHODS:Sex, age, and body weight-matched wide type (WT) and MyD88 knockout (MyD88 KO) mice were orthotopically or intraperitoneally implanted with a pancreatic tumour cell line from a syngeneic C57BL/6 KRAS P53 Pdx-Cre (KPC) mouse. We observed the effects of MyD88 signalling during pancreatic ductal adenocarcinoma progression and the cachexia development through behavioural, histological, molecular, and survival aspects. RESULTS:Blocking MyD88 signalling greatly ameliorated pancreatic ductal adenocarcinoma-associated anorexia and fatigue, attenuated lean mass loss, reduced muscle catabolism and atrophy, diminished systemic and central nervous system inflammation, and ultimately improved survival. Our data demonstrate that MyD88 signalling plays a critical role in mediating pancreatic cancer-induced inflammation that triggers cachexia development and therefore represents a promising therapeutic target. CONCLUSIONS:MyD88-dependent inflammation is crucial in the pathophysiology of pancreatic cancer progression and contributes to high mortality. Our findings implicate the importance of innate immune signalling pathways in pancreatic cancer cachexia and a novel therapeutic target. 10.1002/jcsm.12377
    Cachexia induced by cancer and chemotherapy yield distinct perturbations to energy metabolism. Pin Fabrizio,Barreto Rafael,Couch Marion E,Bonetto Andrea,O'Connell Thomas M Journal of cachexia, sarcopenia and muscle BACKGROUND:Cancer cachexia is a metabolic disorder involving perturbed energy balance and altered mitochondrial function. Chemotherapy is a primary treatment option for many types of cancer, but there is substantial evidence that some chemotherapeutic agents can also lead to the development and progression of cachexia. In this study, we apply a comprehensive and systems level metabolomics approach to characterize the metabolic perturbations in murine models of cancer-induced and chemotherapy-induced cachexia. Knowledge of the unique pathways through which cancer and chemotherapy drive cachexia is necessary in order to develop effective treatments. METHODS:The murine Colon26 (C26) adenocarcinoma xenograft model was used to study the metabolic derangements associated with cancer-induced cachexia. In vivo administration of Folfiri (5-fluorouracil, irinotecan, and leucovorin) was used to model chemotherapy-induced cachexia. Comprehensive metabolic profiling was carried out using both nuclear magnetic resonance-based and mass spectrometry-based platforms. Analyses included plasma, muscle, and liver tissue to provide a systems level profiling. RESULTS:The study involved four groups of CD2F1 male mice (n = 4-5), including vehicle treated (V), C26 tumour hosts (CC), Folfiri treated (F), and C26 tumour hosts treated with Folfiri (CCF). Significant weight loss including skeletal muscle was observed for each of the experimental groups with the tumour hosts showing the most dramatic change (-3.74 g vs. initial body weight in the CC group). Skeletal muscle loss was evident in all experimental groups compared with V, with the CCF combination resulting in the most severe depletion of quadriceps mass (-38% vs. V; P < 0.001). All experimental groups were characterized by an increased systemic glucose demand as evidenced by decreased levels of circulating glucose (-47% in CC vs. V; P < 0.001) and depletion of liver glucose (-51% in CC vs. V; P < 0.001) and glycogen (-74% in CC vs. V; P < 0.001). The cancer-induced and chemotherapy-induced cachexia models displayed unique alterations in flux through the tricarboxylic acid cycle and β-oxidation pathways. Cancer-induced cachexia was uniquely characterized by a dramatic elevation in low-density lipoprotein particles (+6.9-fold vs. V; P < 0.001) and a significant increase in the inflammatory marker, GlycA (+33% vs. V; P < 0.001). CONCLUSIONS:The results of this study demonstrated for the first time that cancer-induced and chemotherapy-induced cachexia is characterized by a number of distinct metabolic derangements. Effective therapeutic interventions for cancer-induced and chemotherapy-induced cachexia must take into account the specific metabolic defects imposed by the pathological or pharmacological drivers of cachexia. 10.1002/jcsm.12360
    Tumour-derived leukaemia inhibitory factor is a major driver of cancer cachexia and morbidity in C26 tumour-bearing mice. Kandarian Susan C,Nosacka Rachel L,Delitto Andrea E,Judge Andrew R,Judge Sarah M,Ganey John D,Moreira Jesse D,Jackman Robert W Journal of cachexia, sarcopenia and muscle BACKGROUND:Cancer cachexia is a metabolic wasting syndrome that is strongly associated with a poor prognosis. The initiating factors causing fat and muscle loss are largely unknown. Previously, we found that leukaemia inhibitory factor (LIF) secreted by C26 colon carcinoma cells was responsible for atrophy in treated myotubes. In the present study, we tested whether C26 tumour-derived LIF is required for cancer cachexia in mice by knockout of Lif in C26 cells. METHODS:A C26 Lif null tumour cell line was made using CRISPR-Cas9. Measurements of cachexia were compared in mice inoculated with C26 vs. C26 tumour cells, and atrophy was compared in myotubes treated with medium from C26 vs. C26 tumour cells. Levels of 25 cytokines/chemokines were compared in serum of mice bearing C26 vs. C26 tumours and in the medium from these tumour cell lines. RESULTS:At study endpoint, C26 mice showed outward signs of sickness while mice with C26 tumours appeared