RESUMEN
BACKGROUND: Cachexia is a wasting syndrome associated with systemic inflammation and metabolic disruption. Detection of the early signs of the disease may contribute to the effective attenuation of associated symptoms. Despite playing a central role in the control of metabolism and inflammation, the liver has received little attention in cachexia. We previously described relevant disruption of metabolic pathways in the organ in an animal model of cachexia, and herein, we adopt the same model to investigate temporal onset of inflammation in the liver. The aim was thus to study inflammation in rodent liver in the well-characterized cachexia model of Walker 256 carcinosarcoma and, in addition, to describe inflammatory alterations in the liver of one cachectic colon cancer patient, as compared to one control and one weight-stable cancer patient. METHODS: Colon cancer patients (one weight stable [WSC] and one cachectic [CC]) and one patient undergoing surgery for cholelithiasis (control, n = 1) were enrolled in the study, after obtainment of fully informed consent. Eight-week-old male rats were subcutaneously inoculated with a Walker 256 carcinosarcoma cell suspension (2 × 107 cells in 1.0 mL; tumour-bearing [T]; or phosphate-buffered saline-controls [C]). The liver was excised on Days 0 (n = 5), 7 (n = 5) and 14 (n = 5) after tumour cell injection. RESULTS: In rodent cachexia, we found progressively higher numbers of CD68+ myeloid cells in the liver along cancer-cachexia development. Similar findings are described for CC, whose liver showed infiltration of the same cell type, compared with both WSC and control patient organs. In advanced rodent cachexia, hepatic phosphorylated c-Jun N-terminal kinase protein content and the inflammasome pathway protein expression were increased in relation to baseline (P < 0.05). These changes were accompanied by augmented expression of the active interleukin-1ß (IL-1ß) form (P < 0.05 for both circulating and hepatic content). CONCLUSIONS: The results show that cancer cachexia is associated with an increase in the number of myeloid cells in rodent and human liver and with modulation of hepatic inflammasome pathway. The latter contributes to the aggravation of systemic inflammation, through increased release of IL-1ß.
Asunto(s)
Carcinosarcoma , Neoplasias del Colon , Humanos , Masculino , Ratas , Animales , Caquexia/patología , Inflamasomas/metabolismo , Hígado/metabolismo , Inflamación/metabolismo , Neoplasias del Colon/complicaciones , Carcinosarcoma/complicaciones , Carcinosarcoma/metabolismoRESUMEN
Cancer cachexia affects about 80% of advanced cancer patients, it is linked to poor prognosis and to date, there is no efficient treatment or cure. The syndrome leads to progressive involuntary loss of muscle and fat mass induced by systemic inflammatory processes. The role of the white adipose tissue (WAT) in the onset and manifestation of cancer cachexia gained importance during the last decade. WAT wasting is not only characterized by increased lipolysis and release of free fatty acids (FFA), but in addition, owing to its high capacity to produce a variety of inflammatory factors. The aim of this study was to characterize plasma lipid profile of cachectic patients and to correlate the FA composition with circulating inflammatory markers; finally, we sought to establish whether the fatty acids released by adipocytes trigger and/or contribute to local and systemic inflammation in cachexia. The study selected 65 patients further divided into 3 groups: control (N); weight stable cancer (WSC); and cachectic cancer (CC). The plasma FA profile was significantly different among the groups and was positively correlated with pro-inflammatory cytokines expression in the CC patients. Therefore, we propose that saturated to unsaturated FFA ratio may serve as a means of detecting cachexia.
RESUMEN
Cancer cachexia is a multifactorial syndrome characterized by body weight loss, atrophy of adipose tissue (AT) and systemic inflammation. However, there is limited information regarding the mechanisms of immunometabolic response in AT from cancer cachexia. Male Wistar rats were inoculated with 2 × 107 of Walker 256 tumor cells [tumor bearing (TB) rats]. The mesenteric AT (MeAT) was collected on d 0, 4, 7 (early stage), and 14 (cachexia stage) after tumor cell injection. Surgical biopsies for MeAT were obtained from patients who had gastrointestinal cancer with cachexia. Lipolysis showed an early decrease in glycerol release in TB d 4 (TB4) rats in relation to the control, followed by a 6-fold increase in TB14 rats, whereas de novo lipogenesis was markedly lower in the incorporation of glucose into fatty acids in TB14 rats during the development of cachexia. CD11b and CD68 were positive in TB7 and TB14 rats, respectively. In addition, we found cachexia stage results similar to those of animals in MeAT from patients: an increased presence of CD68+, iNOS2+, TNFα+, and HSL+ cells. In summary, translational analysis of MeAT from patients and an animal model of cancer cachexia enabled us to identify early disruption in Adl turnover and subsequent inflammatory response during the development of cancer cachexia.-Henriques, F. S., Sertié, R. A. L., Franco, F. O., Knobl, P., Neves, R. X., Andreotti, S., Lima, F. B., Guilherme, A., Seelaender, M., Batista, M. L., Jr. Early suppression of adipocyte lipid turnover induces immunometabolic modulation in cancer cachexia syndrome.
