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Khamoui, Andy V., Dorota Tokmina-Roszyk, Harry B. Rossiter, Gregg B. Fields, and Nishant P. Visavadiya. "Hepatic proteome analysis reveals altered mitochondrial metabolism and suppressed acyl-CoA synthetase-1 in colon-26 tumor-induced cachexia." Physiological Genomics 52, no. 5 (2020): 203–16. http://dx.doi.org/10.1152/physiolgenomics.00124.2019.
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Cachexia is a life-threatening complication of cancer traditionally characterized by weight loss and muscle dysfunction. Cachexia, however, is a systemic disease that also involves remodeling of nonmuscle organs. The liver exerts major control over systemic metabolism, yet its role in cancer cachexia is not well understood. To advance the understanding of how the liver contributes to cancer cachexia, we used quantitative proteomics and bioinformatics to identify hepatic pathways and cellular processes dysregulated in mice with moderate and severe colon-26 tumor-induced cachexia; ~300 differentially expressed proteins identified during the induction of moderate cachexia were also differentially regulated in the transition to severe cachexia. KEGG pathway enrichment revealed representation by oxidative phosphorylation, indicating altered hepatic mitochondrial function as a common feature across cachexia severity. Glycogen catabolism was also observed in cachexic livers along with decreased pyruvate dehydrogenase protein X component (Pdhx), increased lactate dehydrogenase A chain (Ldha), and increased lactate transporter Mct1. Together this suggests altered lactate metabolism and transport in cachexic livers, which may contribute to energetically inefficient interorgan lactate cycling. Acyl-CoA synthetase-1 (ACSL1), known for activating long-chain fatty acids, was decreased in moderate and severe cachexia based on LC-MS/MS analysis and immunoblotting. ACSL1 showed strong linear relationships with percent body weight change and muscle fiber size (R2 = 0.73–0.76, P < 0.01). Mitochondrial coupling efficiency, which is compromised in cachexic livers to potentially increase energy expenditure and weight loss, also showed a linear relationship with ACSL1. Findings suggest altered mitochondrial and substrate metabolism of the liver in cancer cachexia, and possible hepatic targets for intervention.
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Mannelli, Michele, Tania Gamberi, Francesca Magherini, and Tania Fiaschi. "A Metabolic Change towards Fermentation Drives Cancer Cachexia in Myotubes." Biomedicines 9, no. 6 (2021): 698. http://dx.doi.org/10.3390/biomedicines9060698.
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Cachexia is a disorder associated with several pathologies, including cancer. In this paper, we describe how cachexia is induced in myotubes by a metabolic shift towards fermentation, and the block of this metabolic modification prevents the onset of the cachectic phenotype. Cachectic myotubes, obtained by the treatment with conditioned medium from murine colon carcinoma cells CT26, show increased glucose uptake, decreased oxygen consumption, altered mitochondria, and increased lactate production. Interestingly, the block of glycolysis by 2-deoxy-glucose or lactate dehydrogenase inhibition by oxamate prevents the induction of cachexia, thus suggesting that this metabolic change is greatly involved in cachexia activation. The treatment with 2-deoxy-glucose or oxamate induces positive effects also in mitochondria, where mitochondrial membrane potential and pyruvate dehydrogenase activity became similar to control myotubes. Moreover, in myotubes treated with interleukin-6, cachectic phenotype is associated with a fermentative metabolism, and the inhibition of lactate dehydrogenase by oxamate prevents cachectic features. The same results have been achieved by treating myotubes with conditioned media from human colon HCT116 and human pancreatic MIAPaCa-2 cancer cell lines, thus showing that what has been observed with murine-conditioned media is a wide phenomenon. These findings demonstrate that cachexia induction in myotubes is linked with a metabolic shift towards fermentation, and inhibition of lactate formation impedes cachexia and highlights lactate dehydrogenase as a possible new tool for counteracting the onset of this pathology.
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Archid, Solass, Tempfer, et al. "Cachexia Anorexia Syndrome and Associated Metabolic Dysfunction in Peritoneal Metastasis." International Journal of Molecular Sciences 20, no. 21 (2019): 5444. http://dx.doi.org/10.3390/ijms20215444.
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: Patients with peritoneal metastasis (PM) of gastrointestinal and gynecological origin present with a nutritional deficit characterized by increased resting energy expenditure (REE), loss of muscle mass, and protein catabolism. Progression of peritoneal metastasis, as with other advanced malignancies, is associated with cancer cachexia anorexia syndrome (CAS), involving poor appetite (anorexia), involuntary weight loss, and chronic inflammation. Eventual causes of mortality include dysfunctional metabolism and energy store exhaustion. Etiology of CAS in PM patients is multifactorial including tumor growth, host response, cytokine release, systemic inflammation, proteolysis, lipolysis, malignant small bowel obstruction, ascites, and gastrointestinal side effects of drug therapy (chemotherapy, opioids). Metabolic changes of CAS in PM relate more to a systemic inflammatory response than an adaptation to starvation. Metabolic reprogramming is required for cancer cells shed into the peritoneal cavity to resist anoikis (i.e., programmed cell death). Profound changes in hexokinase metabolism are needed to compensate ineffective oxidative phosphorylation in mitochondria. During the development of PM, hypoxia inducible factor-1α (HIF-1α) plays a key role in activating both aerobic and anaerobic glycolysis, increasing the uptake of glucose, lipid, and glutamine into cancer cells. HIF-1α upregulates hexokinase II, phosphoglycerate kinase 1 (PGK1), pyruvate dehydrogenase kinase (PDK), pyruvate kinase muscle isoenzyme 2 (PKM2), lactate dehydrogenase (LDH) and glucose transporters (GLUT) and promotes cytoplasmic glycolysis. HIF-1α also stimulates the utilization of glutamine and fatty acids as alternative energy substrates. Cancer cells in the peritoneal cavity interact with cancer-associated fibroblasts and adipocytes to meet metabolic demands and incorporate autophagy products for growth. Therapy of CAS in PM is challenging. Optimal nutritional intake alone including total parenteral nutrition is unable to reverse CAS. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) stabilized nutritional status in a significant proportion of PM patients. Agents targeting the mechanisms of CAS are under development.
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Michalak, Krzysztof Piotr, Agnieszka Maćkowska-Kędziora, Bogusław Sobolewski, and Piotr Woźniak. "Key Roles of Glutamine Pathways in Reprogramming the Cancer Metabolism." Oxidative Medicine and Cellular Longevity 2015 (2015): 1–14. http://dx.doi.org/10.1155/2015/964321.
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Glutamine (GLN) is commonly known as an important metabolite used for the growth of cancer cells but the effects of its intake in cancer patients are still not clear. However, GLN is the main substrate for DNA and fatty acid synthesis. On the other hand, it reduces the oxidative stress by glutathione synthesis stimulation, stops the process of cancer cachexia, and nourishes the immunological system and the intestine epithelium, as well. The current paper deals with possible positive effects of GLN supplementation and conditions that should be fulfilled to obtain these effects. The analysis of GLN metabolism suggests that the separation of GLN and carbohydrates in the diet can minimize simultaneous supply of ATP (from glucose) and NADPH2(from glutamine) to cancer cells. It should support to a larger extent the organism to fight against the cancer rather than the cancer cells. GLN cannot be considered the effective source of ATP for cancers with the impaired oxidative phosphorylation and pyruvate dehydrogenase inhibition. GLN intake restores decreased levels of glutathione in the case of chemotherapy and radiotherapy; thus, it facilitates regeneration processes of the intestine epithelium and immunological system.