healthy. Mice with C26 tumours showed a 55-75% amelioration of body weight loss, muscle loss, fat loss, and splenomegaly compared with mice with C26 tumours (P < 0.05). The heart was not affected by LIF levels because the loss of cardiac mass was the same in C26 and C26 tumour-bearing mice. LIF levels in mouse serum was entirely dependent on secretion from the tumour cells. Serum levels of interleukin-6 and G-CSF were increased by 79-fold and 68-fold, respectively, in C26 mice but only by five-fold and two-fold, respectively, in C26 mice, suggesting that interleukin-6 and G-CSF increases are dependent on tumour-derived LIF. CONCLUSIONS:This study shows the first use of CRISPR-Cas9 knockout of a candidate cachexia factor in tumour cells. The results provide direct evidence for LIF as a major cachexia initiating factor for the C26 tumour in vivo. Tumour-derived LIF was also a regulator of multiple cytokines in C26 tumour cells and in C26 tumour-bearing mice. The identification of tumour-derived factors such as LIF that initiate the cachectic process is immediately applicable to the development of therapeutics to treat cachexia. This is a proof of principle for studies that when carried out in human cells, will make possible an understanding of the factors causing cachexia in a patient-specific manner. 10.1002/jcsm.12346
    Dysregulation of metabolic-associated pathways in muscle of breast cancer patients: preclinical evaluation of interleukin-15 targeting fatigue. Bohlen Joseph,McLaughlin Sarah L,Hazard-Jenkins Hannah,Infante Aniello M,Montgomery Cortney,Davis Mary,Pistilli Emidio E Journal of cachexia, sarcopenia and muscle BACKGROUND:Breast cancer patients report a perception of increased muscle fatigue, which can persist following surgery and standardized therapies. In a clinical experiment, we tested the hypothesis that pathways regulating skeletal muscle fatigue are down-regulated in skeletal muscle of breast cancer patients and that different muscle gene expression patterns exist between breast tumour subtypes. In a preclinical study, we tested the hypothesis that mammary tumour growth in mice induces skeletal muscle fatigue and that overexpression of the cytokine interleukin-15 (IL-15) can attenuate mammary tumour-induced muscle fatigue. METHODS:Early stage non-metastatic female breast cancer patients (n = 14) and female non-cancer patients (n = 6) provided a muscle biopsy of the pectoralis major muscle during mastectomy, lumpectomy, or breast reconstruction surgeries. The breast cancer patients were diagnosed with either luminal (ER /PR , n = 6), triple positive (ER /PR /Her2/neu , n = 5), or triple negative (ER /PR /Her2/neu , n = 3) breast tumours and were being treated with curative intent either with neoadjuvant chemotherapy followed by surgery or surgery followed by standard post-operative therapy. Biopsies were used for RNA-sequencing to compare the skeletal muscle gene expression patterns between breast cancer patients and non-cancer patients. The C57BL/6 mouse syngeneic mammary tumour cell line, E0771, was used to induce mammary tumours in immunocompetent mice, and isometric muscle contractile properties and fatigue properties were analysed following 4 weeks of tumour growth. RESULTS:RNA-sequencing and subsequent bioinformatics analyses revealed a dysregulation of canonical pathways involved in oxidative phosphorylation, mitochondrial dysfunction, peroxisome proliferator-activated receptor signalling and activation, and IL-15 signalling and production. In a preclinical mouse model of breast cancer, the rate of muscle fatigue was greater in mice exposed to mammary tumour growth for 4 weeks, and this greater muscle fatigue was attenuated in transgenic mice that overexpressed the cytokine IL-15. CONCLUSIONS:Our data identify novel genes and pathways dysregulated in the muscles of breast cancer patients with early stage non-metastatic disease, with particularly aberrant expression among genes that would predispose these patients to greater muscle fatigue. Furthermore, we demonstrate that IL-15 overexpression can attenuate muscle fatigue associated with mammary tumour growth in a preclinical mouse model of breast cancer. Therefore, we propose that skeletal muscle fatigue is an inherent consequence of breast tumour growth, and this greater fatigue can be targeted therapeutically. 10.1002/jcsm.12294
    Growth of ovarian cancer xenografts causes loss of muscle and bone mass: a new model for the study of cancer cachexia. Pin Fabrizio,Barreto Rafael,Kitase Yukiko,Mitra Sumegha,Erne Carlie E,Novinger Leah J,Zimmers Teresa A,Couch Marion E,Bonewald Lynda F,Bonetto Andrea Journal of cachexia, sarcopenia and muscle BACKGROUND:Cachexia frequently occurs in women with advanced ovarian cancer (OC), along with enhanced inflammation. Despite being responsible for one third of all cancer deaths, cachexia is generally under-studied in OC due to a limited number of pre-clinical animal models. We aimed to address this gap by characterizing the cachectic phenotype in a mouse model of OC. METHODS:Nod SCID gamma mice (n = 6-10) were injected intraperitoneally with 1 × 10 ES-2 human OC cells to mimic disseminated abdominal disease. Muscle size and strength, as well as bone morphometry, were assessed. Tumour-derived effects on muscle fibres were investigated in C2C12 myotube cultures. IL-6 levels were detected in serum and ascites from tumour hosts, as well as in tumour sections. RESULTS:In about 2 weeks, ES-2 