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Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Caquexia/etiología , Caquexia/metabolismo , Metabolismo de los Lípidos , Neoplasias/complicaciones , Neoplasias/metabolismo , Animales , Ácidos Grasos/metabolismo , Inflamación/metabolismo , Metabolismo de los Lípidos/fisiología , Masculino , Ratas WistarRESUMEN
Cancer cachexia (CC) is a progressive metabolic syndrome that is marked by severe body weight loss. Metabolic disarrangement of fat tissues is a very early event in CC, followed by adipose tissue (AT) atrophy and remodelling. However, there is little information regarding the possible involvement of cellular turnover in this process. Thus, in this study, we evaluated the effect of CC on AT turnover and fibrosis of mesenteric (MEAT) and retroperitoneal (RPAT) adipose tissue depots as possible factors that contribute to AT atrophy. CC was induced by a subcutaneous injection of Walker tumour cells (2 × 107) in Wistar rats, and control animals received only saline. The experimental rats were randomly divided into four experimental groups: 0 days, 4 days, 7 days and 14 days after injection. AT turnover was analysed according to the Pref1/Adiponectin ratio of gene expression from the stromal vascular fraction and pro-apoptotic CASPASE3 and CASPASE9 from MEAT and RPAT. Fibrosis was verified according to the total collagen levels and expression of extracellular matrix genes. AT turnover was verified by measurements of lipolytic protein expression. We found that the Pref1/Adiponectin ratio was decreased in RPAT (81.85%, P < 0.05) with no changes in MEAT compared with the respective controls. CASPASE3 and CASPASE9 were activated on day 14 only in RPAT. Collagen was increased on day 7 in RPAT (127%) and MEAT (4.3-fold). The Collagen1A1, Collagen3A1, Mmp2 and Mmp9 mRNA levels were upregulated only in MEAT in CC. Lipid turnover was verified in RPAT and was not modified in CC. We concluded that the results suggest that CC affects RPAT cellular turnover, which may be determinant for RPAT atrophy.
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Caquexia/metabolismo , Grasa Intraabdominal/metabolismo , Neoplasias/metabolismo , Animales , Peso Corporal/fisiología , Caquexia/patología , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Grasa Intraabdominal/patología , Masculino , Neoplasias/patología , Ratas , Ratas WistarRESUMEN
Cachexia is associated with increased morbidity and mortality in cancer. The White adipose tissue (WAT) synthesizes and releases several pro-inflammatory cytokines that play a role in cancer cachexia-related systemic inflammation. IFN-γ is a pleiotropic cytokine that regulates several immune and metabolic functions. To assess whether IFN-γ signalling in different WAT pads is modified along cancer-cachexia progression, we evaluated IFN-γ receptors expression (IFNGR1 and IFNGR2) and IFN-γ protein expression in a rodent model of cachexia (7, 10, and 14days after tumour implantation). IFN-γ protein expression was heterogeneously modulated in WAT, with increases in the mesenteric pad and decreased levels in the retroperitoneal depot along cachexia progression. Ifngr1 was up-regulated 7days after tumour cell injection in mesenteric and epididymal WAT, but the retroperitoneal depot showed reduced Ifngr1 gene expression. Ifngr2 gene expression was increased 7 and 14days after tumour inoculation in mesenteric WAT. The results provide evidence that changes in IFN-γ expression and signalling may be perceived at stages preceding refractory cachexia, and therefore, might be employed as a means to assess the early stage of the syndrome.
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Tejido Adiposo Blanco/metabolismo , Caquexia/metabolismo , Regulación Neoplásica de la Expresión Génica , Interferón gamma/biosíntesis , Proteínas de Neoplasias/biosíntesis , Neoplasias Experimentales/metabolismo , Transducción de Señal , Tejido Adiposo Blanco/patología , Animales , Caquexia/patología , Masculino , Neoplasias Experimentales/patología , Ratas , Ratas Wistar , Receptores de Interferón/biosíntesis , Receptor de Interferón gammaRESUMEN
Cancer cachexia, of which the most notable symptom is severe and rapid weight loss, is present in the majority of patients with advanced cancer. Inflammatory mediators play an important role in the development of cachexia, envisaged as a chronic inflammatory syndrome. The white adipose tissue (WAT) is one of the first compartments affected in cancer cachexia and suffers a high rate of lipolysis. It secretes several cytokines capable of directly regulating intermediate metabolism. A common pathway in the regulation of the expression of pro-inflammatory cytokines in WAT is the activation of the nuclear transcription factor kappa-B (NF-κB). We have examined the gene expression of the subunits NF-κBp65 and NF-κBp50, as well as NF-κBp65 and NF-κBp50 binding, the gene expression of pro-inflammatory mediators under NF-κB control (IL-1ß, IL-6, INF-γ, TNF-α, MCP-1), and its inhibitory protein, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκB-α). The observational study involved 35 patients (control group, n = 12 and cancer group, n = 23, further divided into cachectic and non-cachectic). NF-κBp65 and its target genes expression (TNF-α, IL-1ß, MCP-1 and IκB-α) were significantly higher in cachectic cancer patients. Moreover, NF-κBp65 gene expression correlated positively with the expression of its target genes. The results strongly suggest that the NF-κB pathway plays a role in the promotion of WAT inflammation during cachexia.
