Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, PR China.
Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, PR China.
Theranostics. 2017 Aug 23;7(15):3700-3714. doi: 10.7150/thno.19712. eCollection 2017.
Salivary adenoid cystic carcinoma (SACC) is a peculiar malignant tumor, characterized by its slow but inexorable growth, with a high incidence of lung metastasis and poor prognosis. Here, we show the upregulated expression of EGFR ligand epiregulin in a subset of SACC cells correlates with lung metastasis and unfavorable outcome in patients with SACC. We found that upregulation of epiregulin in SACC cells induced epithelial-mesenchymal transition by regulating GLI1/E-cadherin. Elevated epiregulin increased the expression of pro-angiogenic factors, such as VEGFA, bFGF, and IL-8. We also show that epiregulin can be delivered via exosomes and was enriched in exosomes derived from epiregulin-overexpressing SACC cells. Furthermore, treating immunodeficient mice with these epiregulin-enriched exosomes greatly enhanced SACC metastasis to lung. These epiregulin-enriched exosomes significantly enhanced angiogenesis in the neighboring tumor microenvironment and increased vascular permeability in the pre-metastatic lung microenvironment . Therefore, epiregulin, as well as epiregulin-containing exosomes, may be a novel target for controlling SACC lung metastasis.
涎腺腺样囊性癌（SACC）是一种特殊的恶性肿瘤，其特点是生长缓慢但不可阻挡，肺转移发生率高，预后差。在这里，我们显示 SACC 细胞中 EGFR 配体表皮调节素的上调表达与 SACC 患者的肺转移和不良预后相关。我们发现 SACC 细胞中表皮调节素的上调通过调节 GLI1/E-钙粘蛋白诱导上皮-间充质转化。表皮调节素的升高增加了促血管生成因子的表达，如 VEGFA、bFGF 和 IL-8。我们还表明，表皮调节素可以通过外泌体传递，并在外泌体中富集。此外，用这些富含表皮调节素的外泌体处理免疫缺陷小鼠，可大大增强 SACC 向肺的转移。这些富含表皮调节素的外泌体显著增强了邻近肿瘤微环境中的血管生成，并增加了前转移肺微环境中的血管通透性。因此，表皮调节素以及含有表皮调节素的外泌体可能是控制 SACC 肺转移的新靶点。