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Sharma, Raj Kumar, Santosh Kumar Bharti, Balaji Krishnamachary, et al. "Abstract 6353: Metabolic changes in the spleen and pancreas induced by PDAC xenografts with or without glutamine transporter downregulation." Cancer Research 82, no. 12_Supplement (2022): 6353. http://dx.doi.org/10.1158/1538-7445.am2022-6353.
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Abstract Introduction: Our ongoing studies are focused on characterizing metabolic changes induced in the organs of mice with cachexia-inducing Pa04C human pancreatic cancer xenografts. Because pancreatic cancer cells are glutamine dependent [1], we downregulated the glutamine transporter SLC1A5 in Pa04C cells to determine if metabolic changes induced in the spleen and pancreas by Pa04C tumors were normalized when SLC1A5 was downregulated in these tumors. Metabolic patterns were characterized using high-resolution quantitative 1H magnetic resonance spectroscopy (MRS) of spleen and pancreas tissue obtained from normal mice and mice with Pa04C tumors and mice with Pa04C tumors with SLC1A5 downregulated. Method: Patient derived cachexia-inducing Pa04C pancreatic cancer cells were lentivirally transduced to express shRNA to stably downregulate SLC1A5. Mice were euthanized once tumors were ~500 mm3, the spleen and pancreas were excised and snap frozen. Snap frozen spleen (normal n= 5, Pa04C n= 11, Pa04C_SLC1A5 n= 10) and pancreas (normal n= 4, Pa04C n= 16, Pa04C_SLC1A5 n= 10) tissue samples were pulverized for dual phase extraction. The aqueous phase was used for 1H MRS analysis. Topspin 3.5 software was used for data processing and analyses. Results and Discussion: Significant downregulation of SLC1A5 mRNA and protein was confirmed in Pa04C_SLC1A5 cells and tumors. SLC1A5 downregulation resulted in significant growth delay and attenuation of weight loss. A comparison of normal mice vs empty vector/wild type tumor (EV/WT) bearing mice identified significant changes in succinate, aspartate and fumarate in the spleen, lactate, acetate, pyruvate, methionine, asparagine, creatine, choline phosphocholine, uracil, histidine and phenylalanine in the pancreas, with leucine, isoleucine, valine, alanine, glutamate, glutamine, glutathione, glycerophosphocholine, glycine, glucose and tyrosine commonly altered in the spleen and pancreas. A comparison of normal vs Pa04C_ SLC1A5 tumor bearing mice identified similar metabolic changes in the spleen and pancreas but these were reduced. Fumarate did not change in the spleen, and of the metabolic changes common to spleen and pancreas, glutamine did not change when tumor SLC1A5 was downregulated. Metabolite changes induced only in the pancreas were also similar to normal vs EV/WT with the exception of a change in glutamine with SLC1A5 downregulation and no change in lactate. Our data highlight the profound metabolic changes in spleen and pancreas metabolism that occur with growth of a cachexia-inducing pancreatic cancer xenograft, and the impact on these metabolic patterns as a result of downregulating the glutamine transporter in these cancer cells. The metabolic patterns identified in the spleen and pancreas may provide novel targets to reduce the morbidity from cachexia. Reference: 1. Son J et al, Nature. 2013;496(7443):101-5. Citation Format: Raj Kumar Sharma, Santosh Kumar Bharti, Balaji Krishnamachary, Yelena Mironchik, Paul Winnard Jr., Marie-France Penet, Zaver M. Bhujwalla. Metabolic changes in the spleen and pancreas induced by PDAC xenografts with or without glutamine transporter downregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6353.
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Muranaka, Hayato, Natalie Moshayedi, Andrew Eugene Hendifar, et al. "Plasma metabolomics to predict chemotherapy (CTX) response in advanced pancreatic cancer (PC) patients (pts) on enteral feeding for cachexia." Journal of Clinical Oncology 40, no. 4_suppl (2022): 600. http://dx.doi.org/10.1200/jco.2022.40.4_suppl.600.
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600 Background: We evaluated the potential of plasma metabolites as predictors of response to CTX in a prospective cohort of pts who received enteral feeding for cachexia and advanced PC. Methods: The PANCAX-1 (NCT02400398) prospective trial enrolled 31 cachectic advanced PC pts to receive jejunal tube peptide-based diet for 12 weeks (wks) who were planned for palliative CTX. Out of 16 evaluable pts, 62.5% receiving enteral feeding met the primary endpoint of weight stability at 12 wks. As part of an exploratory analysis of the PANCAX-1 trial, serial blood samples were collected at 3 predefined timepoints over 12 wks of enteral feeding. Up to 219 plasma metabolites were analyzed by mass spectrometry and high-performance liquid chromatography. Analytes were compared by relative area under the curve (AUC) and differences evaluated by two-sample t-tests. The mean AUC was used in pts with metabolites measured from > 1 timepoint of collection. Pts were stratified by stable disease (SD), partial response (PR), or progressive disease (PD) as best overall response to standard CTX. Results: Of 31 pts with advanced PC prospectively enrolled for enteral feeding, there were 55 blood samples collected from 28 pts available for plasma metabolomics. 20/28 (71%) pts received first-line CTX, the majority of whom (90%) received gemcitabine-based CTX. There were 2 PRs (7%) and 10 with SD (36%) as best response to CTX. Overall, there were statistically significant differences in levels of intermediates involved in multiple metabolic pathways including glycolysis, the tricarboxylic acid (TCA) cycle, fatty acid synthesis, and nucleoside synthesis in pts with PR/SD vs. PD to CTX (all p < 0.05). When stratified by CTX regimen, PD to 5-fluorouracil-based CTX (e.g., FOLFIRINOX) was associated with decreased levels of essential amino acids (AAs, L-leucine, L-methionine, L-tryptophan) and non-essential AAs (L-arginine, L-serine, L-tyrosine, all p < 0.05). For gemcitabine-based CTX (e.g., gemcitabine/nab-paclitaxel), PD was associated with increased levels of intermediates of glycolysis (pyruvate), TCA cycle (L-glutamate), nucleoside synthesis (xanthine), and bile acid metabolism (taurocholic acid, all p < 0.05). Conclusions: We are the first to demonstrate the feasibility of plasma metabolomics in a prospective cohort of advanced PC pts on enteral feeding as their primary source of nutrition. Metabolic signatures unique to FOLFIRINOX or gemcitabine/nab-paclitaxel may be predictive of response and warrant further study.
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Dalal, Shalini. "Lipid metabolism in cancer cachexia." Annals of Palliative Medicine 8, no. 1 (2019): 13–23. http://dx.doi.org/10.21037/apm.2018.10.01.
