EGFL6 Regulates the Asymmetric Division, Maintenance, and Metastasis of ALDH+ Ovarian Cancer Cells.
EGFL6 Regulates the Asymmetric Division, Maintenance, and Metastasis of ALDH+ Ovarian Cancer Cells.
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DOI：
10.1158/0008-5472.can-16-0225
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发表时间：
2016-11-01
期刊：
影响因子：
11.2
通讯作者：
Buckanovich RJ
中科院分区：
文献类型：
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作者：
Bai S;Ingram P;Chen YC;Deng N;Pearson A;Niknafs YS;O'Hayer P;Wang Y;Zhang ZY;Boscolo E;Bischoff J;Yoon E;Buckanovich RJ
关于调节癌症干细胞样细胞不对称分裂的因素知之甚少。在这里，我们证明了EGFL 6，一种在卵巢肿瘤细胞和脉管系统中表达的干细胞调节因子，调节ALDH+卵巢癌干细胞样细胞（CSC）。EGFL 6至少部分地通过癌蛋白SHP 2与ERK的伴随激活发出信号。EGFL 6信号促进ALDH+卵巢CSC的迁移和不对称分裂。因此，EGFL 6不仅增加肿瘤生长，而且增加转移。EGFL 6或SHP 2的沉默限制了ALDH+细胞的数量并减少了肿瘤生长，支持EGFL 6/SHP 2在ALDH+细胞维持中的关键作用。值得注意的是，全身给予EGFL 6中和抗体，我们产生了限制肿瘤生长和转移，特别是阻断卵巢癌细胞募集到卵巢。总之，我们的研究结果为EGFL 6作为治疗卵巢癌的新治疗靶点提供了临床前概念证明。
Little is known about the factors that regulate the asymmetric division of cancer stem-like cells. Here we demonstrate that EGFL6, a stem cell regulatory factor expressed in ovarian tumor cells and vasculature, regulates ALDH+ ovarian cancer stem-like cells (CSC). EGFL6 signaled at least in part via the oncoprotein SHP2 with concomitant activation of ERK. EGFL6 signaling promoted the migration and asymmetric division of ALDH+ ovarian CSC. As such, EGFL6 increased not only tumor growth but also metastasis. Silencing of EGFL6 or SHP2 limited numbers of ALDH+ cells and reduced tumor growth, supporting a critical role for EGFL6/SHP2 in ALDH+ cell maintenance. Notably, systemic administration of an EGFL6-neutralizing antibody we generated restricted tumor growth and metastasis, specifically blocking ovarian cancer cell recruitment to the ovary. Together, our results offer a preclinical proof of concept for EGFL6 as a novel therapeutic target for the treatment of ovarian cancer.