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Cachexia is frequently accompanied by severe metabolic derangements, although the mechanisms responsible for this debilitating condition remain unclear. Pyruvate dehydrogenase kinase (PDK)4, a critical regulator of cellular energetic metabolism, was found elevated in experimental models of cancer, starvation, diabetes, and sepsis. Here we aimed to investigate the link between PDK4 and the changes in muscle size in cancer cachexia. High PDK4 and abnormal energetic metabolism were found in the skeletal muscle of colon-26 tumor hosts, as well as in mice fed a diet enriched in Pirinixic acid, previously shown to increase PDK4 levels. Viral-mediated PDK4 overexpression in myotube cultures was sufficient to promote myofiber shrinkage, consistent with enhanced protein catabolism and mitochondrial abnormalities. On the contrary, blockade of PDK4 was sufficient to restore myotube size in C2C12 cultures exposed to tumor media. Our data support, for the first time, a direct role for PDK4 in promoting cancer-associated muscle metabolic alterations and skeletal muscle atrophy.-Pin, F., Novinger, L. J., Huot, J. R., Harris, R. A., Couch, M. E., O'Connell, T. M., Bonetto, A. PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia.
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Caquexia/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Neoplasias/complicações , Piruvato Desidrogenase Quinase de Transferência de Acetil/fisiologia , Animais , Caquexia/etiologia , Linhagem Celular , Masculino , Camundongos , Mitocôndrias Musculares/enzimologia , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/enzimologia , Atrofia Muscular/enzimologia , OxirreduçãoRESUMO
Growth differentiation factor 11 (GDF11), a TGF-beta superfamily member, is highly homologous to myostatin and essential for embryonic patterning and organogenesis. Reports of GDF11 effects on adult tissues are conflicting, with some describing anti-aging and pro-regenerative activities on the heart and skeletal muscle while others opposite or no effects. Herein, we sought to determine the in vivo cardiac and skeletal muscle effects of excess GDF11. Mice were injected with GDF11 secreting cells, an identical model to that used to initially identify the in vivo effects of myostatin. GDF11 exposure in mice induced whole body wasting and profound loss of function in cardiac and skeletal muscle over a 14-day period. Loss of cardiac mass preceded skeletal muscle loss. Cardiac histologic and echocardiographic evaluation demonstrated loss of ventricular muscle wall thickness, decreased cardiomyocyte size, and decreased cardiac function 10 days following initiation of GDF11 exposure. Changes in skeletal muscle after GDF11 exposure were manifest at day 13 and were associated with wasting, decreased fiber size, and reduced strength. Changes in cardiomyocytes and skeletal muscle fibers were associated with activation of SMAD2, the ubiquitin-proteasome pathway and autophagy. Thus, GDF11 over administration in vivo results in cardiac and skeletal muscle loss, dysfunction, and death. Here, serum levels of GDF11 by Western blotting were 1.5-fold increased over controls. Although GDF11 effects in vivo are likely dose, route, and duration dependent, its physiologic changes are similar to myostatin and other Activin receptors ligands. These data support that GDF11, like its other closely related TGF-beta family members, induces loss of cardiac and skeletal muscle mass and function.
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Proteínas Morfogenéticas Ósseas/farmacologia , Caquexia/induzido quimicamente , Fatores de Diferenciação de Crescimento/farmacologia , Coração/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Miocárdio/patologia , Animais , Masculino , Camundongos , Camundongos NusRESUMO
BACKGROUND: An increasing number of women are pursuing a career in surgery. Concurrently, the percentage of surgeons in dual-profession partnerships is increasing. We sought to evaluate the gender differences in professional advancement, work-life balance, and satisfaction at a large academic center. MATERIALS AND METHODS: All surgical trainees and faculty at a single academic medical center were surveyed. Collected variables included gender, academic rank, marital status, family size, division of household responsibilities, and career satisfaction. Student t-test, Fisher's exact test, and chi-square test were used to compare results. RESULTS: There were 127 faculty and 116 trainee respondents (>80% response rate). Respondents were mostly male (77% of faculty, 58% of trainees). Women were more likely than men to be married to a professional (90% versus 37%, for faculty; 82% versus 41% for trainees, P < 0.001 for both) who was working full time (P < 0.001) and were less likely to be on tenure track (P = 0.002). Women faculty were more likely to be primarily responsible for childcare planning (P < 0.001), meal planning (P < 0.001), grocery shopping (P < 0.001), and vacation planning (P = 0.003). Gender-neutral responsibilities included financial planning (P = 0.04) and monthly bill payment (P = 0.03). Gender differences in division of household responsibilities were similar in surgical trainees except for childcare planning, which was a shared responsibility. CONCLUSIONS: Women surgeons are more likely to be partnered with a full-time working spouse and to be primarily responsible for managing their households. Additional consideration for improvement in recruitment and retention strategies for surgeons might address barriers to equalizing these gender disparities.