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Mulligan, HD, SA Beck, and MJ Tisdale. "Lipid metabolism in cancer cachexia." British Journal of Cancer 66, no. 1 (1992): 57–61. http://dx.doi.org/10.1038/bjc.1992.216.
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Penna, Fabio, Riccardo Ballarò, Marc Beltrá, Serena De Lucia, and Paola Costelli. "Modulating Metabolism to Improve Cancer-Induced Muscle Wasting." Oxidative Medicine and Cellular Longevity 2018 (2018): 1–11. http://dx.doi.org/10.1155/2018/7153610.
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Muscle wasting is one of the main features of cancer cachexia, a multifactorial syndrome frequently occurring in oncologic patients. The onset of cachexia is associated with reduced tolerance and response to antineoplastic treatments, eventually leading to clinical conditions that are not compatible with survival. Among the mechanisms underlying cachexia, protein and energy dysmetabolism play a major role. In this regard, several potential treatments have been proposed, mainly on the basis of promising results obtained in preclinical models. However, at present, no treatment yet reached validation to be used in the clinical practice, although several drugs are currently tested in clinical trials for their ability to improve muscle metabolism in cancer patients. Along this line, the results obtained in both experimental and clinical studies clearly show that cachexia can be effectively approached by a multidirectional strategy targeting nutrition, inflammation, catabolism, and inactivity at the same time. In the present study, approaches aimed to modulate muscle metabolism in cachexia will be reviewed.
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Dave, Dhwani T., and Bhoomika M. Patel. "Mitochondrial Metabolism in Cancer Cachexia: Novel Drug Target." Current Drug Metabolism 20, no. 14 (2020): 1141–53. http://dx.doi.org/10.2174/1389200220666190816162658.
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Background: Cancer cachexia is a metabolic syndrome prevalent in the majority of the advanced cancers and is associated with complications such as anorexia, early satiety, weakness, anaemia, and edema, thereby reducing performance and impairing quality of life. Skeletal muscle wasting is a characteristic feature of cancer-cachexia and mitochondria is responsible for regulating total protein turnover in skeletal muscle tissue. Methods: We carried out exhaustive search for cancer cachexia and role of mitochondria in the same in various databases. All the relevant articles were gathered and the pertinent information was extracted out and compiled which was further structured into different sub-sections. Results: Various findings on the mitochondrial alterations in connection to its disturbed normal physiology in various models of cancer-cachexia have been recently reported, suggesting a significant role of the organelle in the pathogenesis of the complications involved in the disorder. It has also been reported that reduced mitochondrial oxidative capacity is due to reduced mitochondrial biogenesis as well as altered balance between fusion and fission protein activities. Moreover, autophagy in mitochondria (termed as mitophagy) is reported to play an important role in cancer cachexia. Conclusions: The present review aims to put forth the changes occurring in mitochondria and hence explore possible targets which can be exploited in cancer-induced cachexia for treatment of such a debilitating condition.
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Zhong, Xiaoling, and Teresa A. Zimmers. "Sex Differences in Cancer Cachexia." Current Osteoporosis Reports 18, no. 6 (2020): 646–54. http://dx.doi.org/10.1007/s11914-020-00628-w.
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Abstract Purpose of Review Cachexia, a feature of cancer and other chronic diseases, is marked by progressive weight loss and skeletal muscle wasting. This review aims to highlight the sex differences in manifestations of cancer cachexia in patients, rodent models, and our current understanding of the potential mechanisms accounting for these differences. Recent Findings Male cancer patients generally have higher prevalence of cachexia, greater weight loss or muscle wasting, and worse outcomes compared with female cancer patients. Knowledge is increasing about sex differences in muscle fiber type and function, mitochondrial metabolism, global gene expression and signaling pathways, and regulatory mechanisms at the levels of sex chromosomes vs. sex hormones; however, it is largely undetermined how such sex differences directly affect the susceptibility to stressors leading to muscle wasting in cancer cachexia. Summary Few studies have investigated basic mechanisms underlying sex differences in cancer cachexia. A better understanding of sex differences would improve cachexia treatment in both sexes.
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Pisters, Peter W. T., and Murray F. Brennan. "Amino Acid Metabolism in Human Cancer Cachexia." Annual Review of Nutrition 10, no. 1 (1990): 107–32. http://dx.doi.org/10.1146/annurev.nu.10.070190.000543.
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Porporato, P. E. "Understanding cachexia as a cancer metabolism syndrome." Oncogenesis 5, no. 2 (2016): e200-e200. http://dx.doi.org/10.1038/oncsis.2016.3.
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Tisdale, Michael J. "Cancer anorexia and cachexia." Nutrition 17, no. 5 (2001): 438–42. http://dx.doi.org/10.1016/s0899-9007(01)00506-8.
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Lai, Shaoqing. "Review: The Commonality of Energy Metabolism of Starvation, Disorders of Glucose-Lipid Metabolism, Diabetes Mellitus and Cachexia." Journal of Biomedical Research & Environmental Sciences 3, no. 5 (2022): 552–55. http://dx.doi.org/10.37871/jbres1478.
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Diabetes mellitus, pathoglycemia, dyslipidemia, non-alcoholic fatty liver, overweight, hypertension, and atherosclerosis are common diseases endangering human health. Cachexia is a life-threatening disease condition. Cachexia is associated with increased mortality. Cancer patients with cachexia are less tolerant and have a decreased response to chemotherapy and radiation. Do these diseases have a common pathogenesis? We will discuss the commonality of energy metabolism in starvation, disorders of glucose-lipid metabolism, diabetes mellitus and cachexia, and how the stress response alters the pattern of energy metabolism.
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Iwagaki, Hiromi, Akio Hizuta, Yasuki Nitta, and Noriaki Tanaka. "Altered Tryptophan and Neopterin Metabolism In Cancer Patients." Pteridines 9, no. 1 (1998): 29–32. http://dx.doi.org/10.1515/pteridines.1998.9.1.29.
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Summary Plasma 5-hydroxytryptamine (serotonin), tryptophan and neopterin levels were measured in patients with depressive cancer cachexia and in healthy controls during the same time period. Patients with advanced cancers had significantly raised neopterin, a marker of endogenous gamma-interferon (IFN-γ) production, but decreased serotonin and tryptophan levels. IFN-γ induces a high level of indoleamine dioxvgenase (IDO), a tryptophan degrading enzyme, which in turn increases metabolism along the tryptophan- nicotinic acid pathway, resulting in decreased synthesis of serotonin. These results suggest that persistent immune activation occur in patients with cancer cachexia, resulting in disorders involving tryptophan metabolism.
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Bing, Chen, and Paul Trayhurn. "Regulation of adipose tissue metabolism in cancer cachexia." Current Opinion in Clinical Nutrition and Metabolic Care 11, no. 3 (2008): 201–7. http://dx.doi.org/10.1097/mco.0b013e3282f948e2.
