Tumor necrosis factor-alpha mediates changes in tissue protein turnover in a rat cancer cachexia model.

Costelli, Paola; Carbó, Neus; Tessitore, Luciana; Bagby, Gregory J.; López‐Soriano, Francisco J.; Argilés, Josep Μ.; Baccino, Francesco M.

doi:10.1172/jci116897

Cited by 280 publications

(173 citation statements)

References 39 publications

(36 reference statements)

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“…As a final remark, tumour necrosis factor (TNF) is an important mediator of cachexia in AH-130 tumour-bearing rats (Costelli et al, 1993;Tessitore et al, 1993a;Llovera et al, 1996) and in other situations. A reported effect of this cytokine, on some cell types at least, is to cause [Ca 2+ ] i elevations (Bick et al, 1997;Furukawa and Mattson, 1998), which, in the light of the present observations, might well have a role in activating the Ca 2+ -dependent proteolysis.…”

Section: Discussionmentioning

confidence: 99%

Activation of Ca2+-dependent proteolysis in skeletal muscle and heart in cancer cachexia

et al. 2001

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Cachexia is a syndrome characterized by profound tissue wasting that frequently complicates malignancies. In a cancer cachexia model we have shown that protein depletion in the skeletal muscle, which is a prominent feature of the syndrome, is mostly due to enhanced proteolysis. There is consensus on the views that the ubiquitin/proteasome pathway plays an important role in such metabolic response and that cytotoxic cytokines such as TNFα are involved in its triggering (Costelli and Baccino, 2000), yet the mechanisms by which the relevant extracellular signals are transduced into protein hypercatabolism are largely unknown. Moreover, little information is presently available as to the possible involvement in muscle protein waste of the Ca 2+ -dependent proteolysis, which may provide a rapidly activated system in response to the extracellular signals. In the present work we have evaluated the status of the Ca 2+ -dependent proteolytic system in the gastrocnemius muscle of AH-130 tumour-bearing rats by assaying the activity of calpain as well as the levels of calpastatin, the natural calpain inhibitor, and of the 130 kDa Ca 2+ -ATPase, both of which are known calpain substrates. After tumour transplantation, total calpastatin activity progressively declined, while total calpain activity remained unchanged, resulting in a progressively increasing unbalance in the calpain/calpastatin ratio. A decrease was also observed for the 130 kDa plasma membrane form of Ca 2+ -ATPase, while there was no change in the level of the 90 kDa sarcoplasmic Ca 2+ -ATPase, which is resistant to the action of calpain. Decreased levels of both calpastatin and 130 kDa Ca 2+ -ATPase have been also detected in the heart of the tumour-bearers. These observations strongly suggest that Ca 2+ -dependent proteolysis was activated in the skeletal muscle and heart of tumour-bearing animals and raise the possibility that such activation may play a role in sparking off the muscle protein hypercatabolic response that characterizes cancer cachexia. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Section: Discussionmentioning

confidence: 99%

Activation of Ca2+-dependent proteolysis in skeletal muscle and heart in cancer cachexia

et al. 2001

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“…1,3 Although little is known about the precise mechanism of cachexia, recent studies indicate that inappropriate production and release of cytokines such as tumor necrosis factor-␣ (TNF-␣), interleukin-1 (IL-1), interleukin-6 (IL-6) and interferon-␥, which are secreted from both cancer cells and host tissues, are involved in the induction of cachexia. [4][5][6][7][8] These cytokines have been pos-tulated to cause metabolic changes in the host, associated with enhanced energy requirements for tumor growth, resulting in the loss of adipose and muscle tissues. Blockade of the cytokines by their antibodies reversed the body weight loss and tissue wasting without affecting tumor growth.…”

Section: Introductionmentioning

confidence: 99%

Intratumoral injection of oligonucleotides to the NFκB binding site inhibits cachexia in a mouse tumor model