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Centros Médicos Acadêmicos/estatística & dados numéricos , Mobilidade Ocupacional , Docentes de Medicina/estatística & dados numéricos , Satisfação no Emprego , Cirurgiões/estatística & dados numéricos , Equilíbrio Trabalho-Vida/estatística & dados numéricos , Centros Médicos Acadêmicos/organização & administração , Docentes de Medicina/organização & administração , Docentes de Medicina/psicologia , Feminino , Humanos , Indiana , Modelos Lineares , Masculino , Estado Civil/estatística & dados numéricos , Análise Multivariada , Fatores Sexuais , Cônjuges/estatística & dados numéricos , Cirurgiões/organização & administração , Cirurgiões/psicologia , Inquéritos e QuestionáriosRESUMO
OBJECTIVES: Patients with head and neck cancer (HNC) frequently present with weight loss secondary to dysphagia and malnutrition. We sought to determine the relationship between weight loss and in-hospital mortality, complications, length of hospitalization, and costs in HNC surgery. METHODS: We analyzed discharge data from the Nationwide Inpatient Sample for 93,663 patients who underwent an ablative procedure for malignant oral cavity, laryngeal, hypopharyngeal, or oropharyngeal neoplasms between 2003 and 2008. RESULTS: Weight loss was significantly associated with dysphagia (relative risk ratio [RRR] = 3.0; p < 0.001), alcohol abuse (RRR = 2.0; p < 0.001), advanced comorbidity (RRR = 1.8; p < 0.001), Medicaid payor status (RRR = 1.6; p = 0.002), urgent or emergent admission (RRR = 1.7; p = 0.015), and major surgical procedures (RRR = 2.3; p < 0.001). Patients with weight loss had increased risks of acute cardiac events, pneumonia, renal failure, sepsis, pulmonary failure (RRR = 2.6; p < 0.001), and postoperative wound healing complications, including fistula, dehiscence, and surgical site infection (RRR = 2.0; p < 0.001). After we controlled for all other variables, weight loss was associated with significantly increased length of hospitalization and hospital-related costs. CONCLUSIONS: Weight loss is associated with increases in medical complications, surgical complications, length of hospitalization, and hospital-related costs in HNC surgical patients. Aggressive preoperative identification and treatment of underlying dysphagia and malnutrition may reduce the medical and surgical morbidity in this high-risk population.
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Neoplasias de Cabeça e Pescoço/cirurgia , Custos de Cuidados de Saúde , Redução de Peso , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Neoplasias de Cabeça e Pescoço/economia , Neoplasias de Cabeça e Pescoço/mortalidade , Mortalidade Hospitalar , Humanos , Tempo de Internação/economia , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Adulto JovemRESUMO
Cancer is a physically disabling condition. Functional disability, defined as an inability or impaired ability to perform simple tasks of daily life, afflicts a large majority of the cancer population and dramatically impacts patient well-being, negatively affecting treatment decisions, quality of life, and clinical outcomes. Our current understanding of the fundamental mechanisms underlying physical disability in cancer patients, however, is limited. This review will evaluate how cancer and cancer treatments and their pathological sequelae alter skeletal muscle structure and function to promote functional disability. Briefly, factors associated with cancer and its treatment can diminish skeletal muscle size and contractile function, which lead to a reduced physiological capacity for work and, in turn, functional disability. We outline the clinical evidence for the involvement of each of these factors in disability in cancer patients and then review structural and functional evidence at various anatomic levels to explore the tissue, cellular, and molecular mechanisms underlying cancer-related disability.