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Tijerina, Amanda J. "The Biochemical Basis of Metabolism in Cancer Cachexia." Dimensions of Critical Care Nursing 23, no. 6 (2004): 237–43. http://dx.doi.org/10.1097/00003465-200411000-00001.
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NORTON, JEFFREY A. "Protein and Amino Acid Metabolism in Cancer Cachexia." Annals of Surgery 226, no. 1 (1997): 102–3. http://dx.doi.org/10.1097/00000658-199707000-00019.
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Camargo, Rodolfo Gonzalez, Henrique Quintas Teixeira Ribeiro, Murilo Vieira Geraldo, et al. "Cancer Cachexia and MicroRNAs." Mediators of Inflammation 2015 (2015): 1–5. http://dx.doi.org/10.1155/2015/367561.
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Cancer cachexia is a paraneoplastic syndrome compromising quality of life and survival, mainly characterized by involuntary weight loss, fatigue, and systemic inflammation. The syndrome is described as a result of tumor-host interactions characterized by an inflammatory response by the host to the presence of the tumor. Indeed, systemic inflammation is considered a pivotal feature in cachexia progression and maintenance. Cytokines are intimately related to chronic systemic inflammation and the mechanisms underlying the release of these factors are not totally elucidated, the etiology of cachexia being still not fully understood. Therefore, the understanding of cachexia-related mechanisms, as well as the establishment of markers for the syndrome, is very relevant. MicroRNAs (miRNAs) are a class of noncoding RNAs interfering with gene regulation. Different miRNA expression profiles are associated with different diseases and inflammatory processes. miRNAs modulate adipose and skeletal muscle tissue metabolism in cancer cachexia and also tumor and tissue derived inflammation. Therefore, we propose a possible role for miRNAs in the modulation of the host inflammatory response during cachexia. Moreover, the establishment of a robust body of evidence in regard to miRNAs and the mechanisms underlying cachexia is mandatory, and shall contribute to the improvement of its diagnosis and treatment.
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Luan, Yi, Mikyoung You, Pauline C. Xu, Tom Thompson, and So-Youn Kim. "Activin A Plays a Critical Role in Adipose Tissue Wasting in the Progression of Cancer Cachexia." Journal of the Endocrine Society 5, Supplement_1 (2021): A40. http://dx.doi.org/10.1210/jendso/bvab048.078.
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Abstract Background: Nearly 50% of cancer patients suffer from cancer cachexia, a wasting syndrome with atrophy of white adipose tissue (WAT) and skeletal muscle. Cachexia leads to negative energy balance, limits cancer therapies, and reduces survival rate. It is characterized by body weight loss due to negative nutrients and energy balance from involuntary reduced food intake and abnormal metabolic conditions such as insulin resistance and hypertriglyceridemia. Cancer-driven factors such as activin A and IL-6 (interlukein-6) contribute to the occurrence of cachexia symptoms during cancer progression. While the importance of muscle atrophy has been emphasized in cachexia research, the underlying mechanism of adipose tissue wasting remains unclear. One proposed theory is that WAT switches to brown adipose tissue (BAT), characterized by the high expression level of UCP1 (uncoupling protein 1). Hypothesis: We hypothesize that activin A plays a critical role in adipose tissue wasting during cancer cachexia progression. Experiment: GDF9-iCre+; PIK3CA* female mice which shows cachexia symptoms in cancer progression were sacrificed before and after cachexia development. In addition, we injected FST288, an antagonist to activin A, for two weeks during cancer cachexia development. We harvested and analyzed multi-sites adipose tissues (gonadal, subcutaneous, interscapular and perirenal), muscle and liver. Serum activin A and IL-6 were measured using ELISA kits. DEXA and calorimetry analyses were performed, as well as immunohistochemistry, qPCR and western blotting assay. Results:GDF9-iCre+; PIK3CA* female mice started to display bilateral ovarian tumors around postnatal day (PD) 60, lose body weight around PD70 and became cachexia condition around PD80 with an increased level of serum activin A. Along with that, other body organs including liver, pancreas, muscle, and adipose tissues became dramatically small in mass. Our data proved that cachexia progression is correlated with the level of activin A rather than IL-6 in serum of GDF9-iCre+; PIK3CA* female mice. As serum activin A increased, adipocytes lost lipids and had distinct browning phenotypes in some adipocytes within WAT. Interestingly, calorimetry analysis did not display an increase in energy expenditure in cachectic mice although browning was evident in WAT. However, treatment with FST288 during cancer progression kept body weight and WAT in GDF9-iCre+; PIK3CA* female mice. Most of all, FST288 protected the size and lipid droplets of adipose tissues against WAT wasting during cachexia development. Conclusion: The progression of cancer cachexia impacts adipose tissues. Injection of FST288 supports the key role of activin A in the progress of cachexia. FST288 prevented adipose tissue wasting and cachexia development, revealing another evidence of the efficacy of activin A antagonist in preventing cancer cachexia development.
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Rauckhorst, Adam J., and Eric B. Taylor. "Mitochondrial pyruvate carrier function and cancer metabolism." Current Opinion in Genetics & Development 38 (June 2016): 102–9. http://dx.doi.org/10.1016/j.gde.2016.05.003.
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Sørensen, Jonas. "Lung Cancer Cachexia: Can Molecular Understanding Guide Clinical Management?" Integrative Cancer Therapies 17, no. 3 (2018): 1000–1008. http://dx.doi.org/10.1177/1534735418781743.
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Cachexia has been recognized for a long time as an adverse effect of cancer. It is associated with reduced physical function, reduced tolerance to anticancer therapy, and reduced survival. This wasting syndrome is mainly known for an ongoing loss of skeletal muscle leading to progressive functional impairment and is driven by a variable combination of reduced food intake and abnormal metabolism. Cytokines derived from host immune system or the tumor itself is believed to play a role in promoting cancer cachexia. Circulating levels of cytokines, including IL-1α, IL-6, and TNFα have been identified in cancer patients but they probably only represent a small part of a changed and abnormal metabolism. Murine models have shown that browning of white adipose tissue (WAT) takes place early in the progression of cancer cachexia. Thus, browning of white adipose tissue is believed to be a strong contributor to the increased energy expenditure common in cachectic patients. Despite the severe implications of cancer cachexia for the patients and extensive research efforts, a more coherent and mechanistic explanation of the syndrome is lacking, and for many clinicians, cancer cachexia is still a vague concept. From a lung cancer perspective this commentary reviews the current knowledge on cancer cachexia mechanisms and identifies specific ways of clinical management regarding food intake, systemic inflammation, and muscular dysfunction. Much of what we know comes from preclinical studies. More translational research is needed for a future cancer cachexia screening tool to guide clinicians, and here possible variables for a cancer cachexia screening tool are considered.
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Argilés, Josep M., Britta Stemmler, Francisco J. López-Soriano, and Silvia Busquets. "Inter-tissue communication in cancer cachexia." Nature Reviews Endocrinology 15, no. 1 (2018): 9–20. http://dx.doi.org/10.1038/s41574-018-0123-0.