cells developed abdominal tumours infiltrating omentum, mesentery, and adjacent organs. The ES-2 tumours caused severe cachexia with marked loss of body weight (-12%, P < 0.01) and ascites accumulation in the peritoneal cavity (4.7 ± 1.5 mL). Skeletal muscles appeared markedly smaller in the tumour-bearing mice (approximately -35%, P < 0.001). Muscle loss was accompanied by fibre atrophy, consistent with reduced muscle cross-sectional area (-34%, P < 0.01) and muscle weakness (-50%, P < 0.001). Body composition assessment by dual-energy X-ray absorptiometry revealed decreased bone mineral density (-8%, P < 0.01) and bone mineral content (-19%, P < 0.01), also consistent with reduced trabecular bone in both femurs and vertebrae, as suggested by micro-CT imaging of bone morphometry. In the ES-2 mouse model, cachexia was also associated with high tumour-derived IL-6 levels in plasma and ascites (26.3 and 279.6 pg/mL, respectively) and with elevated phospho-STAT3 (+274%, P < 0.001), reduced phospho-AKT (-44%, P < 0.001) and decreased mitochondrial proteins, as well as with increased protein ubiquitination (+42%, P < 0.001) and expression of ubiquitin ligases in the skeletal muscle of tumour hosts. Similarly, ES-2 conditioned medium directly induced fibre atrophy in C2C12 mouse myotubes (-16%, P < 0.001), consistent with elevated phospho-STAT3 (+1.4-fold, P < 0.001) and altered mitochondrial homoeostasis and metabolism, while inhibition of the IL-6/STAT3 signalling by means of INCB018424 was sufficient to restore the myotubes size. CONCLUSIONS:Our results suggest that the development of ES-2 OC promotes muscle atrophy in both in vivo and in vitro conditions, accompanied by loss of bone mass, enhanced muscle protein catabolism, abnormal mitochondrial homoeostasis, and elevated IL-6 levels. Therefore, this represents an appropriate model for the study of OC cachexia. Our model will aid in identifying molecular mediators that could be effectively targeted in order to improve muscle wasting associated with OC. 10.1002/jcsm.12311
    Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses. Nissinen Tuuli A,Hentilä Jaakko,Penna Fabio,Lampinen Anita,Lautaoja Juulia H,Fachada Vasco,Holopainen Tanja,Ritvos Olli,Kivelä Riikka,Hulmi Juha J Journal of cachexia, sarcopenia and muscle BACKGROUND:Cancer cachexia increases morbidity and mortality, and blocking of activin receptor ligands has improved survival in experimental cancer. However, the underlying mechanisms have not yet been fully uncovered. METHODS:The effects of blocking activin receptor type 2 (ACVR2) ligands on both muscle and non-muscle tissues were investigated in a preclinical model of cancer cachexia using a recombinant soluble ACVR2B (sACVR2B-Fc). Treatment with sACVR2B-Fc was applied either only before the tumour formation or with continued treatment both before and after tumour formation. The potential roles of muscle and non-muscle tissues in cancer cachexia were investigated in order to understand the possible mechanisms of improved survival mediated by ACVR2 ligand blocking. RESULTS:Blocking of ACVR2 ligands improved survival in tumour-bearing mice only when the mice were treated both before and after the tumour formation. This occurred without effects on tumour growth, production of pro-inflammatory cytokines or the level of physical activity. ACVR2 ligand blocking was associated with increased muscle (limb and diaphragm) mass and attenuation of both hepatic protein synthesis and splenomegaly. Especially, the effects on the liver and the spleen were observed independent of the treatment protocol. The prevention of splenomegaly by sACVR2B-Fc was not explained by decreased markers of myeloid-derived suppressor cells. Decreased tibialis anterior, diaphragm, and heart protein synthesis were observed in cachectic mice. This was associated with decreased mechanistic target of rapamycin (mTOR) colocalization with late-endosomes/lysosomes, which correlated with cachexia and reduced muscle protein synthesis. CONCLUSIONS:The prolonged survival with continued ACVR2 ligand blocking could potentially be attributed in part to the maintenance of limb and respiratory muscle mass, but many observed non-muscle effects suggest that the effect may be more complex than previously thought. Our novel finding showing decreased mTOR localization in skeletal muscle with lysosomes/late-endosomes in cancer opens up new research questions and possible treatment options for cachexia. 10.1002/jcsm.12310
    Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour-bearing mice. Brown Jacob L,Rosa-Caldwell Megan E,Lee David E,Blackwell Thomas A,Brown Lemuel A,Perry Richard A,Haynie Wesley S,Hardee Justin P,Carson James A,Wiggs Michael P,Washington Tyrone A,Greene Nicholas P Journal of cachexia, sarcopenia and muscle BACKGROUND:Cancer cachexia is largely irreversible, at least via nutritional means, and responsible for 20-40% of cancer-related deaths. Therefore, preventive measures are of primary importance; however, little is known about muscle perturbations prior to onset of cachexia. Cancer cachexia is associated with mitochondrial degeneration; yet, it remains to be determined if mitochondrial degeneration precedes muscle wasting in cancer cachexia. Therefore, our purpose was to determine if mitochondrial degeneration precedes cancer-induced muscle wasting in tumour-bearing mice. METHODS:First, weight-stable (MinStable) and cachectic (MinCC) Apc mice were compared with