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Antineoplásicos/uso terapêutico , Músculo Esquelético/patologia , Atrofia Muscular/etiologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Adaptação Fisiológica , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Humanos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Neoplasias/complicaçõesRESUMO
The mechanism by which cancer mediates muscle atrophy has been delineated in the past 3 decades and includes a prominent role of tumor-derived cytokines, such as IL-6, TNFα, and IL-1. These cytokines interact with their cognate receptors on muscle to activate the downstream transcription factor NF-κB and induce sarcomere proteolysis. Experimentally, inhibiting NF-κB signaling largely prevents cancer-induced muscle wasting, indicating its prominent role in muscle atrophy. Resveratrol, a natural phytoalexin found in the skin of grapes, has recently been shown to inhibit NF-κB in cancer cells, which led us to hypothesize that it might have a protective role in cancer cachexia. Therefore, we investigated whether daily oral resveratrol could protect against skeletal muscle loss and cardiac atrophy in an established mouse model. We demonstrate resveratrol inhibits skeletal muscle and cardiac atrophy induced by C26 adenocarcinoma tumors through its inhibition of NF-κB (p65) activity in skeletal muscle and heart. These studies demonstrate for the first time the utility of oral resveratrol therapy to provide clinical benefit in cancer-induced atrophy through the inhibition of NF-κB in muscle. These findings may have application in the treatment of diseases with parallel pathophysiologies such as muscular dystrophy and heart failure.
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Adenocarcinoma/fisiopatologia , Coração/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Atrofia Muscular/prevenção & controle , Miocárdio/patologia , Estilbenos/uso terapêutico , Adenocarcinoma/metabolismo , Administração Oral , Animais , Composição Corporal/efeitos dos fármacos , Caquexia/prevenção & controle , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ecocardiografia/efeitos dos fármacos , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Camundongos , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/etiologia , Miocárdio/metabolismo , Transplante de Neoplasias , RNA Mensageiro/metabolismo , Distribuição Aleatória , Resveratrol , Estilbenos/administração & dosagem , Estilbenos/efeitos adversos , Fator de Transcrição RelA/metabolismo , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Redução de Peso/efeitos dos fármacosRESUMO
Background: Cancer cachexia is a severe metabolic disorder characterized by progressive weight loss along with a dramatic loss in skeletal muscle and adipose tissue. Like cancer, cachexia progresses in stages starting with pre-cachexia to cachexia and finally to refractory cachexia. In the refractory stage, patients are no longer responsive to therapy and management of weight loss is no longer possible. It is therefore critical to detect cachexia as early as possible. In this study we applied a metabolomics approach to search for early biomarkers of cachexia. Methods: Multi-platform metabolomics analyses were applied to the murine Colon-26 (C26) model of cachexia. Tumor bearing mice (n = 5) were sacrificed every other day over the 14-day time course and control mice (n = 5) were sacrificed every fourth day starting at day 2. Linear regression modeling of the data yielded metabolic trajectories that were compared with the trajectories of body weight and skeletal muscle loss to look for early biomarkers of cachexia. Results: Weight loss in the tumor-bearing mice became significant at day 9 as did the loss of tibialis muscle. The loss of muscle in the gastrocnemius and quadriceps was significant at day 7. Reductions in amino acids were among the earliest metabolic biomarkers of cachexia. The earliest change was in methionine at day 4. Significant alterations in acylcarnitines and lipoproteins were also detected several days prior to weight loss. Conclusion: The results of this study demonstrate that metabolic alterations appear well in advance of observable weight loss. The earliest and most significant alterations were found in amino acids and lipoproteins. Validation of these results in other models of cachexia and in clinical studies will pave the way for a clinical diagnostic panel for the early detection of cachexia. Such a panel would provide a tremendous advance in cachectic patient management and in the design of clinical trials for new therapeutic interventions.
