EGFL6 Regulates the Asymmetric Division, Maintenance, and Metastasis of ALDH+ Ovarian Cancer Cells

Cancer Res. 2016 Nov 1;76(21):6396-6409. doi: 10.1158/0008-5472.CAN-16-0225.


Little is known about the factors that regulate the asymmetric division of cancer stem-like cells (CSC). Here, we demonstrate that EGFL6, a stem cell regulatory factor expressed in ovarian tumor cells and vasculature, regulates ALDH+ ovarian 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. Cancer Res; 76(21); 6396-409. ©2016 AACR.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aldehyde Dehydrogenase / analysis*
  • Animals
  • Calcium-Binding Proteins
  • Cell Adhesion Molecules
  • Cell Division*
  • Cell Line, Tumor
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • Female
  • Humans
  • Membrane Glycoproteins / physiology*
  • Mice
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplastic Stem Cells / pathology
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / pathology*
  • Prognosis
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / physiology


  • Calcium-Binding Proteins
  • Cell Adhesion Molecules
  • EGFL6 protein, human
  • Membrane Glycoproteins
  • Aldehyde Dehydrogenase
  • Extracellular Signal-Regulated MAP Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11