EGFL6 Regulates the Asymmetric Division, Maintenance, and Metastasis of ALDH+ Ovarian Cancer Cells.
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.
Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
Shoumei
S
Bai
Department of Electrical Engineering, University of Michigan, Ann Arbor, Michigan.
Patrick
P
Ingram
Department of Electrical Engineering, University of Michigan, Ann Arbor, Michigan.
Yu-Chih
YC
Chen
Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
Ning
N
Deng
Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
Alex
A
Pearson
Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
Yashar S
YS
Niknafs
Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
Patrick
P
O'Hayer
Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
Yun
Y
Wang
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.
Zhong-Yin
ZY
Zhang
Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Elisa
E
Boscolo
Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Joyce
J
Bischoff
Department of Electrical Engineering, University of Michigan, Ann Arbor, Michigan.
Euisik
E
Yoon
Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. ronaldbu@med.umich.edu.|Division of Gynecologic-Oncology, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan.
Ronald J
RJ
Buckanovich
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000444:Aldehyde Dehydrogenase / Q000032:analysis*; D000818:Animals; D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; D002455:Cell Division; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000473:pathology; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology*; D011379:Prognosis; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000502:physiology
D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; C403518:EGFL6 protein, human; D008562:Membrane Glycoproteins; D000444:Aldehyde Dehydrogenase; D048049:Extracellular Signal-Regulated MAP Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11