Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China.
Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, 1825 Pressler St., Houston, TX, 77030, USA.
Oncogene. 2019 Mar;38(12):2123-2134. doi: 10.1038/s41388-018-0565-9. Epub 2018 Nov 19.
EGFL6, a member of the EGF-like superfamily, plays an important role during embryonic development and has been implicated in promotion of tumor angiogenesis without affecting wound healing. There is very little known about the function of EGFL6 in cancer cells. Here, we investigated whether EGFL6 plays a direct role in cancer cells in addition to the promotion of tumor angiogenesis. Our study showed that EGFL6 promoted epithelial-mesenchymal transition (EMT) and stemness of breast cancer cells and increased cell migration and invasion in cell culture studies. We also found that EGFL6 reduced apoptotic signaling in cancer cells and promoted tumor growth in vivo. Importantly, expression of EGFL6 in cancer cells and tumor endothelial cells not only increased tumor angiogenesis but also promoted migration of cancer cells. Such dual engagement of cancer and stromal cells suggests crosstalk mediated by EGFL6 in the tumor microenvironment. Blockade of EGFL6 using our novel anti-EGFL6 monoclonal antibody significantly reduced cancer cell migration, tumor angiogenesis, and tumor growth in mouse xenograft tumor models. Silencing EGFL6 mRNA by shRNA transfection of cancer cells also significantly reduced cancer cell migration, tumor angiogenesis, and tumor growth in mouse xenograft tumor models. Taken together, the results of this study indicate that targeting EGFL6 is a unique strategy for inhibiting both cancer cell metastasis and tumor angiogenesis.
EGFL6 是 EGF 样超家族的成员，在胚胎发育过程中发挥重要作用，并被认为可促进肿瘤血管生成而不影响伤口愈合。目前对于 EGFL6 在癌细胞中的功能知之甚少。在这里，我们研究了 EGFL6 是否除了促进肿瘤血管生成之外，还直接作用于癌细胞。我们的研究表明，EGFL6 促进乳腺癌细胞上皮-间充质转化（EMT）和干细胞特性，并增加细胞培养研究中的细胞迁移和侵袭。我们还发现 EGFL6 减少了癌细胞中的凋亡信号，并促进了体内肿瘤的生长。重要的是，癌细胞和肿瘤内皮细胞中 EGFL6 的表达不仅增加了肿瘤血管生成，还促进了癌细胞的迁移。这种癌细胞和基质细胞的双重参与表明 EGFL6 在肿瘤微环境中存在细胞间的串扰。使用我们新型的抗 EGFL6 单克隆抗体阻断 EGFL6，可显著减少癌细胞迁移、肿瘤血管生成和小鼠异种移植瘤模型中的肿瘤生长。通过 shRNA 转染沉默癌细胞中的 EGFL6 mRNA，也可显著减少癌细胞迁移、肿瘤血管生成和小鼠异种移植瘤模型中的肿瘤生长。总之，这项研究的结果表明，靶向 EGFL6 是抑制癌细胞转移和肿瘤血管生成的独特策略。