C57Bl6/J controls for mRNA contents of mitochondrial quality regulators in quadriceps muscle. Next, Lewis lung carcinoma (LLC) cells or PBS (control) were injected into the hind flank of C57Bl6/J mice at 8 week age, and tumour allowed to develop for 1, 2, 3, or 4 weeks to examine time course of cachectic development. Succinate dehydrogenase stain was used to measure oxidative phenotype in tibialis anterior muscle. Mitochondrial quality and function were assessed using the reporter MitoTimer by transfection to flexor digitorum brevis and mitochondrial function/ROS emission in permeabilized adult myofibres from plantaris. RT-qPCR and immunoblot measured the expression of mitochondrial quality control and antioxidant proteins. Data were analysed by one-way ANOVA with Student-Newman-Kuels post hoc test. RESULTS:MinStable mice displayed ~50% lower Pgc-1α, Pparα, and Mfn2 compared with C57Bl6/J controls, whereas MinCC exhibited 10-fold greater Bnip3 content compared with C57Bl6/J controls. In LLC, cachectic muscle loss was evident only at 4 weeks post-tumour implantation. Oxidative capacity and mitochondrial content decreased by ~40% 4 weeks post-tumour implantation. Mitochondrial function decreased by ~25% by 3 weeks after tumour implantation. Mitochondrial degeneration was evident by 2 week LLC compared with PBS control, indicated by MitoTimer red/green ratio and number of pure red puncta. Mitochondrial ROS production was elevated by ~50 to ~100% when compared with PBS at 1-3 weeks post-tumour implantation. Mitochondrial quality control was dysregulated throughout the progression of cancer cachexia in tumour-bearing mice. In contrast, antioxidant proteins were not altered in cachectic muscle wasting. CONCLUSIONS:Functional mitochondrial degeneration is evident in LLC tumour-bearing mice prior to muscle atrophy. Contents of mitochondrial quality regulators across Apc and LLC mice suggest impaired mitochondrial quality control as a commonality among pre-clinical models of cancer cachexia. Our data provide novel evidence for impaired mitochondrial health prior to cachectic muscle loss and provide a potential therapeutic target to prevent cancer cachexia. 10.1002/jcsm.12232
    Establishment and characterization of a novel murine model of pancreatic cancer cachexia. Michaelis Katherine A,Zhu Xinxia,Burfeind Kevin G,Krasnow Stephanie M,Levasseur Peter R,Morgan Terry K,Marks Daniel L Journal of cachexia, sarcopenia and muscle BACKGROUND:Cachexia is a complex metabolic and behavioural syndrome lacking effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is one of the most important conditions associated with cachexia, with >80% of PDAC patients suffering from the condition. To establish the cardinal features of a murine model of PDAC-associated cachexia, we characterized the effects of implanting a pancreatic tumour cell line from a syngeneic C57BL/6 KRAS P53 Pdx-Cre (KPC) mouse. METHODS:Male and female C57BL/6 mice were inoculated subcutaneously, intraperitoneally, or orthotopically with KPC tumour cells. We performed rigorous phenotypic, metabolic, and behavioural analysis of animals over the course of tumour development. RESULTS:All routes of administration produced rapidly growing tumours histologically consistent with moderate to poorly differentiated PDAC. The phenotype of this model was dependent on route of administration, with orthotopic and intraperitoneal implantation inducing more severe cachexia than subcutaneous implantation. KPC tumour growth decreased food intake, decreased adiposity and lean body mass, and decreased locomotor activity. Muscle catabolism was observed in both skeletal and cardiac muscles, but the dominant catabolic pathway differed between these tissues. The wasting syndrome in this model was accompanied by hypothalamic inflammation, progressively decreasing brown and white adipose tissue uncoupling protein 1 (Ucp1) expression, and increased peripheral inflammation. Haematological and endocrine abnormalities included neutrophil-dominant leukocytosis and anaemia, and decreased serum testosterone. CONCLUSIONS:Syngeneic KPC allografts are a robust model for studying cachexia, which recapitulate key features of the PDAC disease process and induce a wide array of cachexia manifestations. This model is therefore ideally suited for future studies exploring the physiological systems involved in cachexia and for preclinical studies of novel therapies. 10.1002/jcsm.12225
    Metabolism: WAT browning--key feature of cancer-associated cachexia. Holmes David Nature reviews. Endocrinology 10.1038/nrendo.2014.134
    Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia. Fukawa Tomoya,Yan-Jiang Benjamin Chua,Min-Wen Jason Chua,Jun-Hao Elwin Tan,Huang Dan,Qian Chao-Nan,Ong Pauline,Li Zhimei,Chen Shuwen,Mak Shi Ya,Lim Wan Jun,Kanayama Hiro-Omi,Mohan Rosmin Elsa,Wang Ruiqi Rachel,Lai Jiunn Herng,Chua Clarinda,Ong Hock Soo,Tan Ker-Kan,Ho Ying Swan,Tan Iain Beehuat,Teh Bin Tean,Shyh-Chang Ng Nature medicine Cachexia is a devastating muscle-wasting syndrome that occurs in patients who have chronic diseases. It is most commonly observed in individuals with advanced cancer, presenting in 80% of these patients, and it is one of the primary causes of morbidity and mortality associated with cancer. Additionally, although many people with cachexia show hypermetabolism, the causative role of metabolism in muscle atrophy has been unclear. To understand the molecular basis of cachexia-associated muscle