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The vast majority of patients with pancreatic ductal adenocarcinoma (PDAC) suffer cachexia. Although cachexia results from concurrent loss of adipose and muscle tissue, most studies focus on muscle alone. Emerging data demonstrate the prognostic value of fat loss in cachexia. Here we sought to identify the muscle and adipose gene profiles and pathways regulated in cachexia. Matched rectus abdominis muscle and subcutaneous adipose tissue were obtained at surgery from patients with benign conditions (n = 11) and patients with PDAC (n = 24). Self-reported weight loss and body composition measurements defined cachexia status. Gene profiling was done using ion proton sequencing. Results were queried against external datasets for validation. 961 DE genes were identified from muscle and 2000 from adipose tissue, demonstrating greater response of adipose than muscle. In addition to known cachexia genes such as FOXO1, novel genes from muscle, including PPP1R8 and AEN correlated with cancer weight loss. All the adipose correlated genes including SCGN and EDR17 are novel for PDAC cachexia. Pathway analysis demonstrated shared pathways but largely non-overlapping genes in both tissues. Age related muscle loss predominantly had a distinct gene profiles compared to cachexia. This analysis of matched, externally validate gene expression points to novel targets in cachexia.
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BACKGROUND: Treatment of head, neck, and esophageal cancers with radiation therapy can lead to esophageal strictures. In some cases, these can progress to complete esophageal obstruction, precluding typical antegrade endoscopic dilation. OBJECTIVE: The aim of this study was to review our experience with a combined antegrade/retrograde technique for dilation of complete esophageal strictures. DESIGN: Case series. SETTING: Tertiary-care referral center. PATIENTS: Twelve patients with complete esophageal radiation-induced strictures. INTERVENTIONS: In collaboration with otolaryngologists who performed direct antegrade esophagoscopy, retrograde endoscopy via gastrostomy was simultaneously performed. While visualizing the stricture from both sides and transilluminating, it was recannulated with use of a biliary or spring-tipped guidewire, and then dilated. MAIN OUTCOME MEASUREMENTS: Dilation method, complications, and postdilation oral intake. RESULTS: Combined antegrade and retrograde dilation was technically possible in 10 of the 12 patients (83%). Two cases were unsuccessful due to an inability to achieve transillumination. The only significant complication was a contained esophageal perforation that was managed nonoperatively. The mean number of repeat dilations was 7 (range, 1-22); none were complicated by perforation. Esophageal patency allowing at least some oral intake and tolerance of secretions was ultimately successful in 8 patients (67%). LIMITATIONS: Retrospective, single center. CONCLUSIONS: A combined antegrade/retrograde approach for dilation of complete esophageal radiation-induced strictures in collaboration with colleagues from otolaryngology is a viable treatment option. The procedure is technically feasible, effective, and well tolerated, although there may be an increased risk of esophageal perforation. This strategy may obviate a more invasive surgical approach.
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Cateterismo/métodos , Neoplasias Esofágicas/radioterapia , Estenose Esofágica/terapia , Esofagoscopia/métodos , Esôfago/efeitos da radiação , Lesões por Radiação/complicações , Gravação em Vídeo , Adulto , Idoso , Estenose Esofágica/diagnóstico , Estenose Esofágica/etiologia , Esôfago/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Lesões por Radiação/diagnóstico , Lesões por Radiação/terapia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Some chemotherapeutic agents have been shown to lead to the severe wasting syndrome known as cachexia resulting in dramatic losses of both skeletal muscle and adipose tissue. Previous studies have shown that chemotherapy-induced cachexia is characterized by unique metabolic alterations. Recent results from our laboratory and others have shown that the use of ACVR2B/Fc, a soluble form of the activin receptor 2B (ACVR2B), can mitigate muscle wasting induced by chemotherapy, although the underlying mechanisms responsible for such protective effects are unclear. In order to understand the biochemical mechanisms through which ACVR2B/Fc functions, we employed a comprehensive, multi-platform metabolomics approach. Using both nuclear magnetic resonance (NMR) and mass-spectrometry (MS), we profiled the metabolome of both serum and muscle tissue from four groups of mice including (1) vehicle, (2) the chemotherapeutic agent, Folfiri, (3) ACVR2B/Fc alone, and (4) combined treatment with both Folfiri and ACVR2B/Fc. The metabolic profiles demonstrated large effects with Folfiri treatment and much weaker effects with ACVR2B/Fc treatment. Interestingly, a number of significant effects were observed in the co-treatment group, with the addition of ACVR2B/Fc providing some level of rescue to the perturbations induced by Folfiri alone. The most prominent of these were a normalization of systemic glucose and lipid metabolism. Identification of these pathways provides important insights into the mechanism by which ACVR2B/Fc protects against chemotherapy-induced cachexia.
