New insights into adipose tissue atrophy in cancer cachexia

Abstract

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.

Heterogeneous time-dependent response of adipose tissue during the development of cancer cachexia

“…Involuntary weight loss, such as that present in cancer cachexia, causes a decrease in the size of adipocytes without changes in their number, resulting in adipose tissue atrophy (Bing & Trayhurn 2009). Bing et al (2006) showed that the epididymal adipose tissue (EAT) of cachectic mice contained shrunken adipocytes with dramatically reduced cell size that may have resulted from the down-regulation of key adipogenic and lipogenic factors.…”

Zinc-α2-glycoprotein: an adipokine modulator of body fat mass?

“…31 However, the most studied property of ZAG is its involvement in lipid metabolism associated with adipose tissue atrophy in cachexia. 32 …”

Carcinoma-associated fibroblasts: orchestrating the composition of malignancy

“…The recombination of wing epithelium with leg (fibroblastic) mesenchyme resulted in the generation of scales instead of feathers (Dhouailly et al 1978). Thus, each of the components of the stroma described above is essential for proper tissue homeostasis, maintaining architecture, and, most importantly, physiologically appropriate functions (Kalluri and Zeisberg 2006;Tlsty and Coussens 2006;Bing and Trayhurn 2009). …”

“…As we now know, alterations of each of these stromal cell types can contribute to the tumorigenic process through remodeling of the stroma (Karagiannis et al 2012) and widespread dysregulation of cell signaling and intercellular cross-talk (Kalluri and Zeisberg 2006;Tlsty and Coussens 2006;Bing and Trayhurn 2009;Ishii et al 2016). Similar to reports for the malignant epithelium, the malignant stroma exhibits expression profiles that provide prognostic information independent of epithelial biomarkers (Finak et al 2008;Ma et al 2009;Ostman and Augsten 2009;Sharma et al 2010).…”