Molecular Pathways: Adipose Inflammation as a Mediator of Obesity-Associated Cancer
Molecular Pathways: Adipose Inflammation as a Mediator of Obesity-Associated Cancer
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DOI：
10.1158/1078-0432.ccr-12-2603
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发表时间：
2013-11-15
影响因子：
11.5
通讯作者：
Dannenberg, Andrew J.
中科院分区：
文献类型：
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作者：
Howe, Louise R.;Subbaramaiah, Kotha;Dannenberg, Andrew J.
据预测，全球肥胖率的上升与疾病的激增有关。值得注意的是，肥胖与美国约20%的癌症病例有关;肥胖与诊断后风险增加和预后不良有关。循环因子水平的改变与此密切相关，包括胰岛素、胰岛素样生长因子1、瘦素、脂联素和白细胞介素-6（IL-6）。此外，越来越多的注意力集中在局部脂肪炎症的后果。炎性病灶特征为冠状结构，由巨噬细胞包围的死亡脂肪细胞组成，发生在大多数超重和肥胖女性的白色脂肪库，包括乳腺组织。肥胖相关脂解释放的饱和脂肪酸通过Toll样受体4诱导巨噬细胞活化，从而刺激NF-κ B信号传导。这反过来又激活促炎基因的转录，包括考克斯-2、IL-6、IL-1 β和TNF α。促炎介质水平升高引起局部和全身效应。与乳腺癌特别相关的是编码芳香酶的CYP 19基因的转录增加，芳香酶是雌激素合成的限速酶。值得注意的是，肥胖-炎症-芳香化酶轴为绝经后激素受体阳性乳腺癌与肥胖相关的发病率增加提供了一个合理的解释，因此可能为降低风险或改善预后的干预措施提供目标。潜在的方法包括减轻体重，运动，以及使用药物或饮食剂抑制肥胖驱动的信号通路。未来的一个关键目标是确定准确报告脂肪炎症的生物标志物，用于识别高危个体和评估干预措施的有效性。(C)2013年AACR。
The increasing rate of obesity worldwide is predicted to be associated with a surge in diseases. Notably, obesity has been linked to approximately 20% of cancer cases in the United States; obesity is associated with both increased risk and worse outcomes after diagnosis. Altered levels of circulating factors are strongly implicated, including insulin, insulin-like growth factor 1, leptin, adiponectin, and interleukin-6 (IL-6). In addition, increasing attention has focused on the consequences of local adipose inflammation. Inflammatory foci characterized by crown-like structures consisting of dead adipocytes encircled by macrophages occur in white adipose depots, including the breast tissue, of most overweight and obese women. Saturated fatty acids, released as a consequence of obesity-associated lipolysis, induce macrophage activation via Toll-like receptor 4, thereby stimulating NF-kappa B signaling. This, in turn, activates transcription of proinflammatory genes including COX-2, IL-6, IL-1 beta, and TNF alpha. Elevated levels of proinflammatory mediators cause both local and systemic effects. Of particular relevance with regard to breast cancer is increased transcription of the CYP19 gene encoding aromatase, the rate-limiting enzyme for estrogen synthesis. Notably, this obesity-inflammation-aromatase axis provides a plausible explanation for increased rates of postmenopausal, hormone receptor-positive breast cancer associated with obesity and hence may offer targets for interventions to attenuate risk or improve prognosis. Potential approaches include weight reduction, exercise, and suppression of obesity-driven signaling pathways using pharmaceutical or dietary agents. A key future goal is to identify biomarkers that accurately report adipose inflammation, both for identification of at-risk individuals and to assess the efficacy of interventions. (C) 2013 AACR.