Histomorphological and inflammatory changes of white adipose tissue in gastrointestinal cancer patients with and without cachexia

Abstract

Background During cancer cachexia, several alterations occur in peripheral tissues, and the adipose tissue may be involved during the catabolic state. We aimed at investigating histological rearrangement and infiltration of inflammatory cells in subcutaneous adipose tissue (SAT) of patients with cancer undergoing surgery, according to the presence/absence of cachexia. Methods We considered gastrointestinal cancer patients and controls with non-malignant diseases undergoing surgery. We collected SAT samples and performed histomorphological analyses [cross-sectional area (CSA) and per cent of fibrosis] and immunohistochemistry to characterize the inflammatory cells. By computed tomography (CT) scan, we calculated SAT and visceral adipose tissue (VAT). ResultsWe enrolled 51 participants (31 gastrointestinal cancer patients and 20 controls). In cancer patients, cachexia was present in 13/31 (42%). The CSA (μm 2 ) of the adipocytes from SAT was reduced in cancer patients vs. controls (3148, inter-quartile range 2574-3755 vs. 4474, inter-quartile range 3654-5183) (P < 0.001), in particular in cachectic patients vs. non-cachectic (median 2518 vs. median 3470) (P = 0.03) and in cachectic vs. controls (P < 0.001), as well as in non-cachectic vs. controls (P = 0.04). The median per cent of fibrosis was higher in cancer patients vs. controls (9 vs. 3) (P = 0.0001), in particular in cachectic vs. non-cachectic (13.35 vs. 7.13) (P = 0.03). We observed a higher number of macrophages (CD68) (P = 0.0001) and T lymphocytes (CD3) (P = 0.002) in SAT of cancer patients vs. controls, and the number of T lymphocytes was higher in cachectic vs. non-cachectic patients (P = 0.025). Anorexic cancer patients showed in SAT a higher number of macrophages and T lymphocytes with respect to controls (P < 0.0001), whereas no difference was present between anorexic and non-anorexic patients. At CT scan, cachectic patients showed lower VAT

Metabolic and histomorphological changes of adipose tissue in cachexia

“…We recently provided evidences in gastrointestinal cancer patients undergoing surgery, highlighting that both fibrosis and enhanced inflammatory infiltration were present within SAT according to the presence of cachexia [26]. Also, these phenomena reflected the changes in adiposity (lower SAT) evaluated by CT-scan [26]. We also observed increased inflammatory infiltrate of T-lymphocyte according to body weight loss, supporting the hypothesis that the modifications of the adipose tissue microenvironment may favor the process of cachexia [9].…”

“…The process of wasting of adipose tissue in cachexia is manifested histologically as a reduced dimension (size) of the adipocytes, increased fibrosis and increased inflammatory infiltration [26,27]. We recently provided evidences in gastrointestinal cancer patients undergoing surgery, highlighting that both fibrosis and enhanced inflammatory infiltration were present within SAT according to the presence of cachexia [26].…”

Evaluation of Browning Markers in Subcutaneous Adipose Tissue of Newly Diagnosed Gastrointestinal Cancer Patients with and without Cachexia

“…We recently showed that gastrointestinal cancer patients with cachexia showed decreased adipocyte size, increased fibrosis and inflammatory changes in subcutaneous adipose tissue and that histological changes reflected alterations in adiposity evaluated using CT scan [14].…”

Reducing White Adipose Tissue Browning Using p38α MAPK Inhibitors Ameliorates Cancer-Associated Cachexia as Assessed by Magnetic Resonance Imaging

“…While it is known that the beige adipocyte is closely related to the ability to resist body weight gain and fat accumulation [ 37 ], weight loss due to the browning of adipocytes in cancer patients has been suggested as a contributing factor to CAC [ 38 , 39 , 40 ]. Some studies demonstrated that vWAT is largely resistant to browning, while others showed that there are increased expressions of genes involved in browning in animal models of cancer and cancer patients, [ 41 , 42 ]. When tumors are developing, cytokines, hormones, neuropeptides/neurotransmitters and tumor-derived factors can play a role in alliterating the metabolism of the adipose tissue throughout the body, such as inducing mitogen-activated protein kinases and the mitogen-activated protein kinase cascade reaction, thereby activating the p38 MAPK pathway [ 43 , 44 ].…”