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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 ß-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.
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Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Caquexia/metabolismo , Camptotecina/análogos & derivados , Metabolismo Energético , Neoplasias/metabolismo , Animais , Caquexia/induzido quimicamente , Caquexia/patologia , Camptotecina/efeitos adversos , Linhagem Celular Tumoral , Fluoruracila/efeitos adversos , Glucose/metabolismo , Leucovorina/efeitos adversos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Metabolômica , Camundongos , Força Muscular , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Neoplasias/induzido quimicamente , Neoplasias/patologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de LDL/metabolismoRESUMO
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-ßA but not activin-ßB. 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-ßA (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.
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Ativinas/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores de Activinas Tipo II/metabolismo , Ativinas/sangue , Animais , Biomarcadores , Pesos e Medidas Corporais , Caquexia/etiologia , Caquexia/metabolismo , Caquexia/mortalidade , Caquexia/terapia , Carcinoma Ductal Pancreático/complicações , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Gerenciamento Clínico , Modelos Animais de Doenças , Expressão Gênica , Humanos , Imuno-Histoquímica , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/mortalidade , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
Patients present with a differential baseline risk of cancer based on normal and expected variations in genes associated with cancer. The baseline risk of developing cancer is acted on throughout life as the genome of different cells interacts with the environment in the form of exposures (eg, toxins, infections). As genetic damage is incurred throughout a lifetime (directly to DNA sequences or to the epigenome), events are set in motion to progressively disrupt normal cellular pathways toward tumorigenesis. This article attempts to characterize broad categories of genetic aberrations and pathways in a manner that might be useful for the clinician to understand the risk of developing cancer, the pathways that are disrupted, and the potential for molecular-based diagnostics.
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Epigênese Genética , Neoplasias de Cabeça e Pescoço , Neoplasias de Células Escamosas , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Neoplasias de Células Escamosas/diagnóstico , Neoplasias de Células Escamosas/genética , Neoplasias de Células Escamosas/metabolismo , Neoplasias de Células Escamosas/patologia , Neoplasias de Células Escamosas/terapia , Fatores de RiscoRESUMO
PURPOSE: Cancer cachexia is a devastating and understudied illness in patients with head and neck squamous cell carcinoma (HNSCC). The primary objective was to identify clinical characteristics and serum levels of cytokines and cachexia-related factors in patients with HNSCC. The secondary objective was to detect the occurrence of cytokine and cachexia-related factor gene expression in HNSCC tumors. EXPERIMENTAL DESIGN: For the primary objective, cross-sectional data were obtained from prospectively recruited patients identified as cachexia cases and matching cachexia-free controls. For the secondary objective, a retrospective cohort design with matched controls was used. RESULTS: Clinical characteristics associated with cancer cachexia in HNSCC were T(4) status (P = 0.01), increased C-reactive protein (P = 0.01), and decreased hemoglobin (P < 0.01). Exploratory multiplex analysis of serum cytokine levels found increased interleukin (IL)-6 (P = 0.04). A highly sensitive ELISA confirmed the multiplex result for increased IL-6 in cachectic patients (P = 0.02). Quality of life was substantially reduced in patients with cachexia compared with noncachectic patients (P < 0.01). All tumors of HNSCC patients both with and without cachexia expressed RNA for each cytokine tested and the cachexia factor lipid-mobilizing factor. There were no statistically significant differences between the cytokine and cachexia factor RNA expression of cachectic and noncachectic patients (each P > 0.05). No tumors expressed the cachexia factor proteolysis-inducing factor. CONCLUSION: We have identified clinical characteristics and pathophysiologic mechanisms associated with cancer cachexia in a carefully defined population of patients with HNSCC. The data suggest that the acute-phase response and elevated IL-6 are associated with this complex disease state. We therefore hypothesize that IL-6 may represent an important therapeutic target for HNSCC patients with cancer cachexia.
