Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China.
Breast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China.
FASEB J. 2021 Apr;35(4):e21531. doi: 10.1096/fj.202002533R.
Lymphangiogenesis is thought to contribute to promote tumor cells to enter lymphatic vessels and plant at a secondary site. Endothelial cells are the cornerstone of the generation of new lymphatic vessels. NADPH oxidase 4 (Nox4) is the most abundant one of NADPH oxidases in endothelial cells and the most studied one in relevance with cancer. Our purpose is to analyze the relationship between Nox4 and lymphangiogenesis and find out whether the newborn lymphatic vessels lead to cancer metastasis. We first explored the expression of Nox4 in lymphatic endothelial cells of primary invasive breast tumors and human normal mammary glands using GEO databases and found that Nox4 was upregulated in primary invasive breast tumors samples. In addition, its high expression correlated with lymph node metastasis in breast cancer patients. Nox4 could increase the tube formation and lymphatic vessel sprouting in a three-dimensional setting. In vivo, inhibition of Nox4 in 4T1 tumor-bearing mice could significantly decrease the tumor lymphangiogenesis and metastasis. Nox4 may increase tumor lymphangiogenesis via ROS/ERK/CCL21 pathway and attract CCR7-positive breast cancer cells to entry lymphatic vessels and distant organs. In conclusion, our results show that Nox4 is a factor that promotes lymphangiogenesis and is a potential target of antitumor metastasis.
淋巴管生成被认为有助于促进肿瘤细胞进入淋巴管并在继发性部位定植。内皮细胞是新淋巴管生成的基石。NADPH 氧化酶 4（Nox4）是内皮细胞中 NADPH 氧化酶中最丰富的一种，也是与癌症相关性研究最多的一种。我们的目的是分析 Nox4 与淋巴管生成之间的关系，并探讨新生淋巴管是否导致癌症转移。我们首先使用 GEO 数据库探索了原发性浸润性乳腺癌和人正常乳腺淋巴管内皮细胞中 Nox4 的表达，发现 Nox4 在原发性浸润性乳腺癌样本中上调。此外，其高表达与乳腺癌患者的淋巴结转移相关。Nox4 可以在三维环境中增加管形成和淋巴管发芽。在体内，在 4T1 荷瘤小鼠中抑制 Nox4 可显著降低肿瘤淋巴管生成和转移。Nox4 可能通过 ROS/ERK/CCL21 途径增加肿瘤淋巴管生成，并吸引 CCR7 阳性乳腺癌细胞进入淋巴管和远处器官。总之，我们的结果表明 Nox4 是促进淋巴管生成的因素，是抗肿瘤转移的潜在靶点。