Kawamura¹,

et al. 1999

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Cancer cachexia, characterized by anorexia, weight loss muscle mass and food intake, which were induced by the and progressive tissue wasting, has been postulated to be tumor presence. Interleukin 6 mRNA in the tumor was also mediated by various cytokines. However, the precise markedly decreased by the transfection of NF B decoy mechanism of cachexia induction is not fully explained. We ODN. It is known that the transcriptional factor E2F plays have developed synthetic double-stranded oligodeoxynua pivotal role in the coordinated transactivation of cell cycle cleotides (ODN) as 'decoy' cis-elements that block the regulatory genes. Therefore, we hypothesized that the binding of nuclear factors to promoter regions of targeted introduction of synthetic double-stranded DNA with high genes, resulting in the inhibition of gene transactivation in affinity for E2F in vivo as 'decoy' cis-elements might inhibit vivo as well as in vitro. This novel molecular strategy could the tumor growth of colon26, resulting in turn in inhibition of be useful for treating a broad range of human diseases cachexia induction. However, injection of E2F decoy ODN including cancer. In this study, we injected decoy ODN tarfailed to inhibit tumor growth and cachexia induction, as geting the transcriptional factor, NF-kappaB (NF B) bindcompared with mismatched decoy ODN. Overall, the ing cis-elements, which are essential for transactivation of present study demonstrated that cachexia induced by gene expression of cytokines, directly into tumors of adenocarcinoma colon26 was inhibited by blocking of adenocarcinoma colon26 in mice, in order to examine NF B, using a novel molecular decoy strategy, without an whether or not cachexia is alleviated by inhibiting the action effect on tumor growth, and also that tumor growth and of cytokines. Tumor growth was not affected by transfeccachexia induction in the colon26 model were not affected tion of NF B decoy ODN as compared with scrambled by E2F decoy ODN. These results suggest that cytokines decoy ODN. Nevertheless, transfection of NF B decoy, but regulated by NF B may play a pivotal role in the induction not scrambled decoy, ODN resulted in attenuation of the of cachexia by colon26, providing a new therapeutic reductions in body weight, epididymal fat, gastrocnemius strategy for cancer cachexia.

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“…As an example, muscle wasting, increased ubiquitin expression and proteasome enzymatic activity are induced in healthy animals by administration of TNF or IL-1 (reviewed in Tisdale, 2008). Consistently, at least in cancer cachexia, many years ago few studies demonstrated the crucial role played by cytokines in the onset of muscle wasting, showing that loss of muscle mass, protein hypercatabolism and ubiquitin hyperexpression could be prevented by treatment of tumor-bearing animals with antibodies directed against IL-6, TNF, or IFN (Matthys et al, 1991;Costelli et al, 1993;Strassmann et al, 1993). Altered cytokine homeostasis, positively correlated with disease progression and mortality rates, was reported also in cancer patients (Attard-Montalto et al, 1998;Nakashima et al, 1998).…”

Section: Inflammationmentioning

confidence: 96%

“…Only few data are actually available about the effectiveness of such kind of drugs in preventing or delaying cancer cachexia. In this regard, anti-TNF antibodies, while not an antagonist of IL-1 receptor, proved effective in reducing anorexia, body weight loss and protein hypercatabolism in tumor-bearing rats (Costelli et al, 1993;Costelli et al, 1995). More recently, a clinical trial performed on advanced cancer patients receiving etanercept showed the lack of any significant improvement of weight loss, anorexia and survival rate (Jatoi et al, 2007).…”

Section: Inhibition Of Cytokine Productionmentioning

confidence: 99%

“…Such a strategy appears to work perfectly well in several experimental models of muscle wasting including denervation, amyotrophic lateral sclerosis, disuse (reviewed in Glass, 2010). However, it is useless in experimental cancer cachexia, where, despite high protein breadown rates occur, the insulin/IGF-1 pathway is not down-regulated, protein synthesis rates are only slightly reduced or even unchanged, and the protein synthetic signaling is poised into the activated state (Costelli et al, 1993;Penna, Bonetto, et al, 2010;Aversa et al, 2012).…”

Section: Strategies To Correct Metabolic Alterationsmentioning

confidence: 99%

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Mechanism-Based Therapeutic Approaches to Cachexia

et al. 2013

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Cachexia is a multifactorial syndrome characterized by body weight loss, depletion of adipose tissue and skeletal muscle mass, and marked alterations of the metabolic homeostasis.The occurrence of cachexia significantly impinges on patient's morbidity and mortality, and on quality of life. Inflammation, anorexia/malnutrition, alterations of protein and lipid metabolism are among the main mechanisms involved in the development of cachexia. While anorexia and malnutrition are long known contributing factors, the mechanisms leading to inflammation and metabolic alterations were clarified later on. On these premises, several therapeutic approaches were proposed. Most of them are in the pre-clinical phase, but some already reached the clinical experimentation. The present review will focus on treatment options proposed on the basis of mechanistic alterations. In this regard, in addition to nutritional and anti-inflammatory strategies, also approaches based on perturbation of specific signal transduction pathways are taken into consideration.

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Tumor necrosis factor-alpha mediates changes in tissue protein turnover in a rat cancer cachexia model.

Cited by 280 publications

References 39 publications

Activation of Ca2+-dependent proteolysis in skeletal muscle and heart in cancer cachexia

Activation of Ca2+-dependent proteolysis in skeletal muscle and heart in cancer cachexia

Intratumoral injection of oligonucleotides to the NFκB binding site inhibits cachexia in a mouse tumor model

Mechanism-Based Therapeutic Approaches to Cachexia

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