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Caquexia/diagnóstico , Carcinoma de Células Escamosas/complicações , Neoplasias de Cabeça e Pescoço/complicações , Interleucina-6/metabolismo , Idoso , Caquexia/etiologia , Caquexia/metabolismo , Carcinoma de Células Escamosas/patologia , Citocinas/sangue , Citocinas/genética , Citocinas/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Interleucina-6/sangue , Interleucina-6/genética , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , RNA Mensageiro/análise , RNA Mensageiro/metabolismoRESUMO
PURPOSE: To determine if serologic recognition of p53 mutations at the protein level depends upon the ability of mutant p53 to express new peptide epitopes that bind to human leukocyte antigen (HLA) class II molecules, we used anti-p53 antibody production as a marker for HLA class II-restricted T-cell involvement in head and neck cancer. EXPERIMENTAL DESIGN: An anti-p53 antibody response was correlated with specific p53 mutations and the patients' HLA class II alleles and haplotypes. HLA binding studies and in vitro stimulation (IVS) of peripheral blood mononuclear cells were done using a mutant versus wild-type HLA-DQ7-binding p53 peptide. RESULTS: Certain HLA-DQ and HLA-DR alleles were frequently present in p53 seropositive patients who produced serum anti-p53 antibodies. Selected mutated p53 peptides fit published allele-specific HLA class II binding motifs for the HLA-DQ7 or HLA-DR1 molecules. Moreover, a mutant p53 peptide bound with a 10-fold greater affinity than the wild-type p53 peptide to HLA-DQ7 molecules. IVS of CD4(+) T cells from seven healthy HLA-DQ7(+) donors using this mutant p53 peptide (p53(220C)) was associated with a partial T helper type 2 phenotype compared with IVS using the wild-type p53(210-223) peptide. CONCLUSIONS: Our results support the hypothesis that mutated p53 neoantigens can bind to specific HLA class II molecules, leading to a break in tolerance. This may lead to skewing of the CD4(+) T lymphocyte response toward a tumor-permissive T helper type 2 profile in head and neck cancer patients, as manifested by seropositivity for p53.
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Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/imunologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/imunologia , Sequência de Aminoácidos , Anticorpos Antineoplásicos/biossíntese , Anticorpos Antineoplásicos/imunologia , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito B/imunologia , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologia , Antígenos HLA-DR/genética , Antígenos HLA-DR/imunologia , Humanos , Interferon gama/imunologia , Interleucina-5/imunologia , Leucócitos Mononucleares/imunologia , Dados de Sequência Molecular , Polimorfismo Genético , Células Th2/imunologiaRESUMO
PURPOSE OF REVIEW: Cancer patients undergoing chemotherapy often experience very debilitating side effects, including unintentional weight loss, nausea, and vomiting. Changes in body composition, specifically lean body mass (LBM), are known to have important implications for anticancer drug toxicity and cancer prognosis. Currently, chemotherapy dosing is based on calculation of body surface area, although this approximation does not take into consideration the variability in lean and adipose tissue mass. RECENT FINDINGS: Patients with depletion of muscle mass present higher chemotherapy-related toxicity, whereas patients with larger amounts of LBM show fewer toxicities and better outcomes. Commonly used chemotherapy regimens promote changes in body composition, primarily by affecting skeletal muscle, as well as fat and bone mass. Experimental evidence has shown that pro-atrophy mechanisms, abnormal mitochondrial metabolism, and reduced protein anabolism are primarily implicated in muscle depletion. Muscle-targeted pro-anabolic strategies have proven successful in preserving lean tissue in the occurrence of cancer or following chemotherapy. SUMMARY: Muscle wasting often occurs as a consequence of anticancer treatments and is indicative of worse outcomes and poor quality of life in cancer patients. Accurate assessment of body composition and preservation of muscle mass may reduce chemotherapy toxicity and improve the overall survival.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Composição Corporal/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Relação Dose-Resposta a Droga , Grelina/uso terapêutico , Humanos , Atrofia Muscular/tratamento farmacológico , Doenças Musculoesqueléticas/induzido quimicamente , Doenças Musculoesqueléticas/fisiopatologia , Avaliação Nutricional , Qualidade de Vida , Receptores de Grelina/agonistasRESUMO
