Molecular and neuroendocrine mechanisms of cancer cachexia

Mendes, Maria Carolina Santos; Pimentel, Gustavo D.; Costa, Felipe Osório; Carvalheira, José Barreto Campello

doi:10.1530/joe-15-0170

Cited by 78 publications

(74 citation statements)

References 187 publications

(172 reference statements)

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“…A large body of evidence demonstrates that the hypothalamus is a critical driver of cachexia, transducing systemic inflammatory messages stemming from acute and chronic disease processes into a local and paracrine inflammatory response in the central nervous system 23, 24, 25. Consistent with this evidence, KPC induces an array of genes responsive to inflammatory stimuli in the hypothalamus.…”

Section: Resultsmentioning

confidence: 79%

Establishment and characterization of a novel murine model of pancreatic cancer cachexia

Michaelis

Zhu

Burfeind

et al. 2017

J cachexia sarcopenia muscle

119

161

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BackgroundCachexia is a complex metabolic and behavioural syndrome lacking effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is one of the most important conditions associated with cachexia, with >80% of PDAC patients suffering from the condition. To establish the cardinal features of a murine model of PDAC‐associated cachexia, we characterized the effects of implanting a pancreatic tumour cell line from a syngeneic C57BL/6 KRASG12D P53R172H Pdx‐Cre+/+ (KPC) mouse.MethodsMale and female C57BL/6 mice were inoculated subcutaneously, intraperitoneally, or orthotopically with KPC tumour cells. We performed rigorous phenotypic, metabolic, and behavioural analysis of animals over the course of tumour development.ResultsAll routes of administration produced rapidly growing tumours histologically consistent with moderate to poorly differentiated PDAC. The phenotype of this model was dependent on route of administration, with orthotopic and intraperitoneal implantation inducing more severe cachexia than subcutaneous implantation. KPC tumour growth decreased food intake, decreased adiposity and lean body mass, and decreased locomotor activity. Muscle catabolism was observed in both skeletal and cardiac muscles, but the dominant catabolic pathway differed between these tissues. The wasting syndrome in this model was accompanied by hypothalamic inflammation, progressively decreasing brown and white adipose tissue uncoupling protein 1 (Ucp1) expression, and increased peripheral inflammation. Haematological and endocrine abnormalities included neutrophil‐dominant leukocytosis and anaemia, and decreased serum testosterone.ConclusionsSyngeneic KPC allografts are a robust model for studying cachexia, which recapitulate key features of the PDAC disease process and induce a wide array of cachexia manifestations. This model is therefore ideally suited for future studies exploring the physiological systems involved in cachexia and for preclinical studies of novel therapies.

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Section: Resultsmentioning

confidence: 79%

Establishment and characterization of a novel murine model of pancreatic cancer cachexia

Michaelis

Zhu

Burfeind

et al. 2017

J cachexia sarcopenia muscle

119

161

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“…[25][26][27] Disturbance of aforementioned humoural factors is the most common cause of a variety of clinical symptoms of cancer cachexia. 9 It was noticed that none of these elements, except for systemic inflammation (ie, high CRP), are incorporated into the criteria according to Evans et al and that it would be valuable to explore if adding humoural factors would mean a surplus in the diagnosis of cancer cachexia. Moreover, in view of the current therapeutic approach, which targets the fundamental pathways involved in the pathogenesis of cancer cachexia, 28 29 monitoring the humoural factors in daily practice would create the possibility to capture the diagnosis of cancer cachexia up close.…”

Section: Cancer Cachexia Assessment In Clinical Practicementioning

confidence: 99%

Cachexia in cancer: what is in the definition?

Vanhoutte

Wiel

Wouters

et al. 2016

BMJ Open Gastroenterol

112

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ObjectiveThis study aimed to provide evidence-based results on differences in overall survival (OS) rate to guide the diagnosis of cancer cachexia.DesignData collection and clinical assessment was performed every 3 months (5 visits): baseline data, muscle strength, nutritional and psychosocial status. 2 definitions on cachexia using different diagnostic criteria were applied for the same patient population. Fearon et al's definition is based on weight loss, body mass index (BMI) and sarcopenia. Evans et al nuances the contribution of sarcopenia and attaches additional attention to abnormal biochemistry parameters, fatigue and anorexia. The mean OS rates were compared between patients with and without cachexia for both definitions.ResultsBased on the population of 167 patients who enrolled, 70% developed cachexia according to Fearon et al's definition and 40% according to Evans et al's definition. The OS in the cachectic population is 0.97 and 0.55 years, respectively. The difference in OS between patients with and without cachexia is more significant using the diagnostic criteria of Evans et al. The focus of Fearon et al on weight loss and sarcopenia over-rates the assignment of patients to the cachectic group and OS rates have less prognostic value.ConclusionThis study presents a correlation with prognosis in favour of Evans et al’ definition as a tool for cachexia diagnosis. This means that weight loss and BMI decline are both key factors in patients with cancer leading to cachexia but less decisive as stated by Fearon et al. Instead, extra factors gain importance in order to predict survival, such as chronic inflammation, anaemia, protein depletion, reduced food intake, fatigue, decreased muscle strength and lean tissue depletion.Trial registration numberB300201112334.

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“…Even though the mechanisms behind muscle wasting have been widely studied, less is known about the factors implicated in adipose tissue loss in cancer cachectic patients, such as lipidmobilizing factor, as well as about the derangement in the neuroendocrine regulation of food intake and anorexia [60]. Additionally, changes in carbohydrate, lipid, and protein metabolism account for altered substrate metabolism.…”

Section: Mechanisms Of Malnutritionmentioning

confidence: 99%

Nutritional Management of Esophageal Cancer Patients

Schizas¹,

Lidoriki²,

Moris³

et al. 2017

Esophageal Abnormalities

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Esophageal cancer is associated with malnutrition in the vast majority of patients. This phenomenon is partly attributed to the disease process itself, the location of the tumor and other factors, such as dysphagia which is often accentuated due to chemotherapy/ radiotherapy treatment or surgical intervention. The poor nutritional status of these patients is often related to the presence of cancer cachexia, altered metabolism, and tissue wasting. Malnutrition in this patient population affects quality of life, worsens patient's tolerance to chemotherapy and accounts for lower survival. Nutritional management of these patients includes both proper nutritional assessment and support and might prevent, to a certain extent, the manifestation of malnutrition-related consequences. The purpose of this article is to review the current literature in order to focus on the etiology and diagnosis of malnutrition in esophageal cancer patients, emphasizing also on the optimal nutritional support during multimodality treatment.

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Molecular and neuroendocrine mechanisms of cancer cachexia

Cited by 78 publications

References 187 publications

Establishment and characterization of a novel murine model of pancreatic cancer cachexia

Establishment and characterization of a novel murine model of pancreatic cancer cachexia

Cachexia in cancer: what is in the definition?

Nutritional Management of Esophageal Cancer Patients

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