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Caquexia/patología , Neoplasias/patología , Grasa Subcutánea/metabolismo , Factor de Transcripción ReIA/metabolismo , Linfocitos B/metabolismo , Estudios de Casos y Controles , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Femenino , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Interferón gamma/genética , Interferón gamma/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipólisis , Masculino , Persona de Mediana Edad , Inhibidor NF-kappaB alfa , Calidad de Vida , Transducción de Señal , Factor de Transcripción ReIA/genética , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia ArribaRESUMEN
OBJECTIVE: To evaluate the effects of carbon dioxide infusion to abdominal wall adipocytes. METHODS: Fifteen volunteers were subjected to sessions of CO2 infusion for three consecutive weeks (two sessions per week with intervals of two to three days between each). The volume of carbon dioxide infused per session, at points previously marked, was always calculated on the basis of surface area to be treated, with a fixed infused volume of 250 ml/100 cm² of treated surface. The infiltration points were marked respecting the limit of 2 cm equidistant between them. At each point 10 ml was injected per session, with a flow of 80 ml/min. Fragments were collected from subcutaneous tissue of the anterior abdominal wall before and after treatment. The number and histomorphological changes of adipocytes (mean diameter, perimeter, length, width and number of adipocytes per field of observation) were measured by computerized cytometry. The results were analyzed with paired Student t test, adopting a significance level of 5% (p <0.05). RESULTS: There was a significant reduction in the number of adipocytes in the abdominal wall, as well as the area, diameter, perimeter, length and width of the adipocytes, after the infusion of CO2 (p = 0.0001). CONCLUSION: The percutaneous infiltration of CO2 reduces the population of adipocytes of the anterior abdominal wall and modifies their morphology.
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Adipocitos/efectos de los fármacos , Dióxido de Carbono/farmacología , Adulto , Dióxido de Carbono/administración & dosificación , Técnicas Citológicas , Femenino , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Grasa Subcutánea Abdominal , Adulto JovenRESUMEN
OBJETIVO: Avaliar os efeitos da infiltração de dióxido de carbono em adipócitos presentes na parede abdominal. MÉTODOS: Quinze voluntárias foram submetidas a sessões de infusão de CO2 durante três semanas consecutivas (duas sessões por semana com intervalos de dois a três dias entre cada sessão). O volume de gás carbônico infundido por sessão, em pontos previamente demarcados, foi sempre calculado com base na superfície da área a ser tratada, com volume infundido fixo de 250 mL/100cm² de superfície tratada. Os pontos de infiltração foram demarcados respeitando-se o limite eqüidistante 2cm entre eles. Em cada ponto se injetou 10mL, por sessão, com fluxo de 80mL/min. Foram colhidos fragmentos de tecido celular subcutâneo da parede abdominal anterior antes e após o tratamento. O número e as alterações histomorfológicas dos adipócitos (diâmetro médio, perímetro, comprimento, largura e número de adipócitos por campos de observação) foram mensurados por citometria computadorizada. Os resultados foram analisados com o teste t de Student pareado, adotando-se nível de significância de 5 por cento (p<0,05). RESULTADOS: Encontrou-se redução significativa no número de adipócitos da parede abdominal e na área, diâmetro, perímetro, comprimento e largura após o uso da hipercapnia (p=0,0001). CONCLUSÃO: A infiltração percutânea de CO2 reduz a população e modifica a morfologia dos adipócitos presentes na parede abdominal anterior.
OBJECTIVE: To evaluate the effects of carbon dioxide infusion to abdominal wall adipocytes. METHODS: Fifteen volunteers were subjected to sessions of CO2 infusion for three consecutive weeks (two sessions per week with intervals of two to three days between each). The volume of carbon dioxide infused per session, at points previously marked, was always calculated on the basis of surface area to be treated, with a fixed infused volume of 250 ml/100cm² of treated surface. The infiltration points were marked respecting the limit of 2cm equidistant between them. At each point 10 ml was injected per session, with a flow of 80ml/min. Fragments were collected from subcutaneous tissue of the anterior abdominal wall before and after treatment. The number and histomorphological changes of adipocytes (mean diameter, perimeter, length, width and number of adipocytes per field of observation) were measured by computerized cytometry. The results were analyzed with paired Student t test, adopting a significance level of 5 percent (p <0.05). RESULTS: There was a significant reduction in the number of adipocytes in the abdominal wall, as well as the area, diameter, perimeter, length and width of the adipocytes, after the infusion of CO2 (p = 0.0001). CONCLUSION: The percutaneous infiltration of CO2 reduces the population of adipocytes of the anterior abdominal wall and modifies their morphology.