A compounding feature of greater than 50% of all cancers is the high incidence of the cachexia syndrome, a complex metabolic disorder characterized by extreme weight loss due mainly to the gross depletion of skeletal muscle tissue. Although studies into the cause of cancer cachexia has spanned over multiple decades, little is known about the effects of various cancer treatments themselves on cachexia. For example, chemotherapy agents induce side effects such as nausea and anorexia, but these symptoms do not fully account for the changes seen with cancer cachexia. In this study we examine the effects of chemotherapeutic compounds, specifically, cisplatin in the colon-26 adenocarcinoma model of cancer cachexia. We find that although cisplatin is able to reduce tumor burden as expected, muscle wasting in mice nevertheless persists. Strikingly, cisplatin alone was seen to regulate muscle atrophy, which was independent of the commonly implicated ubiquitin proteasome system. Finally, we show that cisplatin is able to induce NF-κB activity in both mouse muscles and myotube cultures, suggesting that an additional side effect of cancer treatment is the regulation of muscle wasting that may be mediated through activation of the NF-κB signaling pathway.
RESUMO
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 × 107 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.
Assuntos
Osso e Ossos/patologia , Caquexia/diagnóstico , Caquexia/etiologia , Atrofia Muscular/patologia , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/patologia , Animais , Biomarcadores , Composição Corporal , Densidade Óssea , Osso e Ossos/diagnóstico por imagem , Linhagem Celular Tumoral , Modelos Animais de Doenças , Metabolismo Energético , Feminino , Xenoenxertos , Humanos , Camundongos , Mitocôndrias/metabolismo , Força Muscular , Atrofia Muscular/diagnóstico por imagem , Atrofia Muscular/metabolismo , Tamanho do Órgão , Neoplasias Ovarianas/metabolismo , Transdução de Sinais , Microtomografia por Raio-XRESUMO
BACKGROUND: By the traditional definition of unintended weight loss, cachexia develops in ~80% of patients with pancreatic ductal adenocarcinoma (PDAC). Here, we measure the longitudinal body composition changes in patients with advanced PDAC undergoing 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin therapy. METHODS: We performed a retrospective review of 53 patients with advanced PDAC on 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin as first line therapy at Indiana University Hospital from July 2010 to August 2015. Demographic, clinical, and survival data were collected. Body composition measurement by computed tomography (CT), trend, univariate, and multivariate analysis were performed. RESULTS: Among all patients, three cachexia phenotypes were identified. The majority of patients, 64%, had Muscle and Fat Wasting (MFW), while 17% had Fat-Only Wasting (FW) and 19% had No Wasting (NW). NW had significantly improved overall median survival (OMS) of 22.6 months vs. 13.0 months for FW and 12.2 months for MFW (P = 0.02). FW (HR = 5.2; 95% confidence interval = 1.5-17.3) and MFW (HR = 1.8; 95% confidence interval = 1.1-2.9) were associated with an increased risk of mortality compared with NW. OMS and risk of mortality did not differ between FW and MFW. Progression of disease, sarcopenic obesity at diagnosis, and primary tail tumours were also associated with decreased OMS. On multivariate analysis, cachexia phenotype and chemotherapy response were independently associated with survival. Notably, CT-based body composition analysis detected tissue loss of >5% in 81% of patients, while the traditional definition of >5% body weight loss identified 56.6%. CONCLUSIONS: Distinct cachexia phenotypes were observed in this homogeneous population of patients with equivalent stage, diagnosis, and first-line treatment. This suggests cellular, molecular, or genetic heterogeneity of host or tumour. Survival among patients with FW was as poor as for MFW, indicating adipose tissue plays a crucial role in cachexia and PDAC mortality. Adipose tissue should be studied for its mechanistic contributions to cachexia.