Adipose tissue in Walker 256 tumour-induced cachexia: possible association between decreased leptin concentration and mononuclear cell infiltration

Abstract

The adipose tissue (AT) is severely affected by cachexia, a paraneoplastic syndrome, which increases the morbidity and mortality of cancer. There is, however, a heterogeneous response to the condition, according to the AT depot. As plasma leptin concentration has been often reported to vary in cachexia, we have measured (species specific radioimmunoassay) the local concentration of leptin in three AT depots: retroperitoneal (RPAT), epididymal (EAT) and mesenteric (MES) of Walker 256 tumour-bearing rats. A reduced concentration of leptin ( P<0.0001) was found in all the depots and in the plasma of the cachectic rats, compared with controls already from day 4 after tumour cell injection. The presence of a cell infiltrate was observed in all AT obtained from the tumour-bearing animals. Ultrastructural analysis, along with immunocytochemistry for RT1B (indicating the presence of MHCII) and using antibody against mononuclear phagocytes, showed the cells to be macrophages. The profile of TNFalpha and PGE2 secretion by the infiltrate was investigated (commercial kits). There was increased production of both factors by the cells of all AT ( P<0.05) compared with peritoneal macrophages obtained from the cachectic rats, while the cells isolated from MES showed the highest synthesis of TNFalpha. The results suggest a possible modulation of the chronic locally produced TNFalpha and PGE2 upon leptin synthesis by the AT of the cachectic rats.

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

“…While MEAT and RPAT mass decreased to the greatest extent, at least on day 14 (with no change in the intermediary stage of cachexia -day 7), the mass of EAT did not differ from control. This finding is in agreement with our previous study (Machado et al 2004) and we further demonstrate that reduction in WAT depot weight (absolute and relative) of Walker 256 tumour-bearing rats seems to occur only on the 14th day post-inoculation (after which animals spontaneously die due to cachexia). Adipocyte morphometrical data also changed in the late stage of cachexia, at which time cells from MEAT were found to be larger compared with day 0.…”

“…Cancer cachexia induces wasting of fat mass that accounts for a large part of the dramatic weight loss observed both in humans (Fouladiun et al 2005, Agustsson et al 2007, Dahlman et al 2010) and in animals (Machado et al 2004, Bing et al 2006, Asp et al 2010, and lipid metabolism is markedly altered (Seelaender et al 1996, Tisdale 2009, Arner 2011. Walker 256-induced cachexia was efficient at eliciting loss of body weight in terms of both absolute and relative weight (percentage of total body mass) of the fat depots, with consequent abnormalities in plasma biochemical profile.…”

“…Previous studies from our group using an animal model of cachexia have shown that different depots are heterogeneously and in a time-dependent fashion affected by the syndrome (Bertevello & Seelaender 2001, Machado et al 2004. Nevertheless, whether there is a corresponding timedependent and site-specific change in the way fat loss occurs is still controversial.…”

Cachexia-associated adipose tissue morphological rearrangement in gastrointestinal cancer patients

“…In a different way, CD3 Ly positive cells were the main immune cells found in the fibrotic areas. We previously hypothesized that infiltrating ATMϕs may play an important role(s) in cachexia‐associated AT remodelling, based on our observation that ATMϕs in cachectic rats and humans are placed surrounding or in close proximity to the adipocytes 46. In addition, we demonstrated that ATMϕs aggregates display a CLS pattern.…”

“…Consequently, CLS become lipid‐laden ‘foam cells’47 frequently observed in AT in obesity. In an animal model of cachexia, we have shown46 that foam‐cell resembling macrophages are present in the AT. During CC, increased lipolysis has been consistently demonstrated in both patients7, 11 and animal models9, 32 and that might be an important source of lipids to ATMϕs.…”