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Rosa-Caldwell, Megan E., Jacob L. Brown, David E. Lee, et al. "Hepatic alterations during the development and progression of cancer cachexia." Applied Physiology, Nutrition, and Metabolism 45, no. 5 (2020): 500–512. http://dx.doi.org/10.1139/apnm-2019-0407.
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Cancer-associated bodyweight loss (cachexia) is a hallmark of many cancers and is associated with decreased quality of life and increased mortality. Hepatic function can dramatically influence whole-body energy expenditure and may therefore significantly influence whole-body health during cancer progression. The purpose of this study was to examine alterations in markers of hepatic metabolism and physiology during cachexia progression. Male C57BL/6J mice were injected with 1 × 106 Lewis Lung Carcinoma cells dissolved in 100 μL PBS and cancer was allowed to develop for 1, 2, 3, or 4 weeks. Control animals were injected with an equal volume of phosphate-buffered saline. Livers were analyzed for measures of metabolism, collagen deposition, protein turnover, and mitochondrial quality. Animals at 4 weeks had ∼30% larger livers compared with all other groups. Cancer progression was associated with altered regulators of fat metabolism. Additionally, longer duration of cancer development was associated with ∼3-fold increased regulators of collagen deposition as well as phenotypic collagen content, suggesting increased liver fibrosis. Mitochondrial quality control regulators appeared to be altered before any phenotypic alterations to collagen deposition. While induction of Akt was noted, downstream markers of protein synthesis were not altered. In conclusions, cancer cachexia progression is associated with hepatic pathologies, specifically liver fibrosis. Alterations to mitochondrial quality control mechanisms appear to precede this fibrotic phenotype, potentially suggesting mitochondrial mechanisms for the development of hepatic pathologies during the development and progression of cancer cachexia. Novelty Cachexia progression results in liver collagen deposition and fibrosis. Alterations in mitochondrial quality control may precede liver pathologies during cachexia.
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Miyaguti, Natália Angelo da Silva, Gabriela de Matuoka e. Chiocchetti, Carla de Moraes Salgado, et al. "Walker-256 Tumour-Induced Cachexia Altered Liver Metabolomic Profile and Function in Weanling and Adult Rats." Metabolites 11, no. 12 (2021): 831. http://dx.doi.org/10.3390/metabo11120831.
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Cancer cachexia occurs in up to 85% of advanced cancer patients, affecting different tissues and organs, mainly the liver, which plays a central role in body metabolism control. However, liver responses to cancer cachexia progression are still poorly understood. Considering the possible different challenges provided by the rodent’s phase of life and the cachexia progression, we evaluated the liver metabolic alterations affected by Walker-256 tumour growth in weanling and young-adult rats. For this, we applied a metabolomics approach associated with protein and gene expression analyses. Higher amino acid levels and impaired glucose metabolism were important features in tumour-bearing animals’ liver tissue. The weanling hosts had more pronounced cachexia, with higher carcass spoliation, liver lipid metabolism and impaired CII and CIV mitochondrial complexes. The liver alterations in young adult tumour-bearing rats were related to energy status and nucleotide metabolites, such as uridine, NAD+, xanthosine, hypoxanthine and inosine. In conclusion, the Walker-256 tumour-induced cachexia impaired liver metabolism, being more severe in the weanling hosts. Further studies are needed to correlate these changes in the preclinical model, which can be correlated to the clinical features of cancer cachexia, allowing for a translational potential involving the liver function and its responses to potential treatments.
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Durham, William J., Edgar Lichar Dillon, and Melinda Sheffield-Moore. "Inflammatory burden and amino acid metabolism in cancer cachexia." Current Opinion in Clinical Nutrition and Metabolic Care 12, no. 1 (2009): 72–77. http://dx.doi.org/10.1097/mco.0b013e32831cef61.
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Reiter, Russel J. "Melatonin Reprograms Glucose Metabolism in Cancer Cell Mitochondria." Series of Endocrinology, Diabetes and Metabolism 1, no. 3 (2019): 52–61. http://dx.doi.org/10.54178/jsedmv1i3001.
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Melatonin has a long history of studies which confirm its ability to inhibit cancer growth. Melatonin is present in high concentrations in the mitochondria of normal cells but is likely absent from the mitochondria of cancer cells, at least when isolated from tumors harvested during the day. Herein, we hypothesize that melatonin’s absence from cancer cell mitochondria prevents these organelles from metabolizing pyruvate to acetyl coenzyme A (acetyl-CoA) due to suppression of the activity of the enzyme pyruvate dehydrogenase complex (PDC), the enzyme that catalyzes the conversion of pyruvate to acetyl-CoA. This causes cancer cells to metabolize glucose to lactate in the cytosol (the Warburg effect). Since cancer cell mitochondria can take up nighttime pineal-derived melatonin from the blood, the indoleamine predictably promotes the conversion of pyruvate to acetyl-CoA in the mitochondria during the night. Thus, while cancer cells exhibit a typical cancer phenotype during the day, at night cancer cells have a more normal cell phenotype. Via similar actions, melatonin probably overcomes the insensitivity of cancers to chemotherapies. Hopefully, the hypothetical processes proposed herein will soon be experimentally tested.
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Mitchell, Toni, Lewis Clarke, Alexandra Goldberg, and Karen S. Bishop. "Pancreatic Cancer Cachexia: The Role of Nutritional Interventions." Healthcare 7, no. 3 (2019): 89. http://dx.doi.org/10.3390/healthcare7030089.
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Pancreatic cancer is a cancer with one of the highest mortality rates and many pancreatic cancer patients present with cachexia at diagnosis. The definition of cancer cachexia is not consistently applied in the clinic or across studies. In general, it is “defined as a multifactorial syndrome characterised by an ongoing loss of skeletal muscle mass with or without loss of fat mass that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment.” Many regard cancer cachexia as being resistant to dietary interventions. Cachexia is associated with a negative impact on survival and quality of life. In this article, we outline some of the mechanisms of pancreatic cancer cachexia and discuss nutritional interventions to support the management of pancreatic cancer cachexia. Cachexia is driven by a combination of reduced appetite leading to reduced calorie intake, increased metabolism, and systemic inflammation driven by a combination of host cytokines and tumour derived factors. The ketogenic diet showed promising results, but these are yet to be confirmed in human clinical trials over the long-term. L-carnitine supplementation showed improved quality of life and an increase in lean body mass. As a first step towards preventing and managing pancreatic cancer cachexia, nutritional support should be provided through counselling and the provision of oral nutritional supplements to prevent and minimise loss of lean body mass.
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Argilés, Josep M., Francisco J. López-Soriano, and Silvia Busquets. "Mediators of cachexia in cancer patients." Nutrition 66 (October 2019): 11–15. http://dx.doi.org/10.1016/j.nut.2019.03.012.
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Madeddu, Clelia, Giulia Gramignano, Luciana Tanca, Maria Cristina Cherchi, Carlo Aurelio Floris, and Antonio Macciò. "A combined treatment approach for cachexia and cancer-related anemia in advanced cancer patients: A randomized placebo-controlled trial." Journal of Clinical Oncology 32, no. 31_suppl (2014): 189. http://dx.doi.org/10.1200/jco.2014.32.31_suppl.189.
