Adipose atrophy in cancer cachexia: morphologic and molecular analysis of adipose tissue in tumour-bearing mice

Chen, Bing; Russell, Stewart; Becket, E.; Pope, Marion; Tisdale, Michael J.; Trayhurn, Paul; Jenkins, Jennifer

doi:10.1038/sj.bjc.6603360

Cited by 149 publications

(191 citation statements)

References 34 publications

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“…This pattern is also observed at the tissue level, as morphological examination has shown marked changes in adipose tissue plasticity in mice with cancer cachexia compared with ad libitum-fed and pair-fed controls (26) . Adipose tissue from tumour-bearing mice contains shrunken adipocytes of various sizes with a dilated interstitial space.…”

Section: Adipose Atrophy In Cachexiamentioning

confidence: 59%

“…1). Moreover, the ultrastructural features of 'slimmed' adipocytes are characterised by severe delipidation and alterations in cell membrane conformation, with irregular cytoplamic projections and increased (26) . )…”

Section: Adipose Atrophy In Cachexiamentioning

confidence: 99%

“…Recent work has demonstrated that recombinant ZAG stimulates lipolysis in human adipocytes (T Mracek, (26) .) P Trayhurn and C Bing, unpublished results).…”

Section: Adipose-derived Zag In Cancer Cachexiamentioning

confidence: 99%

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New insights into adipose tissue atrophy in cancer cachexia

Chen

Trayhurn

2009

Proc. Nutr. Soc.

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Profound loss of adipose and other tissues is a hallmark of cancer cachexia, a debilitating condition associated with increased morbidity and mortality. Fat loss cannot be attributable to reduced appetite alone as it precedes the onset of anorexia and is much more severe in experimental models of cachexia than in food restriction. Morphological examination has shown marked remodelling of adipose tissue in cancer cachexia. It is characterised by the tissue containing shrunken adipocytes with a major reduction in cell size and increased fibrosis in the tissue matrix. The ultrastructure of ‘slimmed’ adipocytes has revealed severe delipidation and modifications in cell membrane conformation. Although the molecular mechanisms remain to be established, evidence suggests that altered adipocyte metabolism may lead to adipose atrophy in cancer cachexia. Increased lipolysis appears to be a key factor underlying fat loss, while inhibition of adipocyte development and lipid deposition may also contribute. Both tumour and host-derived factors are implicated in adipose atrophy. Zinc-α2-glycoprotein (ZAG), which is overexpressed by certain malignant tumours, has been identified as a novel adipokine. ZAG transcripts and protein expression in adipose tissue are up regulated in cancer cachexia but reduced with adipose tissue expansion in obesity. Studies in vitro demonstrate that recombinant ZAG stimulates lipolysis. ZAG may therefore act locally, as well as systemically, to promote lipid mobilisation in cancer cachexia. Further elucidation of ZAG function in adipose tissue may lead to novel targets for preventing adipose atrophy in malignancy.

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Section: Adipose Atrophy In Cachexiamentioning

confidence: 59%

Section: Adipose Atrophy In Cachexiamentioning

confidence: 99%

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New insights into adipose tissue atrophy in cancer cachexia

Chen

Trayhurn

2009

Proc. Nutr. Soc.

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“…Such changes in fat cell volume may alter the demand of nutrient and oxygen support by the microvasculature, thereby necessitating an adaptation of the structure of the extracellular matrix. In rodent models of cachexia, WAT is characterised by shrunken adipocytes with dramatically reduced cell size and dilated interstitial space (Bing et al, 2006). Furthermore, the shrinking fat cell may have to adjust its cytoskeleton to maintain its intracellular volume to account for the remaining lipid droplet.…”

