The role of adipose tissue in cancer-associated cachexia

Abstract

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.

Cancer cachexia and its pathophysiology: links with sarcopenia, anorexia and asthenia

“…The importance of pathologic changes in adipose tissue has been increasingly recognized in recent years, and some of those changes are involved in cachexia ( Figure ) . Histologically, there are two types of adipose tissue: white adipose tissue (WAT), which is mostly involved in energy storage in the form of triglycerides, and brown adipose tissue (BAT) involved in thermoregulation . Until recently, BAT was thought to be functionally present only on neonates, but in fact is also present in adults …”

“…During cancer cachexia, WAT cells may acquire some of the features that characterize BAT cells (‘beige adipocytes’), a process known as ‘WAT browning’ that takes place during the initial steps of cancer cachexia, before muscle wasting . BAT is an active tissue associated with hypermetabolism because of the presence of UCP1 .…”

Low Levels of High-density Lipoprotein in Patients with Pediatric Cancer at Diagnosis

“…The presence of malignant tumor cells stimulates the host to produce cytokines and other pro-inflammatory mediators responsible for alterations in substrate metabolism. In some studies with cancer patients, albumin has been suggested as a prognostic factor and its alterations may be associated with other aspects, in addition to the inflammatory response 40,41 . This profile depends on the cancer diagnosis and stage/ severity of the disease 36 .…”

Tumour‐derived transforming growth factor‐β signalling contributes to fibrosis in patients with cancer cachexia

“…Chronic inflammation has been reported in the majority of patients with CAC and causes disruption of morphofunctional aspects of many tissues, such as the brain, the adipose tissue, and the muscle, while also affecting tumour biology . The secretory profile of the tumour may be associated with cachexia–muscle wasting, as proposed by de Matos‐Neto et al .…”

“…3 Clinically, CAC consists of chronic systemic inflammation and catabolism, leading to reduction of quality of life, diminished treatment tolerance, tumour metabolic reprograming, and, consequently, decreased survival. [4][5][6] Chronic inflammation has been reported in the majority of patients with CAC 7 and causes disruption of morphofunctional aspects of many tissues, such as the brain, 8,9 the adipose tissue, [10][11][12][13] and the muscle, 14,15 while also affecting tumour biology. 5,16 The secretory profile of the tumour may be associated with cachexia-muscle wasting, as proposed by de Matos-Neto et al.…”