Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
Center for Immunology and Immune Based Diseases, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
Nat Commun. 2016 Oct 6;7:13007. doi: 10.1038/ncomms13007.
Obesity is associated with an increased risk of developing breast cancer and is also associated with worse clinical prognosis. The mechanistic link between obesity and breast cancer progression remains unclear, and there has been no development of specific treatments to improve the outcome of obese cancer patients. Here we show that obesity-associated NLRC4 inflammasome activation/ interleukin (IL)-1 signalling promotes breast cancer progression. The tumour microenvironment in the context of obesity induces an increase in tumour-infiltrating myeloid cells with an activated NLRC4 inflammasome that in turn activates IL-1β, which drives disease progression through adipocyte-mediated vascular endothelial growth factor A (VEGFA) expression and angiogenesis. Further studies show that treatment of mice with metformin inhibits obesity-associated tumour progression associated with a marked decrease in angiogenesis. This report provides a causal mechanism by which obesity promotes breast cancer progression and lays out a foundation to block NLRC4 inflammasome activation or IL-1β signalling transduction that may be useful for the treatment of obese cancer patients.
肥胖与乳腺癌发病风险增加相关，且与更差的临床预后相关。肥胖与乳腺癌进展之间的机制联系尚不清楚，也没有开发出专门的治疗方法来改善肥胖癌症患者的结局。在这里，我们发现肥胖相关的 NLRC4 炎性小体激活/白细胞介素（IL）-1 信号通路促进了乳腺癌的进展。肥胖背景下的肿瘤微环境诱导肿瘤浸润的髓样细胞增加，这些细胞带有激活的 NLRC4 炎性小体，进而激活 IL-1β，通过脂肪细胞介导的血管内皮生长因子 A（VEGFA）表达和血管生成来驱动疾病进展。进一步的研究表明，二甲双胍治疗小鼠可抑制与血管生成显著减少相关的肥胖相关肿瘤进展。本报告提供了肥胖促进乳腺癌进展的因果机制，并为阻断 NLRC4 炎性小体激活或 IL-1β 信号转导奠定了基础，这可能对肥胖癌症患者的治疗有用。
