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Cachexia is a wasting syndrome that manifests in more than half of all cancer patients. Cancer‐associated cachexia negatively influences the survival of patients and their quality of life. It is characterized by a rapid loss of adipose and skeletal muscle tissues, which is partly mediated by inflammatory cytokines. Here, we explored the crucial roles of interleukin‐6 (IL‐6) family cytokines, including IL‐6, leukemia inhibitory factor, and oncostatin M, in the development of cancer cachexia. These cytokines have been shown to exacerbate cachexia by promoting the wasting of adipose and muscle tissues, activating mechanisms that enhance lipolysis and proteolysis. Overlapping effects of the IL‐6 family cytokines depend on janus kinase/signal transducer and activator of transcription 3 signaling. We argue that the blockade of these cytokine pathways individually may fail due to redundancy and future therapeutic approaches should target common downstream elements to yield effective clinical outcomes. [ABSTRACT FROM AUTHOR]

Purpose: of review Cachexia is a debilitating condition causing weight loss and skeletal muscle wasting that negatively influences treatment and survival of cancer patients. The objective of this review is to describe recent discoveries on the role of a novel signaling pathway involving ectodysplasin A2 receptor (EDA2R) and nuclear factor κB (NFκB)-inducing kinase (NIK) in muscle atrophy. Recent findings: Studies identified tumor-induced upregulation of EDA2R expression in muscle tissues in pre-clinical cachexia models and patients with various cancers. Activation of EDA2R by its ligand promoted atrophy in cultured myotubes and muscle tissue, which depended on NIK activity. The non-canonical NFκB pathway via NIK also stimulated muscle atrophy. Mice lacking EDA2R or NIK were protected from muscle loss due to tumors. Tumorinduced cytokine oncostatin M (OSM) upregulated EDA2R expression in muscles whereas OSM receptordeficient mice were resistant to muscle wasting. Summary: Recent discoveries revealed a mechanism involving EDA2R-NIK signaling and OSM that drives cancerassociated muscle loss, opening up new directions for designing anti-cachexia treatments. The therapeutic potential of targeting this mechanism to prevent muscle loss should be further investigated. Future research should also explore broader implications of the EDA2R-NIK pathway in other muscle wasting diseases and overall muscle health. [ABSTRACT FROM AUTHOR]

Objective: Thermogenesis in white and brown adipose tissues can be induced by various stimuli, including cold exposure, β-adrenergic stimulation, and tumor growth. Fibroblast growth factor (FGF) 21 has emerged as an important mediator of thermogenesis. This study investigated the involvement of other FGF family members in the regulation of adipose tissue thermogenesis. Materials and Methods: Mice were exposed to cold and administrated a β-adrenergic agonist (CL-316,243) to stimulate a thermogenic response in adipose tissues. Stromavascular fractions isolated from white and brown adipose tissues were cultured and differentiated into primary adipocytes. These cells were treated with recombinant FGFs. Changes in the expression levels of thermogenic genes and FGFs were determined by real-time quantitative PCR. Results: Cold exposure stimulated thermogenic gene expression in the adipose tissue, which was accompanied by the upregulation of certain FGFs. Ffg9 and Fgf21 were prominently induced in white and brown adipose tissues. β-adrenergic stimulation also upregulated thermogenic genes in adipocytes. Fgf21 was identified as the main responder to the β-adrenergic pathway. The administration of recombinant FGFs to cultured primary white and brown adipocytes induced thermogenic genes, including uncoupling protein-1 (Ucp1). FGF2, FGF9, and FGF21 triggered the most significant Ucp1-inducing effects in these cells. Conclusion: FGF21 is as a prominent inducer of thermogenesis in adipose tissue and a promising therapeutic target against cardiovascular and metabolic diseases. FGF2 and FGF9 potently promote thermogenic gene expression in adipocytes. Therefore, their therapeutic targeting should be considered to enhance energy metabolism in adipose tissues. [ABSTRACT FROM AUTHOR]

Cachexia is a wasting disorder that accompanies many chronic diseases such as cancer and congestive heart failure. The hallmarks of cachexia are weight loss with atrophy of fat and skeletal [...], Cachexia is a wasting disorder of adipose and skeletal muscle tissues that leads to profound weight loss and frailty. About half of all cancer patients suffer from cachexia, which impairs quality of life, limits cancer therapy and decreases survival. One key characteristic of cachexia is higher resting energy expenditure levels than in healthy individuals, which has been linked to greater thermogenesis by brown fat (1-6). How tumours induce brown fat activity is unknown. Here, using a Lewis lung carcinoma model of cancer cachexia, we show that tumour-derived parathyroid-hormone-related protein (PTHrP) has an important role in wasting, through driving the expression of genes involved in thermogenesis in adipose tissues. Neutralization of PTHrP in tumour-bearing mice blocked adipose tissue browning and the loss of muscle mass and strength. Our results demonstrate that PTHrP mediates energy wasting in fat tissues and contributes to the broader aspects of cancer cachexia. Thus, neutralization of PTHrP might hold promise for ameliorating cancer cachexia and improving patient survival.

Abstract Background Accuracy in the diagnosis of breast cancer and classification of cancer subtypes has improved over the years with the development of well-established immunohistopathological criteria. More recently, diagnostic gene-sets at the mRNA expression level have been tested as better predictors of disease state. However, breast cancer is heterogeneous in nature; thus extraction of differentially expressed gene-sets that stably distinguish normal tissue from various pathologies poses challenges. Meta-analysis of high-throughput expression data using a collection of statistical methodologies leads to the identification of robust tumor gene expression signatures. Methods A resampling-based meta-analysis strategy, which involves the use of resampling and application of distribution statistics in combination to assess the degree of significance in differential expression between sample classes, was developed. Two independent microarray datasets that contain normal breast, invasive ductal carcinoma (IDC), and invasive lobular carcinoma (ILC) samples were used for the meta-analysis. Expression of the genes, selected from the gene list for classification of normal breast samples and breast tumors encompassing both the ILC and IDC subtypes were tested on 10 independent primary IDC samples and matched non-tumor controls by real-time qRT-PCR. Other existing breast cancer microarray datasets were used in support of the resampling-based meta-analysis. Results The two independent microarray studies were found to be comparable, although differing in their experimental methodologies (Pearson correlation coefficient, R = 0.9389 and R = 0.8465 for ductal and lobular samples, respectively). The resampling-based meta-analysis has led to the identification of a highly stable set of genes for classification of normal breast samples and breast tumors encompassing both the ILC and IDC subtypes. The expression results of the selected genes obtained through real-time qRT-PCR supported the meta-analysis results. Conclusion The proposed meta-analysis approach has the ability to detect a set of differentially expressed genes with the least amount of within-group variability, thus providing highly stable gene lists for class prediction. Increased statistical power and stringent filtering criteria used in the present study also make identification of novel candidate genes possible and may provide further insight to improve our understanding of breast cancer development.