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189 Background: Cancer progression is characterized by specific energy metabolism alterations and by symptoms including fatigue, anorexia, nausea, depression, which results in cachexia syndrome and compromised quality of life (QL). This condition is often associated to anemia (cancer-related anemia, CRA), which negatively impacts patient QL and disease outcome. Methods: Adult advanced cancer patients with cachexia (i.e., weight loss > 5% in the previous 6 months) and CRA were randomly assigned (1:1 by computer generated list) to receive 3 months of a combined approach consisting of celecoxib (200 mg/day), L-carnitine (2 g/day), curcumin (Meriva) (4 g/day) and lactoferrin (200 mg/day) or placebo. The rationale for selecting these agents was: L-carnitine for modulating cell energy metabolism; celecoxib for counteracting inflammation, which is a key feature of cachexia; curcumin for its antiinflammatory and antioxidant action, without disregarding its action on the NF-kB and JAK-STAT pathway and the related synthesis of proinflammatory cytokines; lactoferrin for its ability to regulate iron metabolism in anemic cancer patients. Primary endpoints were improvement of lean body mass (LBM), appetite, fatigue and anemia. Additionally, we assessed the impact of treatment on the main metabolic/inflammatory and iron metabolism parameters: C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor (TNF)-α, leptin, reactive oxygen species (ROS), glutathione peroxidase, serum iron, ferritin, hepcidin and erythropoietin (EPO). Results: From January 2013 to March 2014, 66 patients have been enrolled. The combination arm was more effective than placebo arm in improving body weight, LBM, appetite, fatigue, and anemia. Among secondary parameters IL-6, TNF-α, CRP, ROS, ferritin, hepcidin and EPO decreased, while leptin increased significantly in the combination arm. No significant changes were observed in the placebo arm. Conclusions: To date a standard effective treatment of cancer cachexia is lacking. Our combined multitargeted approach was able to improve the nutritional and immunometabolic alterations of cachexia, ameliorate patient QL and correct CRA.
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Dalise, Stefania, Peppino Tropea, Luca Galli, Andrea Sbrana, and Carmelo Chisari. "Muscle function impairment in cancer patients in pre-cachexia stage." European Journal of Translational Myology 30, no. 2 (2020): 258–67. http://dx.doi.org/10.4081/ejtm.2020.8931.
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Cancer cachexia has been reported to be directly responsible for at least 20% of cancer deaths. Management of muscle wasting in cancer-associated cachexia appears to be of pivotal importance for survival of patients. In this regard, it would be interesting to identify before its patent appearance eventual functional markers of muscle damage, to plan specific exercise protocols to counteract cachexia. The muscle function of 13 oncologic patients and 15 controls was analyzed through: i) analysis of the oxidative metabolism, indirectly evaluated trough dosage of blood lactate levels before and after a submaximal incremental exercise on a treadmill; ii) analysis of strength and, iii) endurance, in both lower and upper limbs muscles, employing an isokinetic dynamometer. Statistical analyses were carried out to compare the muscle activities between groups. Analysis of oxidative metabolism during the incremental exercise on a treadmill showed that patients performed a shorter exercise than controls. Lactate levels were significantly higher in patients both at baseline and after the task. Muscle strength analysis in patients group showed a reduction of Maximum Voluntary Contraction during the isometric contraction and, a tendency to fatigue during endurance task. Data emerging from this study highlight an impairment of muscle oxidative metabolism in subjects affected by a pre-cachexia stage of cancer. A trend of precocious fatigability and an impairment of muscle strength production were also observed. This evidence underlines the relevance of assessing muscle function in order to develop novel rehabilitative approaches able to counteract motor impairment and eventually to prevent cachexia in these patients.
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Giacosa, Attilio, and Mariangela Rondanelli. "Fish oil and treatment of cancer cachexia." Genes & Nutrition 3, no. 1 (2008): 25–28. http://dx.doi.org/10.1007/s12263-008-0078-1.
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van de Haterd, Britt, Kenneth Verboven, Frank Vandenabeele, and Anouk Agten. "The Role of Skeletal Muscle Mitochondria in Colorectal Cancer Related Cachexia: Friends or Foes?" International Journal of Molecular Sciences 23, no. 23 (2022): 14833. http://dx.doi.org/10.3390/ijms232314833.
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Up to 60% of colorectal cancer (CRC) patients develop cachexia. The presence of CRC related cachexia is associated with more adverse events during systemic therapy, leading to a high mortality rate. The main manifestation in CRC related cachexia is the loss of skeletal muscle mass, resulting from an imbalance between skeletal muscle protein synthesis and protein degradation. In CRC related cachexia, systemic inflammation, oxidative stress, and proteolytic systems lead to mitochondrial dysfunction, resulting in an imbalanced skeletal muscle metabolism. Mitochondria fulfill an important function in muscle maintenance. Thus, preservation of the skeletal muscle mitochondrial homeostasis may contribute to prevent the loss of muscle mass. However, it remains elusive whether mitochondria play a benign or malignant role in the development of cancer cachexia. This review summarizes current (mostly preclinical) evidence about the role of skeletal muscle mitochondria in the development of CRC related cachexia. Future human research is necessary to determine the physiological role of skeletal muscle mitochondria in the development of human CRC related cachexia.
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Donohoe, Claire L., Aoife M. Ryan, and John V. Reynolds. "Cancer Cachexia: Mechanisms and Clinical Implications." Gastroenterology Research and Practice 2011 (2011): 1–13. http://dx.doi.org/10.1155/2011/601434.
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Cachexia is a multifactorial process of skeletal muscle and adipose tissue atrophy resulting in progressive weight loss. It is associated with poor quality of life, poor physical function, and poor prognosis in cancer patients. It involves multiple pathways: procachectic and proinflammatory signals from tumour cells, systemic inflammation in the host, and widespread metabolic changes (increased resting energy expenditure and alterations in metabolism of protein, fat, and carbohydrate). Whether it is primarily driven by the tumour or as a result of the host response to the tumour has yet to be fully elucidated. Cachexia is compounded by anorexia and the relationship between these two entities has not been clarified fully. Inconsistencies in the definition of cachexia have limited the epidemiological characterisation of the condition and there has been slow progress in identifying therapeutic agents and trialling them in the clinical setting. Understanding the complex interplay of tumour and host factors will uncover new therapeutic targets.
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Petruzzelli, Michele, Miriam Ferrer, Martijn J. Schuijs, et al. "Early Neutrophilia Marked by Aerobic Glycolysis Sustains Host Metabolism and Delays Cancer Cachexia." Cancers 14, no. 4 (2022): 963. http://dx.doi.org/10.3390/cancers14040963.