atrophy, it is necessary to develop accurate models of the condition. By using transcriptomics and cytokine profiling of human muscle stem cell-based models and human cancer-induced cachexia models in mice, we found that cachectic cancer cells secreted many inflammatory factors that rapidly led to high levels of fatty acid metabolism and to the activation of a p38 stress-response signature in skeletal muscles, before manifestation of cachectic muscle atrophy occurred. Metabolomics profiling revealed that factors secreted by cachectic cancer cells rapidly induce excessive fatty acid oxidation in human myotubes, which leads to oxidative stress, p38 activation and impaired muscle growth. Pharmacological blockade of fatty acid oxidation not only rescued human myotubes, but also improved muscle mass and body weight in cancer cachexia models in vivo. Therefore, fatty acid-induced oxidative stress could be targeted to prevent cancer-induced cachexia. 10.1038/nm.4093
    Cancer cachexia: mediators, signaling, and metabolic pathways. Fearon Kenneth C H,Glass David J,Guttridge Denis C Cell metabolism Cancer cachexia is characterized by a significant reduction in body weight resulting predominantly from loss of adipose tissue and skeletal muscle. Cachexia causes reduced cancer treatment tolerance and reduced quality and length of life, and remains an unmet medical need. Therapeutic progress has been impeded, in part, by the marked heterogeneity of mediators, signaling, and metabolic pathways both within and between model systems and the clinical syndrome. Recent progress in understanding conserved, molecular mechanisms of skeletal muscle atrophy/hypertrophy has provided a downstream platform for circumventing the variations and redundancy in upstream mediators and may ultimately translate into new targeted therapies. 10.1016/j.cmet.2012.06.011
    Energy metabolism in cachexia. Rohm Maria,Zeigerer Anja,Machado Juliano,Herzig Stephan EMBO reports Cachexia is a wasting disorder that accompanies many chronic diseases including cancer and results from an imbalance of energy requirements and energy uptake. In cancer cachexia, tumor-secreted factors and/or tumor-host interactions cause this imbalance, leading to loss of adipose tissue and skeletal and cardiac muscle, which weakens the body. In this review, we discuss how energy enters the body and is utilized by the different organs, including the gut, liver, adipose tissue, and muscle, and how these organs contribute to the energy wasting observed in cachexia. We also discuss futile cycles both between the organs and within the cells, which are often used to fine-tune energy supply under physiologic conditions. Ultimately, understanding the complex interplay of pathologic energy-wasting circuits in cachexia can bring us closer to identifying effective treatment strategies for this devastating wasting disease. 10.15252/embr.201847258
    Cancer-associated cachexia. Baracos Vickie E,Martin Lisa,Korc Murray,Guttridge Denis C,Fearon Kenneth C H Nature reviews. Disease primers Cancer-associated cachexia is a disorder characterized by loss of body weight with specific losses of skeletal muscle and adipose tissue. Cachexia is driven by a variable combination of reduced food intake and metabolic changes, including elevated energy expenditure, excess catabolism and inflammation. Cachexia is highly associated with cancers of the pancreas, oesophagus, stomach, lung, liver and bowel; this group of malignancies is responsible for half of all cancer deaths worldwide. Cachexia involves diverse mediators derived from the cancer cells and cells within the tumour microenvironment, including inflammatory and immune cells. In addition, endocrine, metabolic and central nervous system perturbations combine with these mediators to elicit catabolic changes in skeletal and cardiac muscle and adipose tissue. At the tissue level, mechanisms include activation of inflammation, proteolysis, autophagy and lipolysis. Cachexia associates with a multitude of morbidities encompassing functional, metabolic and immune disorders as well as aggravated toxicity and complications of cancer therapy. Patients experience impaired quality of life, reduced physical, emotional and social well-being and increased use of healthcare resources. To date, no effective medical intervention completely reverses cachexia and there are no approved drug therapies. Adequate nutritional support remains a mainstay of cachexia therapy, whereas drugs that target overactivation of catabolic processes, cell injury and inflammation are currently under investigation. 10.1038/nrdp.2017.105
    Cancer and heart failure-more than meets the eye: common risk factors and co-morbidities. Anker Markus S,von Haehling Stephan,Landmesser Ulf,Coats Andrew J S,Anker Stefan D European journal of heart failure 10.1002/ejhf.1252
