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

Abstract

BackgroundCancer cachexia (CC) is a multifactorial syndrome, often irreversible, that affects patients with cancer influenced, in part, by the inflammatory condition. Peritumoural adipose tissue produces adipokines and angiogenic, apoptotic, and growth factors; given the possible crosstalk between the peritumoural adipose tissue and tumour, these may play an important role in cancer biology and carcinogenesis.MethodsThe aim of this study was to evaluate the factors produced by peritumoural adipose tissue in a cohort of 16 colorectal cancer patients with either weight‐stable cancer (WSC; n = 7) or CC (n = 9). The study was approved by the Ethics Research Committee (972.914). Samples of peritumoural adipose tissue were analysed for concentrations of TNF‐α, IL‐1β, STAT‐1, STAT‐3, RANTES, IL‐1Ra, IP‐10, IL‐15, MCP‐1, IFN‐α, GCSF, FADD, and TGF‐β. The cytokines and proteins were measured using Multiplex. Correlations between the proteins and cytokines were evaluated.ResultsTNF‐α, STAT‐1, and FADD, a factor involved in apoptosis, were significantly higher in CC group than in the WSC group. In the peritumoural adipose tissue of the CC group, RANTES showed a significant positive correlation with IL‐1Ra and IP‐10 and a negative correlation with IFN‐α; and GCSF showed significant negative correlations with IL‐1Ra, IP‐10, IL‐15, and MCP‐1 and a positive correlation with IFN‐α. In the peritumoural adipose tissue of the WSC group, no significant correlations were detected between RANTES, GCSF, IL‐3, FADD, and STAT‐1 and the cytokines/chemokines analysed.ConclusionsThese results indicated that inflammatory and tumorigenic pathways were altered in peritumoural adipose tissue in CC. Furthermore, inflammatory cytokines were correlated with growth factors in the peritumoural adipose tissue of cachectic patients, suggesting that inflammatory cytokines modulated the proliferative environment closely linked to the tumour.

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 .…”

“…Recently, we demonstrated higher expression of STAT-1 in the adipose tissue of cachectic patients, which was correlated with increased inflammation, as compared with WSC. 20 STAT-1 has been shown to present an antitumourigenic and anti-proliferative role in both human and murine studies, 65 while other studies show that the increase of STAT-1 is related to oesophageal cancer invasion associated with p53 mutation, tumour growth, and immune evasion. 63,66 Tauriello et al (2018) showed that increased content of TGF-β in the tumour micro-environment could represent a primary mechanism for immune evasion.…”

“…In previous studies, we demonstrated that the tumour microenvironment and the adipose tissue contribute to systemic pro-inflammatory profile and to the alterations of immunomodulatory function in cachectic patients. 5,10,12,20 Zhang et al (2017) suggested that tumour-derived exosomes may be responsible for the induction of cachexia. 21 A plethora of studies show that inflammatory mediators, including tumour necrosis factor-α (TNF-α), 22 interferon-γ (IFN-γ), 23 interleukin (IL)-1 and IL-6, myostatin, 24 and transforming growth factor β (TGF-β) 25 are involved in the etiology of the loss of skeletal muscle and adipose tissue mass.…”

LPS Inhibits Fatty Acid Absorption in Enterocytes through TNF-α Secreted by Macrophages

“…Such pro-inflammatory factors could mediate tissue damage; in particular, TNF-α can directly recognize death domain to active caspase-8/3 pathways, leading to apoptosis [45,46]. Prolonged exposure to low concentrations of TNF-α can result in cachexia, a wasting syndrome, which can be found in cancer patients [53].…”

Latest advances in STAT signaling and function in adipocytes

“…Recently, peritumoral adipose tissue has been shown to promote tumor growth and to play a role in inflammation and angiogenesis [88]. A study in colorectal cancer patients found that peritumoral adipose tissue in those diagnosed with cancer cachexia (CC) had increased expression of STAT1 compared with that observed in weight-stable patients [89]. The involvement of STAT1 in cancer is complex however, as it has been reported as a tumor suppressor, but can also promote tumor growth (reviewed in [90]).…”