Adipose tissue fibrosis in human cancer cachexia: the role of TGFβ pathway.
Adipose tissue fibrosis in human cancer cachexia: the role of TGFβ pathway.
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DOI：
10.1186/s12885-017-3178-8
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发表时间：
2017-03-14
期刊：
影响因子：
3.8
通讯作者：
Seelaender M
中科院分区：
文献类型：
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作者：
Alves MJ;Figuerêdo RG;Azevedo FF;Cavallaro DA;Neto NI;Lima JD;Matos-Neto E;Radloff K;Riccardi DM;Camargo RG;De Alcântara PS;Otoch JP;Junior ML;Seelaender M
癌症恶病质是一种多因素综合征，可显著降低生存率。白色脂肪组织（WAT）的损失是恶病质的关键特征之一。在恶性肿瘤患者中，WAT的消耗与微结构重构是平行的。纤维化是由不受控制的ECM合成引起的，在这个过程中，转化生长因子- β (tgf - β)起着关键作用。到目前为止，脂肪组织（AT）重排的机制以及TGFβ在减肥癌症患者诱导AT重塑中的作用尚不清楚。本研究检测了TGFβ通路介导的ECM成分在恶病质胃肠道癌纤维化AT中的调节作用。签署知情同意书后，患者被分为以下组：恶性恶病质组（CC, n = 21）、体重稳定癌组（WSC, n = 17）和对照组（n = 21）。采用组织学分析和免疫组织化学方法测定皮下AT组织中胶原和弹性纤维的总量。采用Multiplex法和免疫组织化学分析tgf - β亚型的表达。采用qPCR和/或免疫组化方法定量α -平滑肌肌动蛋白（αSMA）、成纤维细胞特异性蛋白（FSP1）、Smad3和4。用Multiplex法测定与纤维化相关的白细胞介素（IL） 2、IL5、IL8、IL13和IL17的含量。与WSC和对照组相比，CC的AT中胶原蛋白和弹性纤维有所积累。与WSC和对照组相比，CC组织中I型、III型、VI型胶原和纤维连接蛋白的表达增强。脂肪细胞周围α - sma明显表达，FSP1 mRNA含量增加20倍，提示肌成纤维细胞活化；tgf - β1和tgf - β3水平在AT和离体脂肪细胞中被恶病质上调。Smad3和Smad4标记在CC脂肪组织的纤维化区域更为明显。癌症恶病质促进AT纤维化的发展，与TGFβ信号的改变有关，损害AT的组织和功能。
Cancer 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. After 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. There 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. Cancer cachexia promotes the development of AT fibrosis, in association with altered TGFβ signaling, compromising AT organization and function.