Inflammation Based Regulation of Cancer Cachexia

Onesti, Jill K.; Guttridge, Denis C.

doi:10.1155/2014/168407

Cited by 135 publications

(137 citation statements)

References 86 publications

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“…Previous studies have demonstrated that systemic inflammation, particularly NF-κB-evoked pro-inflammatory cytokine formation, plays a critical role in inducing muscle wasting by activating the UPS through inhibition of Akt activity and impairment of muscle differentiation and myogenesis [27–29]. The levels of pro-inflammatory cytokines in the serum and NF-κB activation are dramatically increased in patients with cancer cachexia [28].…”

Section: Discussionmentioning

confidence: 99%

Combined administration of fucoidan ameliorates tumor and chemotherapy-induced skeletal muscle atrophy in bladder cancer-bearing mice

et al. 2016

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Cancer cachexia is characterized by anorexia, skeletal muscle atrophy, and systemic inflammation. Fucoidan extracted from brown algae exhibits anti-inflammatory and anticancer activities. However, whether fucoidan ameliorates tumour and chemotherapy-induced muscle atrophy and -related cachectic symptoms remains unknown. Compared with mice with bladder cancer treated with chemotherapy alone (TGC group), those treated with a combination of low molecular weight fucoidan (LMWF) and chemotherapy drugs such as gemcitabine and cisplatin (TGCF) showed a significant reduction of body weight loss, muscle atrophy, and intestinal injury and dysfunction. Moreover, myostatin, activin A, and pro-inflammatory cytokine production, FoxO3 expression and activation, NF-κB activation, MuRF-1 and MAFbx/atrogin-1 expression, and proteasome activity in muscle were significantly decreased in the TGCF group compared with the TGC group. In addition, insulin-like growth factor 1 (IGF-1) expression and formation, and IGF-1-regulated mTOR/p70S6k/4EBP-1 protein synthesis signalling were elevated in the TGCF group compared with the TGC group. Taken together, these results suggest that LMWF is a potential agent for preventing cancer cachexia-associated muscle atrophy during chemotherapy. Furthermore, the beneficial effect of LMWF may be attributed to suppressing NF-κB-evoked inflammation, myostatin and activin A production, and subsequent muscle proteolysis, and enhancing IGF-1-dependent protein synthesis.

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Section: Discussionmentioning

confidence: 99%

Combined administration of fucoidan ameliorates tumor and chemotherapy-induced skeletal muscle atrophy in bladder cancer-bearing mice

et al. 2016

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“…Mouse models of cancer cachexia like the Apc Min/+ and C-26 adenocarcinoma implant models, have demonstrated a clear dependence on IL-6, with IL-6 signaling inhibition being able to attenuate cachexia progression [1, 2]. However, another widely used mouse implant model, Lewis Lung Carcinoma, has been equivocal related to IL-6 dependence [32].…”

Section: Il-6 Targeted Therapeutics: Progress In Preclinical Models Omentioning

confidence: 99%

“…Cancer cachexia is wasting syndrome that occurs in approximately 80% of cancer patients and is the primary cause of death for 22–30% of all cancer patients [1, 2]. A significant complication related to prevention of cachexia is that cancer patients are not usually diagnosed with cachexia until they have lost more than 5-7% of body mass [3, 4].…”

Section: Introductionmentioning

confidence: 99%

“…Chronic inflammation in cachectic patients is often a combination of both tumor and host derived factors. A multitude of cytokines including; TNF–α, IL-1β IL-6, glucocorticoids, and myostatin have been implicated in facilitating a cachectic state [1, 2, 9]. Researchers have been examining potential cachexia treatments for some time and extensive research has emerged on the role of individual cytokines for regulating cachexia progression in rodent cancer models.…”

Section: Introductionmentioning

confidence: 99%

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Role of interleukin-6 in cachexia

Narsale¹,

Carson²

2014

Current Opinion in Supportive &Amp; Palliative Care

173

148

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Purpose of review Interleukin-6 (IL-6) has emerged as a cytokine involved in cachexia progression with some cancers. This review will present recent breakthroughs in animal models and humans related to targeting IL-6 as a cancer cachexia therapy. Recent Findings IL-6 can target adipose, skeletal muscle, gut, and liver tissue, which can all affect cachectic patient recovery. IL-6 trans-signaling through the soluble IL-6r has the potential to amplify IL-6 signaling in the cachectic patient. In skeletal muscle chronic IL-6 exposure induces proteasome and autophagy protein degradation pathways that lead to wasting. IL-6 is also indirectly associated with AMPK and NF-κB activation. Several mouse cancer models have clearly demonstrated that blocking IL-6 and associated signaling can attenuate cachexia progression. Additionally, pharmaceuticals targeting IL-6 and associated signaling can relieve some cachectic symptoms in cancer patients. Research with cachectic mice has demonstrated that exercise and nutraceutical administration can interact with chronic IL-6 signaling during cachexia progression. Summary IL-6 remains a promising therapeutic strategy for attenuating cachexia progression with many types of cancer. However, improvement of this treatment will require a better understanding of the indirect and direct effects of IL-6 as well as its tissue specific actions in the cancer patient.

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“…In several rodent models of cachexia and some human cancers, IL-6 is associated with the development of muscle wasting and body weight loss (6, 8, 19-21). Classical IL-6 signaling involves binding of the cytokine to the membrane-bound IL-6 receptor (mIL-6r) on target tissues, which include hepatocytes, immune cells, and skeletal muscle (22-24). mIL-6r is a heterodimer comprising the ligand-specific gp80 unit and the signal-transducing gp130 unit (25).…”

Section: Introductionmentioning

confidence: 99%

Sex differences in the relationship of IL-6 signaling to cancer cachexia progression

Hetzler

Hardee

Puppa

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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A devastating aspect of cancer cachexia is severe loss of muscle and fat mass. Though cachexia occurs in both sexes, it is not well-defined in the female. The Apc Min/+ mouse is genetically predisposed to develop intestinal tumors; circulating IL-6 is a critical regulator of cancer cachexia in the male Apc Min/+ mouse. The purpose of this study was to examine the relationship between IL-6 signaling and cachexia progression in the female Apc Min/+ mouse. Male and female Apc Min/+ mice were examined during the initiation and progression of cachexia. Another group of females had IL-6 overexpressed between 12-14 weeks or 15-18 weeks of age to determine whether IL-6 could induce cachexia. Cachectic female Apc Min/+ mice lost body weight, muscle mass, and fat mass; increased muscle IL-6 mRNA expression was associated with these changes, but circulating IL-6 levels were not. Circulating IL-6 levels did not correlate with downstream signaling in muscle in the female. Muscle IL-6r mRNA expression and SOCS3 mRNA expression as well as muscle IL-6r protein and STAT3 phosphorylation increased with severe cachexia in both sexes. Muscle SOCS3 protein increased in cachectic females but decreased in cachectic males. IL-6 overexpression did not affect cachexia progression in female Apc Min/+ mice. Our results indicate that female Apc Min/+ mice undergo cachexia progression that is at least initially IL-6-independent. Future studies in the female will need to determine mechanisms underlying regulation of IL-6 response and cachexia induction.

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Inflammation Based Regulation of Cancer Cachexia

Cited by 135 publications

References 86 publications

Combined administration of fucoidan ameliorates tumor and chemotherapy-induced skeletal muscle atrophy in bladder cancer-bearing mice

Combined administration of fucoidan ameliorates tumor and chemotherapy-induced skeletal muscle atrophy in bladder cancer-bearing mice

Role of interleukin-6 in cachexia

Sex differences in the relationship of IL-6 signaling to cancer cachexia progression

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