Adipose tissue fibrosis in human cancer cachexia: the role of TGFβ pathway

Abstract

BackgroundCancer cachexia is a multifactorial syndrome that dramatically decreases survival. Loss of white adipose tissue (WAT) is one of the key characteristics of cachexia. WAT wasting is paralleled by microarchitectural remodeling in cachectic cancer patients. Fibrosis results from uncontrolled ECM synthesis, a process in which, transforming growth factor-beta (TGFβ) plays a pivotal role. So far, the mechanisms involved in adipose tissue (AT) re-arrangement, and the role of TGFβ in inducing AT remodeling in weight-losing cancer patients are poorly understood. This study examined the modulation of ECM components mediated by TGFβ pathway in fibrotic AT obtained from cachectic gastrointestinal cancer patients.MethodsAfter signing the informed consent form, patients were enrolled into the following groups: cancer cachexia (CC, n = 21), weight-stable cancer (WSC, n = 17), and control (n = 21). The total amount of collagen and elastic fibers in the subcutaneous AT was assessed by histological analysis and by immunohistochemistry. TGFβ isoforms expression was analyzed by Multiplex assay and by immunohistochemistry. Alpha-smooth muscle actin (αSMA), fibroblast-specific protein (FSP1), Smad3 and 4 were quantified by qPCR and/or by immunohistochemistry. Interleukin (IL) 2, IL5, IL8, IL13 and IL17 content, cytokines known to be associated with fibrosis, was measured by Multiplex assay.ResultsThere was an accumulation of collagen and elastic fibers in the AT of CC, as compared with WSC and controls. Collagens type I, III, VI, and fibronectin expression was enhanced in the tissue of CC, compared with both WSC and control. The pronounced expression of αSMA in the surrounding of adipocytes, and the increased mRNA content for FSP1 (20-fold) indicate the presence of activated myofibroblasts; particularly in CC. TGFβ1 and TGFβ3 levels were up-regulated by cachexia in AT, as well in the isolated adipocytes. Smad3 and Smad4 labeling was found to be more evident in the fibrotic areas of CC adipose tissue.ConclusionsCancer cachexia promotes the development of AT fibrosis, in association with altered TGFβ signaling, compromising AT organization and function.

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

“…A recent study showed that up‐regulation of HIF‐1α and TGF‐β pathways contributes to cell survival and chemoresistance in colorectal cancer . In line with these observations, we previously demonstrated that the adipose tissue, while playing an important role in systemic inflammation by secreting cytokines and chemokines, undergoes extensive fibrosis in CAC and that one such effect is partly mediated by TGF‐β, which causes the rearrangement of extracellular matrix components and leads to severe tissue architecture disruption in cancer patients with cachexia . TGF‐β signalling promotes fibroblast to myofibroblast transdifferentiation by inducing the expression of α‐SMA, a specific myofibroblast marker.…”

“…Gene expression of COL1A and COL3A was significantly increased in CC, relative to WSC ( Figure A; P = 0.03 and P = 0.05, respectively). Vimentin (a type III intermediate filament related to cellular motility) expression was increased in the tumour of CC ( Figure A; P = 0.02), and this feature was shown to be correlated with the numbers of activated fibroblasts in cachexia . Recently, the metastatic potential of cancer cell has been correlated with cachexia development .…”

“…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

“…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). These changes were associated with increased myofibroblast content and elevated activation of TGF-β/SMAD signaling pathways (11). As described later in the Adipocytes and adipocyte-cancer interactions section , cancer-associated cachexia is also associated with metabolic dysfunction in adipocytes, which may be mediated in part by ECM modifications.…”