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An elevated neutrophil–lymphocyte ratio negatively predicts the outcome of patients with cancer and is associated with cachexia, the terminal wasting syndrome. Here, using murine model systems of colorectal and pancreatic cancer we show that neutrophilia in the circulation and multiple organs, accompanied by extramedullary hematopoiesis, is an early event during cancer progression. Transcriptomic and metabolic assessment reveals that neutrophils in tumor-bearing animals utilize aerobic glycolysis, similar to cancer cells. Although pharmacological inhibition of aerobic glycolysis slows down tumor growth in C26 tumor-bearing mice, it precipitates cachexia, thereby shortening the overall survival. This negative effect may be explained by our observation that acute depletion of neutrophils in pre-cachectic mice impairs systemic glucose homeostasis secondary to altered hepatic lipid processing. Thus, changes in neutrophil number, distribution, and metabolism play an adaptive role in host metabolic homeostasis during cancer progression. Our findings provide insight into early events during cancer progression to cachexia, with implications for therapy.
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Ragni, Maurizio, Claudia Fornelli, Enzo Nisoli, and Fabio Penna. "Amino Acids in Cancer and Cachexia: An Integrated View." Cancers 14, no. 22 (2022): 5691. http://dx.doi.org/10.3390/cancers14225691.
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Rapid tumor growth requires elevated biosynthetic activity, supported by metabolic rewiring occurring both intrinsically in cancer cells and extrinsically in the cancer host. The Warburg effect is one such example, burning glucose to produce a continuous flux of biomass substrates in cancer cells at the cost of energy wasting metabolic cycles in the host to maintain stable glycemia. Amino acid (AA) metabolism is profoundly altered in cancer cells, which use AAs for energy production and for supporting cell proliferation. The peculiarities in cancer AA metabolism allow the identification of specific vulnerabilities as targets of anti-cancer treatments. In the current review, specific approaches targeting AAs in terms of either deprivation or supplementation are discussed. Although based on opposed strategies, both show, in vitro and in vivo, positive effects. Any AA-targeted intervention will inevitably impact the cancer host, who frequently already has cachexia. Cancer cachexia is a wasting syndrome, also due to malnutrition, that compromises the effectiveness of anti-cancer drugs and eventually causes the patient’s death. AA deprivation may exacerbate malnutrition and cachexia, while AA supplementation may improve the nutritional status, counteract cachexia, and predispose the patient to a more effective anti-cancer treatment. Here is provided an attempt to describe the AA-based therapeutic approaches that integrate currently distant points of view on cancer-centered and host-centered research, providing a glimpse of several potential investigations that approach cachexia as a unique cancer disease.
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Zangari, Joséphine, Francesco Petrelli, Benoît Maillot, and Jean-Claude Martinou. "The Multifaceted Pyruvate Metabolism: Role of the Mitochondrial Pyruvate Carrier." Biomolecules 10, no. 7 (2020): 1068. http://dx.doi.org/10.3390/biom10071068.
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Pyruvate, the end product of glycolysis, plays a major role in cell metabolism. Produced in the cytosol, it is oxidized in the mitochondria where it fuels the citric acid cycle and boosts oxidative phosphorylation. Its sole entry point into mitochondria is through the recently identified mitochondrial pyruvate carrier (MPC). In this review, we report the latest findings on the physiology of the MPC and we discuss how a dysfunctional MPC can lead to diverse pathologies, including neurodegenerative diseases, metabolic disorders, and cancer.
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Fonseca, Guilherme Wesley Peixoto da, Jerneja Farkas, Eva Dora, Stephan von Haehling, and Mitja Lainscak. "Cancer Cachexia and Related Metabolic Dysfunction." International Journal of Molecular Sciences 21, no. 7 (2020): 2321. http://dx.doi.org/10.3390/ijms21072321.
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Cancer cachexia is a complex multifactorial syndrome marked by a continuous depletion of skeletal muscle mass associated, in some cases, with a reduction in fat mass. It is irreversible by nutritional support alone and affects up to 74% of patients with cancer—dependent on the underlying type of cancer—and is associated with physical function impairment, reduced response to cancer-related therapy, and higher mortality. Organs, like muscle, adipose tissue, and liver, play an important role in the progression of cancer cachexia by exacerbating the pro- and anti-inflammatory response initially activated by the tumor and the immune system of the host. Moreover, this metabolic dysfunction is produced by alterations in glucose, lipids, and protein metabolism that, when maintained chronically, may lead to the loss of skeletal muscle and adipose tissue. Although a couple of drugs have yielded positive results in increasing lean body mass with limited impact on physical function, a single therapy has not lead to effective treatment of this condition. Therefore, a multimodal intervention, including pharmacological agents, nutritional support, and physical exercise, may be a reasonable approach for future studies to better understand and prevent the wasting of body compartments in patients with cancer cachexia.
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Nixon, Daniel W. "Cancer, cancer cachexia, and diet: lessons from clinical research." Nutrition 12, no. 1 (1996): S52—S56. http://dx.doi.org/10.1016/0899-9007(95)00077-1.
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NIXON, D. "Cancer, cancer cachexia, and diet: Lessons from clinical research." Nutrition 12 (January 1996): S52—S56. http://dx.doi.org/10.1016/0899-9007(96)90020-9.
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Hardee, Justin P., Brittany R. Counts, and James A. Carson. "Understanding the Role of Exercise in Cancer Cachexia Therapy." American Journal of Lifestyle Medicine 13, no. 1 (2017): 46–60. http://dx.doi.org/10.1177/1559827617725283.
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Cachexia, the unintentional loss of body weight, is prevalent in many cancer types, and the associated skeletal muscle mass depletion increases patient morbidity and mortality. While anorexia can be present, cachexia is not reversible with nutritional therapies alone. Pharmacological agents have been proposed to treat this condition, but there are currently no approved treatments. Nonetheless, the hallmark characteristics associated with cancer cachexia remain viable foundations for future therapies. Regular physical activity holds a promising future as a nonpharmacological alternative to improve patient survival through cachexia prevention. Evidence suggests exercise training is beneficial during cancer treatment and survival. However, the mechanistic examination of cachectic skeletal muscle’s response to exercise is both needed and justified. The primary objective of this review is to discuss the role of exercise for the prevention and treatment of cancer-associated muscle wasting. Initially, we provide an overview of systemic alterations induced by cancer and their role in the regulation of wasting processes during cachexia progression. We then discuss how exercise could alter disrupted regulatory pathways related to growth and metabolism during cancer-induced muscle atrophy. Last, we outline current exercise prescription guidelines and how exercise could be a potential behavioral therapy to curtail cachexia development in cancer patients.
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Pitzer, Christopher R., Hector G. Paez, and Stephen E. Alway. "The Contribution of Tumor Derived Exosomes to Cancer Cachexia." Cells 12, no. 2 (2023): 292. http://dx.doi.org/10.3390/cells12020292.