Section: Discussionmentioning

confidence: 99%

Adipose tissue pathways involved in weight loss of cancer cachexia

et al. 2010

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BACKGROUND: The regulatory gene pathways that accompany loss of adipose tissue in cancer cachexia are unknown and were explored using pangenomic transcriptome profiling. METHODS: Global gene expression profiles of abdominal subcutaneous adipose tissue were studied in gastrointestinal cancer patients with (n ¼ 13) or without (n ¼ 14) cachexia. RESULTS: Cachexia was accompanied by preferential loss of adipose tissue and decreased fat cell volume, but not number. Adipose tissue pathways regulating energy turnover were upregulated, whereas genes in pathways related to cell and tissue structure (cellular adhesion, extracellular matrix and actin cytoskeleton) were downregulated in cachectic patients. Transcriptional response elements for hepatic nuclear factor-4 (HNF4) were overrepresented in the promoters of extracellular matrix and adhesion molecule genes, and adipose HNF4 mRNA was downregulated in cachexia. CONCLUSIONS: Cancer cachexia is characterised by preferential loss of adipose tissue; muscle mass is less affected. Loss of adipose tissue is secondary to a decrease in adipocyte lipid content and associates with changes in the expression of genes that regulate energy turnover, cytoskeleton and extracellular matrix, which suggest high tissue remodelling. Changes in gene expression in cachexia are reciprocal to those observed in obesity, suggesting that regulation of fat mass at least partly corresponds to two sides of the same coin.

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“…63 A murine model of animals implanted with murine adenocarcinoma 16 (MAC16) tumors reported changes in adipose tissue that included shrunken adipocytes and decreased expression of adipose tissue transcription factors. 64 From a clinical perspective, a critical component of the body mass loss observed in CAC is the depletion of muscle mass, which usually precedes the observation of significant changes in adipose tissue mass and is associated with decrease in muscle function and mobility. Fearon et al's 5 consensus findings highlight that skeletal muscle loss is a necessity for a clinical diagnosis of CAC, but that adipose tissue loss may or not be present.…”

Section: Adipose Tissue Contributions To Cac Lipolysismentioning

confidence: 99%

The role of adipose tissue in cancer-associated cachexia

Vaitkus

Celi

2016

Exp Biol Med (Maywood)

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Adipose tissue (fat) is a heterogeneous organ, both in function and histology, distributed throughout the body. White adipose tissue, responsible for energy storage and more recently found to have endocrine and inflammation-modulatory activities, was historically thought to be the only type of fat present in adult humans. The recent demonstration of functional brown adipose tissue in adults, which is highly metabolic, shifted this paradigm. Additionally, recent studies demonstrate the ability of white adipose tissue to be induced toward the brown adipose phenotype – “beige” or “brite” adipose tissue – in a process referred to as “browning.” While these adipose tissue depots are under investigation in the context of obesity, new evidence suggests a maladaptive role in other metabolic disturbances including cancer-associated cachexia, which is the topic of this review. This syndrome is multifactorial in nature and is an independent factor associated with poor prognosis. Here, we review the contributions of all three adipose depots – white, brown, and beige – to the development and progression of cancer-associated cachexia. Specifically, we focus on the local and systemic processes involving these adipose tissues that lead to increased energy expenditure and sustained negative energy balance. We highlight key findings from both animal and human studies and discuss areas within the field that need further exploration. Impact statement Cancer-associated cachexia (CAC) is a complex, multifactorial syndrome that negatively impacts patient quality of live and prognosis. This work reviews a component of CAC that lacks prior discussion: adipose tissue contributions. Uniquely, it discusses all three types of adipose tissue, white, beige, and brown, their interactions, and their contributions to the development and progression of CAC. Summarizing key bench and clinical studies, it provides information that will be useful to both basic and clinical researchers in designing experiments, studies, and clinical trials.

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Adipose atrophy in cancer cachexia: morphologic and molecular analysis of adipose tissue in tumour-bearing mice

Cited by 149 publications

References 34 publications

New insights into adipose tissue atrophy in cancer cachexia

New insights into adipose tissue atrophy in cancer cachexia

Adipose tissue pathways involved in weight loss of cancer cachexia

The role of adipose tissue in cancer-associated cachexia

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