    Cachexia in patients with oesophageal cancer. Anandavadivelan Poorna,Lagergren Pernilla Nature reviews. Clinical oncology Oesophageal cancer is a debilitating disease with a poor prognosis, and weight loss owing to malnutrition prevails in the majority of patients. Cachexia, a multifactorial syndrome characterized by the loss of fat and skeletal muscle mass and systemic inflammation arising from complex host-tumour interactions is a major contributor to malnutrition, which is a determinant of tolerance to treatment and survival. In patients with oesophageal cancer, cachexia is further compounded by eating difficulties owing to the stage and location of the tumour, and the effects of neoadjuvant therapy. Treatment with curative intent involves exceptionally extensive and invasive surgery, and the subsequent anatomical changes often lead to eating difficulties and severe postoperative malnutrition. Thus, screening for cachexia by means of percentage weight loss and BMI during the cancer trajectory and survivorship periods is imperative. Additionally, markers of inflammation (such as C-reactive protein), dysphagia and appetite loss should be assessed at diagnosis. Routine assessments of body composition are also necessary in patients with oesophageal cancer to enable assessment of skeletal muscle loss, which might be masked by sarcopenic obesity in these patients. A need exists for clinical trials examining the effectiveness of therapeutic and physical-activity-based interventions in mitigating muscle loss and counteracting cachexia in these patients. 10.1038/nrclinonc.2015.200
    Cancer diagnosis in patients with heart failure: epidemiology, clinical implications and gaps in knowledge. Ameri Pietro,Canepa Marco,Anker Markus S,Belenkov Yury,Bergler-Klein Jutta,Cohen-Solal Alain,Farmakis Dimitrios,López-Fernández Teresa,Lainscak Mitja,Pudil Radek,Ruschitska Frank,Seferovic Petar,Filippatos Gerasimos,Coats Andrew,Suter Thomas,Von Haehling Stephan,Ciardiello Fortunato,de Boer Rudolf A,Lyon Alexander R,Tocchetti Carlo G, European journal of heart failure Cancer and heart failure (HF) are common medical conditions with a steadily rising prevalence in industrialized countries, particularly in the elderly, and they both potentially carry a poor prognosis. A new diagnosis of malignancy in subjects with pre-existing HF is not infrequent, and challenges HF specialists as well as oncologists with complex questions relating to both HF and cancer management. An increased incidence of cancer in patients with established HF has also been suggested. This review paper summarizes the epidemiology and the prognostic implications of cancer occurrence in HF, the impact of pre-existing HF on cancer treatment decisions and the impact of cancer on HF therapeutic options, while providing some practical suggestions regarding patient care and highlighting gaps in knowledge. 10.1002/ejhf.1165
    The TLR7/8 agonist R848 remodels tumor and host responses to promote survival in pancreatic cancer. Michaelis Katherine A,Norgard Mason A,Zhu Xinxia,Levasseur Peter R,Sivagnanam Shamilene,Liudahl Shannon M,Burfeind Kevin G,Olson Brennan,Pelz Katherine R,Angeles Ramos Diana M,Maurer H Carlo,Olive Kenneth P,Coussens Lisa M,Morgan Terry K,Marks Daniel L Nature communications A priority in cancer research is to innovate therapies that are not only effective against tumor progression but also address comorbidities such as cachexia that limit quality and quantity of life. We demonstrate that TLR7/8 agonist R848 induces anti-tumor responses and attenuates cachexia in murine models of pancreatic ductal adenocarcinoma (PDAC). In vivo, tumors from two of three cell lines were R848-sensitive, resulting in smaller tumor mass, increased immune complexity, increased CD8 T-cell infiltration and activity, and decreased Treg frequency. R848-treated mice demonstrated improvements in behavioral and molecular cachexia manifestations, resulting in a near-doubling of survival duration. Knockout mouse studies revealed that stromal, not neoplastic, TLR7 is requisite for R848-mediated responses. In patient samples, we found Tlr7 is ubiquitously expressed in stroma across all stages of pancreatic neoplasia, but epithelial Tlr7 expression is relatively uncommon. These studies indicate immune-enhancing approaches including R848 may be useful in PDAC and cancer-associated cachexia. 10.1038/s41467-019-12657-w
    Depletion of HuR in murine skeletal muscle enhances exercise endurance and prevents cancer-induced muscle atrophy. Janice Sánchez Brenda,Tremblay Anne-Marie K,Leduc-Gaudet Jean-Philippe,Hall Derek T,Kovacs Erzsebet,Ma Jennifer F,Mubaid Souad,Hallauer Patricia L,Phillips Brittany L,Vest Katherine E,Corbett Anita H,Kontoyiannis Dimitris L,Hussain Sabah N A,Hastings Kenneth E M,Di Marco Sergio,Gallouzi Imed-Eddine Nature communications The master posttranscriptional regulator HuR promotes muscle fiber formation in cultured muscle cells. However, its impact on muscle physiology and function in vivo is still unclear. Here, we show that muscle-specific HuR knockout (muHuR-KO) mice have high exercise endurance that is associated with enhanced oxygen consumption and carbon dioxide production. muHuR-KO mice exhibit a significant increase in the proportion of oxidative type I fibers in several skeletal muscles. HuR mediates these effects by collaborating with the mRNA decay factor KSRP to destabilize the PGC-1α mRNA. The type I fiber-enriched phenotype of muHuR-KO mice protects against cancer cachexia-induced muscle loss. Therefore, our study uncovers that under normal conditions HuR modulates muscle fiber type specification by promoting the formation of glycolytic type II fibers. We also provide a proof-of-principle that HuR expression can be targeted therapeutically in skeletal muscles to combat cancer-induced muscle wasting. 10.1038/s41467-019-12186-6
