Department of Oncology, Linköping University, Linköping, Sweden.
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Front Immunol. 2018 Jul 30;9:1767. doi: 10.3389/fimmu.2018.01767. eCollection 2018.
Fat is a major tissue component in human breast cancer (BC). Whether breast adipocytes (BAd) affect early stages of BC metastasis is yet unknown. BC progression is dependent on angiogenesis and inflammation, and interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) are key regulators of these events. Here, we show that BAd increased the dissemination of estrogen receptor positive BC cells (BCC) in the zebrafish model of metastasis, while dissemination of the more aggressive and metastatic BCC such as estrogen receptor negative was unaffected. While anti-VEGF and anti-IL-8 exhibited equal inhibition of angiogenesis at the primary tumor site, anti-IL-8 reduced BCC dissemination whereas anti-VEGF had minor effects on this early metastatic event. Mechanistically, overexpression of cell-adhesion molecules in BCC and neutrophils IL-8 increased the dissemination of BCC. Importantly, the extracellular levels of IL-8 were 40-fold higher than those of VEGF in human BC. Our results suggest that IL-8 is a clinical relevant and promising therapeutic target for human BC.
脂肪是人类乳腺癌（BC）的主要组织成分。乳腺脂肪细胞（BAd）是否会影响 BC 转移的早期阶段尚不清楚。BC 的进展依赖于血管生成和炎症，白细胞介素-8（IL-8）和血管内皮生长因子（VEGF）是这些事件的关键调节剂。在这里，我们表明，BAd 增加了雌激素受体阳性 BC 细胞（BCC）在转移的斑马鱼模型中的扩散，而雌激素受体阴性的侵袭性和转移性 BCC 的扩散则不受影响。虽然抗 VEGF 和抗 IL-8 在原发性肿瘤部位均能同等抑制血管生成，但抗 IL-8 减少了 BCC 的扩散，而抗 VEGF 对这一早期转移事件的影响较小。从机制上讲，BCC 和中性粒细胞中细胞黏附分子的过表达增加了 BCC 的扩散。重要的是，人 BC 中 IL-8 的细胞外水平比 VEGF 高 40 倍。我们的研究结果表明，IL-8 是治疗人类 BC 的一个有临床意义和有前途的治疗靶点。
