Cachexia-associated adipose tissue morphological rearrangement in gastrointestinal cancer patients

Abstract

Background and aimsCachexia is a syndrome characterized by marked involuntary loss of body weight. Recently, adipose tissue (AT) wasting has been shown to occur before the appearance of other classical cachexia markers. We investigated the composition and rearrangement of the extracellular matrix, adipocyte morphology and inflammation in the subcutaneous AT (scAT) pad of gastrointestinal cancer patients.MethodsSurgical biopsies for scAT were obtained from gastrointestinal cancer patients, who were signed up into the following groups: cancer cachexia (CC, n = 11), weight‐stable cancer (WSC, n = 9) and weight‐stable control (non‐cancer) (control, n = 7). The stable weight groups were considered as those with no important weight change during the last year and body mass index <25 kg/m2. Subcutaneous AT fibrosis was quantified and characterized by quantitative PCR, histological analysis and immunohistochemistry.ResultsThe degree of fibrosis and the distribution and collagen types (I and III) were different in WSC and CC patients. CC patients showed more pronounced fibrosis in comparison with WSC. Infiltrating macrophages surrounding adipocytes and CD3 Ly were found in the fibrotic areas of scAT. Subcutaneous AT fibrotic areas demonstrated increased monocyte chemotactic protein 1 (MCP‐1) and Cluster of Differentiation (CD)68 gene expression in cancer patients.ConclusionsOur data indicate architectural modification consisting of fibrosis and inflammatory cell infiltration in scAT as induced by cachexia in gastrointestinal cancer patients. The latter was characterized by the presence of macrophages and lymphocytes, more evident in the fibrotic areas. In addition, increased MCP‐1 and CD68 gene expression in scAT from cancer patients may indicate an important role of these markers in the early phases of cancer.

Peritumoural adipose tissue pro‐inflammatory cytokines are associated with tumoural growth factors in cancer cachexia patients

“…Many of these cytokines have been implicated in the development and progression of tumours . Our research group has previously demonstrated a relationship between changes in cytokines and the growth factor profile and wasting in CC patients . Circulating levels of pro‐inflammatory adipokines have been shown to correlate with the total mass of visceral adipose tissue .…”

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

“…In the last years, data from clinical studies have implicated pro‐inflammatory cytokines in the pathogenesis of CAC. In previous studies, we demonstrated that the tumour micro‐environment and the adipose tissue contribute to systemic pro‐inflammatory profile and to the alterations of immunomodulatory function in cachectic patients . Zhang et al .…”

“…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 .…”

Contribution of Adipose Tissue to Development of Cancer

“…Interestingly, while adipose tissue fibrosis in the context of obesity is well described, increased adipose ECM deposition, fibrosis, and immune cell infiltration are also observed in cancer-associated cachexia (35). Abdominal subcutaneous adipose depots of lean cachectic subjects bearing gastrointestinal cancers displayed extensive adipose ECM remodeling, including a dramatic increase in deposition of collagens I, III, and VI as well as elastin and fibronectin (11).…”