    Epigenetic targeting of bromodomain protein BRD4 counteracts cancer cachexia and prolongs survival. Segatto Marco,Fittipaldi Raffaella,Pin Fabrizio,Sartori Roberta,Dae Ko Kyung,Zare Hossein,Fenizia Claudio,Zanchettin Gianpietro,Pierobon Elisa Sefora,Hatakeyama Shinji,Sperti Cosimo,Merigliano Stefano,Sandri Marco,Filippakopoulos Panagis,Costelli Paola,Sartorelli Vittorio,Caretti Giuseppina Nature communications Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although it is responsible for approximately one-third of cancer deaths, no effective therapies are available and the underlying mechanisms have not been fully elucidated. We previously identified the bromodomain and extra-terminal domain (BET) protein BRD4 as an epigenetic regulator of muscle mass. Here we show that the pan-BET inhibitor (+)-JQ1 protects tumor-bearing mice from body weight loss and muscle and adipose tissue wasting. Remarkably, in C26-tumor-bearing mice (+)-JQ1 administration dramatically prolongs survival, without directly affecting tumor growth. By ChIP-seq and ChIP analyses, we unveil that BET proteins directly promote the muscle atrophy program during cachexia. In addition, BET proteins are required to coordinate an IL6-dependent AMPK nuclear signaling pathway converging on FoxO3 transcription factor. Overall, these findings indicate that BET proteins may represent a promising therapeutic target in the management of cancer cachexia. 10.1038/s41467-017-01645-7
    Tumor induces muscle wasting in mice through releasing extracellular Hsp70 and Hsp90. Zhang Guohua,Liu Zhelong,Ding Hui,Zhou Yong,Doan Hoang Anh,Sin Ka Wai Thomas,Zhu Zhiren J,Flores Rene,Wen Yefei,Gong Xing,Liu Qingyun,Li Yi-Ping Nature communications Cachexia, characterized by muscle wasting, is a major contributor to cancer-related mortality. However, the key cachexins that mediate cancer-induced muscle wasting remain elusive. Here, we show that tumor-released extracellular Hsp70 and Hsp90 are responsible for tumor's capacity to induce muscle wasting. We detected high-level constitutive release of Hsp70 and Hsp90 associated with extracellular vesicles (EVs) from diverse cachexia-inducing tumor cells, resulting in elevated serum levels in mice. Neutralizing extracellular Hsp70/90 or silencing Hsp70/90 expression in tumor cells abrogates tumor-induced muscle catabolism and wasting in cultured myotubes and in mice. Conversely, administration of recombinant Hsp70 and Hsp90 recapitulates the catabolic effects of tumor. In addition, tumor-released Hsp70/90-expressing EVs are necessary and sufficient for tumor-induced muscle wasting. Further, Hsp70 and Hsp90 induce muscle catabolism by activating TLR4, and are responsible for elevation of circulating cytokines. These findings identify tumor-released circulating Hsp70 and Hsp90 as key cachexins causing muscle wasting in mice.Cachexia affects many cancer patients causing weight loss and increasing mortality. Here, the authors identify extracellular Hsp70 and Hsp90, either in soluble form or secreted as part of exosomes from tumor cells, to be responsible for tumor induction of cachexia. 10.1038/s41467-017-00726-x
    Tumour-originated exosomal miR-155 triggers cancer-associated cachexia to promote tumour progression. Wu Qi,Sun Si,Li Zhiyu,Yang Qian,Li Bei,Zhu Shan,Wang Lijun,Wu Juan,Yuan Jingping,Yang Changhua,Li Juanjuan,Sun Shengrong Molecular cancer Emerging evidence supports the pivotal roles of cancer-associated cachexia in breast cancer progression. However, the mediators and mechanisms that mediate cancer-induced cachexia remain unclear. Here, we show that breast cancer-derived exosomes alter adipocytes and muscle cells in terms of increased catabolism characterized by the release of metabolites. Likewise, tumour cells cocultivated with mature adipocytes or C2C12 exhibit an aggressive phenotype through inducing epithelial-mesenchymal transition. Mechanistically, we show that cancer cell-secreted miR-155 promotes beige/brown differentiation and remodel metabolism in resident adipocytes by downregulating the PPARγ expression, but does not significantly affect biological conversion in C2C12. In vitro the use of propranolol ameliorates tumour exosomes-associated cachectic wasting through upregulating the PPARγ expression. These results demonstrate that cancer-derived exosomes reprogram systemic energy metabolism and accelerate cancer-associated cachexia to facilitate tumour progression. 10.1186/s12943-018-0899-5
    Smad7 gene delivery prevents muscle wasting associated with cancer cachexia in mice. Winbanks Catherine E,Murphy Kate T,Bernardo Bianca C,Qian Hongwei,Liu Yingying,Sepulveda Patricio V,Beyer Claudia,Hagg Adam,Thomson Rachel E,Chen Justin L,Walton Kelly L,Loveland Kate L,McMullen Julie R,Rodgers Buel D,Harrison Craig A,Lynch Gordon S,Gregorevic Paul Science translational medicine Patients with advanced cancer often succumb to complications arising from striated muscle wasting associated with cachexia. Excessive activation of the type IIB activin receptor (ActRIIB) is considered an important mechanism underlying this wasting, where circulating procachectic factors bind ActRIIB and ultimately lead to the phosphorylation of SMAD2/3. Therapeutics that antagonize the binding of ActRIIB ligands are in clinical development, but concerns exist about achieving efficacy without off-target effects. To protect striated muscle from harmful ActRIIB signaling, and to reduce the risk of off-target effects, we developed an intervention using recombinant adeno-associated viral vectors (rAAV vectors) that increase expression of Smad7 in skeletal and cardiac muscles. SMAD7 acts as an intracellular negative regulator that prevents SMAD2/3 activation and promotes degradation of ActRIIB complexes. In mouse models of cachexia, rAAV:Smad7 prevented wasting of skeletal muscles and the heart independent of tumor burden and serum levels of procachectic ligands. Mechanistically, rAAV:Smad7 administration abolished SMAD2/3 signaling downstream of ActRIIB and inhibited expression of the atrophy-related ubiquitin ligases MuRF1 and MAFbx. These findings identify muscle-directed Smad7 gene delivery as a potential approach for preventing muscle wasting under conditions where excessive ActRIIB signaling occurs, such as cancer cachexia. 10.1126/scitranslmed.aac4976
