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Adipose tissue pathways involved in weight loss of cancer cachexia.

ABSTRACT: 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=13) or without (n=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.

SUBMITTER: Dahlman I

PROVIDER: S-EPMC2869165 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Adipose tissue pathways involved in weight loss of cancer cachexia.

Dahlman I I Mejhert N N Linder K K Agustsson T T Mutch D M DM Kulyte A A Isaksson B B Permert J J Petrovic N N Nedergaard J J Sjölin E E Brodin D D Clement K K Dahlman-Wright K K Rydén M M Arner P P

British journal of cancer 20100420 10

<h4>Background</h4>The regulatory gene pathways that accompany loss of adipose tissue in cancer cachexia are unknown and were explored using pangenomic transcriptome profiling.<h4>Methods</h4>Global gene expression profiles of abdominal subcutaneous adipose tissue were studied in gastrointestinal cancer patients with (n=13) or without (n=14) cachexia.<h4>Results</h4>Cachexia was accompanied by preferential loss of adipose tissue and decreased fat cell volume, but not number. Adipose tissue pathw ...[more]

PMID: 20407445

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Project description:BackgroundCancer cachexia represents a central obstacle in medical oncology as it is associated with poor therapy response and reduced overall survival. Systemic inflammation is considered to be a key driver of cancer cachexia; however, clinical studies with anti-inflammatory drugs failed to show distinct cachexia-inhibiting effects. To address this contradiction, we investigated the functional importance of innate immune cells for hepatocellular carcinoma (HCC)-associated cachexia.MethodsA transgenic HCC mouse model was intercrossed with mice harbouring a defect in myeloid cell-mediated inflammation. Body composition of mice was analysed via nuclear magnetic resonance spectroscopy and microcomputed tomography. Quantitative PCR was used to determine adipose tissue browning and polarization of adipose tissue macrophages. The activation state of distinct areas of the hypothalamus was analysed via immunofluorescence. Multispectral immunofluorescence imaging and immunoblot were applied to characterize sympathetic neurons and macrophages in visceral adipose tissue. Quantification of pro-inflammatory cytokines in mouse serum was performed with a multiplex immunoassay. Visceral adipose tissue of HCC patients was quantified via the L3 index of computed tomography scans obtained during routine clinical care.ResultsWe identified robust cachexia in the HCC mouse model as evidenced by a marked loss of visceral fat and lean mass. Computed tomography-based analyses demonstrated that a subgroup of human HCC patients displays reduced visceral fat mass, complementing the murine data. While the myeloid cell-mediated inflammation defect resulted in reduced expression of pro-inflammatory cytokines in the serum of HCC-bearing mice, this unexpectedly did not translate into diminished but rather enhanced cachexia-associated fat loss. Defective myeloid cell-mediated inflammation was associated with decreased macrophage abundance in visceral adipose tissue, suggesting a role for local macrophages in the regulation of cancer-induced fat loss.ConclusionsMyeloid cell-mediated inflammation displays a rather unexpected beneficial function in a murine HCC model. These results demonstrate that immune cells are capable of protecting the host against cancer-induced tissue wasting, adding a further layer of complexity to the pathogenesis of cachexia and providing a potential explanation for the contradictory results of clinical studies with anti-inflammatory drugs.

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Adipose tissue pathways involved in weight loss of cancer cachexia.

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Adipose tissue pathways involved in weight loss of cancer cachexia.

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