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Cancer cachexia is defined as unintentional weight loss secondary to neoplasia and is associated with poor prognosis and outcomes. Cancer cachexia associated weight loss affects both lean tissue (i.e., skeletal muscle) and adipose tissue. Exosomes are extracellular vesicles that originate from multivesicular bodies that contain intentionally loaded biomolecular cargo. Exosome cargo includes proteins, lipids, mitochondrial components, and nucleic acids. The cargo carried in exosomes is thought to alter cell signaling when it enters into recipient cells. Virtually every cell type secretes exosomes and exosomes are known to be present in nearly every biofluid. Exosomes alter muscle and adipose tissue metabolism and biological processes, including macrophage polarization and apoptosis which contribute to the development of the cachexia phenotype. This has led to an interest in the role of tumor cell derived exosomes and their potential role as biomarkers of cancer cell development as well as their contribution to cachexia and disease progression. In this review, we highlight published findings that have studied the effects of tumor derived exosomes (and extracellular vesicles) and their cargo on the progression of cancer cachexia. We will focus on the direct effects of tumor derived exosomes and their cellular cross talk on skeletal muscle and adipose tissue, the primary sites of weight loss due to cancer cachexia.
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Kulyté, Agné, Silvia Lorente-Cebrián, Hui Gao, et al. "MicroRNA profiling links miR-378 to enhanced adipocyte lipolysis in human cancer cachexia." American Journal of Physiology-Endocrinology and Metabolism 306, no. 3 (2014): E267—E274. http://dx.doi.org/10.1152/ajpendo.00249.2013.
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Cancer cachexia is associated with pronounced adipose tissue loss due to, at least in part, increased fat cell lipolysis. MicroRNAs (miRNAs) have recently been implicated in controlling several aspects of adipocyte function. To gain insight into the possible impact of miRNAs on adipose lipolysis in cancer cachexia, global miRNA expression was explored in abdominal subcutaneous adipose tissue from gastrointestinal cancer patients with ( n = 10) or without ( n = 11) cachexia. Effects of miRNA overexpression or inhibition on lipolysis were determined in human in vitro differentiated adipocytes. Out of 116 miRNAs present in adipose tissue, five displayed distinct cachexia-associated expression according to both microarray and RT-qPCR. Four (miR-483–5p/-23a/-744/-99b) were downregulated, whereas one (miR-378) was significantly upregulated in cachexia. Adipose expression of miR-378 associated strongly and positively with catecholamine-stimulated lipolysis in adipocytes. This correlation is most probably causal because overexpression of miR-378 in human adipocytes increased catecholamine-stimulated lipolysis. In addition, inhibition of miR-378 expression attenuated stimulated lipolysis and reduced the expression of LIPE, PLIN1, and PNPLA2, a set of genes encoding key lipolytic regulators. Taken together, increased miR-378 expression could play an etiological role in cancer cachexia-associated adipose tissue loss via effects on adipocyte lipolysis.
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Tisdale, Michael J. "Newly identified factors that alter host metabolism in cancer cachexia." Trends in Pharmacological Sciences 11, no. 11 (1990): 473–75. http://dx.doi.org/10.1016/0165-6147(90)90134-t.
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Bartosch-Härlid, A., and R. Andersson. "Cachexia in pancreatic cancer – Mechanisms and potential intervention." e-SPEN, the European e-Journal of Clinical Nutrition and Metabolism 4, no. 6 (2009): e337-e343. http://dx.doi.org/10.1016/j.eclnm.2009.10.002.
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Lira, Fábio Santos, José Cesar Rosa Neto, and Marília Seelaender. "Exercise training as treatment in cancer cachexia." Applied Physiology, Nutrition, and Metabolism 39, no. 6 (2014): 679–86. http://dx.doi.org/10.1139/apnm-2013-0554.
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Cachexia is a wasting syndrome that may accompany a plethora of diseases, including cancer, chronic obstructive pulmonary disease, aids, and rheumatoid arthritis. It is associated with central and systemic increases of pro-inflammatory factors, and with decreased quality of life, response to pharmacological treatment, and survival. At the moment, there is no single therapy able to reverse cachexia many symptoms, which include disruption of intermediary metabolism, endocrine dysfunction, compromised hypothalamic appetite control, and impaired immune function, among other. Growing evidence, nevertheless, shows that chronic exercise, employed as a tool to counteract systemic inflammation, may represent a low-cost, safe alternative for the prevention/attenuation of cancer cachexia. Despite the well-documented capacity of chronic exercise to counteract sustained disease-related inflammation, few studies address the effect of exercise training in cancer cachexia. The aim of the present review was hence to discuss the results of cachexia treatment with endurance training. As opposed to resistance exercise, endurance exercise may be performed devoid of equipment, is well tolerated by patients, and an anti-inflammatory effect may be observed even at low-intensity. The decrease in inflammatory status induced by endurance protocols is paralleled by recovery of various metabolic pathways. The mechanisms underlying the response to the treatment are considered.
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Heo, Ji-Won, and Sung-Eun Kim. "Comparative Transcriptomic Profiling of Organs Associated With Metabolic Dysfunction in Cancer-Induced Cachexia." Current Developments in Nutrition 5, Supplement_2 (2021): 501. http://dx.doi.org/10.1093/cdn/nzab041_016.
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Abstract Objectives Approximately 50–80% of cancer patients suffer from cachexia represented by weight loss mainly due to loss of skeletal muscle. Cancer-induced cachexia is a complex metabolic syndrome associated with not only systemic inflammation but also perturbations to energy metabolism. In this study, we profiled gene expression patterns of different organs in CT-26 tumor bearing mice in order to understand metabolic dysfunction in cancer cachexia. Methods The transcriptomic profiles of skeletal muscle, adipose tissue, and liver of CT26-tumor bearing mice were generated using SurePrint G3 Mouse Gene Expression 8 × 60 K v2 (Agilent, Inc.). Functional and network analyses were performed using Gene Set Enrichment Analysis and Ingenuity Pathway Analysis (QIAGEN). Results We identified 299, 508, and 1,311 genes differentially regulated in skeletal muscle, adipose tissue, and liver, respectively. In the skeletal muscle, lipid biosynthetic process and mitochondrial electron transport were negatively regulated and network involved in glutamine metabolism was up-regulated. In adipose tissue, tricarboxylic acid cycle was down-regulated and lipid metabolism was associated with several genes including Thrsp, Plvap, and Sphk1. In the liver, regulation of gluconeogenesis was down-regulated, while production of lactic acid and uptake of D-glucose were related with H6pd and Pkm whose expression was up-regulated during cancer cachexia. Furthermore, the top network matched by genes commonly up-regulated in all organs included Bcl3, Csf2rb, Fcgr2a, and Lilrb3, which are known to be associated with inflammation and muscle wasting. Conclusions Our data suggest that skeletal muscle, adipose tissue, and liver present distinct gene expression profiles associated with inflammation and energy metabolism and several genes up-regulated in all organs might be candidate biomarkers for the prevention and early detection of cancer cachexia. Funding Sources This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education.
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Izquierdo-Garcia, Jose L., Pavithra Viswanath, Pia Eriksson, et al. "IDH1 Mutation Induces Reprogramming of Pyruvate Metabolism." Cancer Research 75, no. 15 (2015): 2999–3009. http://dx.doi.org/10.1158/0008-5472.can-15-0840.
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Tisdale, Michael J. "Cancer cachexia: Metabolic alterations and clinical manifestations." Nutrition 13, no. 1 (1997): 1–7. http://dx.doi.org/10.1016/s0899-9007(96)00313-9.
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