    Inter-tissue communication in cancer cachexia. Argilés Josep M,Stemmler Britta,López-Soriano Francisco J,Busquets Silvia Nature reviews. Endocrinology Cachexia is a systemic condition that occurs during many neoplastic diseases, such as cancer. Cachexia in cancer is characterized by loss of body weight and muscle and by adipose tissue wasting and systemic inflammation. Cancer cachexia is often associated with anorexia and increased energy expenditure. Even though the cachectic condition severely affects skeletal muscle, a tissue that accounts for ~40% of total body weight, it represents a multi-organ syndrome that involves tissues and organs such as white adipose tissue, brown adipose tissue, bone, brain, liver, gut and heart. Indeed, evidence suggests that non-muscle tissues and organs, as well as tumour tissues, secrete soluble factors that act on skeletal muscle to promote wasting. In addition, muscle tissue also releases various factors that can interact with the metabolism of other tissues during cancer. In this Review, we examine the effect of non-muscle tissues and inter-tissue communication in cancer cachexia and discuss studies aimed at developing novel therapeutic strategies for the condition. 10.1038/s41574-018-0123-0
    Understanding cachexia in the context of metastatic progression. Biswas Anup K,Acharyya Swarnali Nature reviews. Cancer Tumours reprogram host physiology, metabolism and immune responses during cancer progression. The release of soluble factors, exosomes and metabolites from tumours leads to systemic changes in distant organs, where cancer cells metastasize and grow. These tumour-derived circulating factors also profoundly impact tissues that are rarely inhabited by metastatic cancer cells such as skeletal muscle and adipose tissue. In fact, the majority of patients with metastatic cancer develop a debilitating muscle-wasting syndrome, known as cachexia, that is associated with decreased tolerance to antineoplastic therapy, poor prognosis and accelerated death, with no approved treatments. In this Perspective, we discuss the development of cachexia in the context of metastatic progression. We briefly discuss how circulating factors either directly or indirectly promote cachexia development and examine how signals from the metastatic process can trigger and amplify this process. Finally, we highlight promising therapeutic opportunities for targeting cachexia in the context of metastatic cancers. 10.1038/s41568-020-0251-4
    The clinical significance of interleukin-6 in heart failure: results from the BIOSTAT-CHF study. Markousis-Mavrogenis George,Tromp Jasper,Ouwerkerk Wouter,Devalaraja Matt,Anker Stefan D,Cleland John G,Dickstein Kenneth,Filippatos Gerasimos S,van der Harst Pim,Lang Chim C,Metra Marco,Ng Leong L,Ponikowski Piotr,Samani Nilesh J,Zannad Faiez,Zwinderman Aeilko H,Hillege Hans L,van Veldhuisen Dirk J,Kakkar Rahul,Voors Adriaan A,van der Meer Peter European journal of heart failure AIMS:Inflammation is a central process in the pathophysiology of heart failure (HF), but trials targeting tumour necrosis factor (TNF)-α were largely unsuccessful. Interleukin (IL)-6 is an important inflammatory mediator and might constitute a potential pharmacologic target in HF. However, little is known regarding the association between IL-6 and clinical characteristics, outcomes and other inflammatory biomarkers in HF. We thus aimed to identify and characterize these associations. METHODS AND RESULTS:Interleukin-6 was measured in 2329 patients [89.4% with a left ventricular ejection fraction (LVEF) ≤ 40%] of the BIOSTAT-CHF cohort. The primary outcome was all-cause mortality and HF hospitalization during 2 years, with all-cause, cardiovascular (CV), and non-CV death as secondary outcomes. Approximately half (56%) of all included patients had plasma IL-6 values greater than the previously determined 95th percentile of normal values at baseline. Elevated N-terminal pro-brain natriuretic peptide, procalcitonin and hepcidin, younger age, TNF-α/IL-1-related biomarkers, or having iron deficiency, atrial fibrillation and LVEF > 40% independently predicted elevated IL-6 levels. IL-6 independently predicted the primary outcome [HR (95% confidence interval) per doubling: 1.16 (1.11-1.21), P < 0.001], all-cause mortality [1.22 (1.16-1.29), P < 0.001] and CV as well as non-CV mortality [1.16 (1.09-1.24), P < 0.001; 1.31 (1.18-1.45), P < 0.001], but did not improve discrimination in previously published risk models. CONCLUSIONS:In a large, heterogeneous cohort of HF patients, elevated IL-6 levels were found in more than 50% of patients and were associated with iron deficiency, reduced LVEF, atrial fibrillation and poorer clinical outcomes. These findings warrant further investigation of IL-6 as a potential therapeutic target in specific HF subpopulations. 10.1002/ejhf.1482