Ovarian cancer stem cells express ROR1, which can be targeted for anti-cancer-stem-cell therapy.

Abstract

Although initially responsive to chemotherapy, many patients with ovarian cancer subsequently develop relapsed and potentially fatal metastatic disease, which is thought to develop from cancer stem cells (CSCs) that are relatively resistant to conventional therapy. Here, we show that CSCs express a type I receptor tyrosine kinase-like orphan receptor (ROR1), which is expressed during embryogenesis and by many different cancers, but not normal postpartum tissues. Ovarian cancers with high levels of ROR1 had stem cell-like gene-expression signatures. Furthermore, patients with ovarian cancers with high levels of ROR1 had higher rates of relapse and a shorter median survival than patients with ovarian cancers that expressed low-to-negligible amounts of ROR1. We found that ROR1-positive (ROR1(+)) cells isolated from primary tumor-derived xenografts (PDXs) also expressed aldehyde dehydrogenase 1 (ALDH1) and had a greater capacity to form spheroids and to engraft immune-deficient mice than did ROR1-negative (ROR1(Neg)) ovarian cancer cells isolated from the same tumor population. Treatment with UC-961, an anti-ROR1 mAb, or shRNA silencing of ROR1 inhibited expression of the polycomb ring-finger oncogene, Bmi-1, and other genes associated with the epithelial-mesenchymal transition. Moreover, shRNA silencing of ROR1, depletion of ROR1(+) cells, or treatment with UC-961 impaired the capacity of ovarian cancer cells to form spheroids or tumor xenografts. More importantly, treatment with anti-ROR1 affected the capacity of the xenograft to reseed a virgin mouse, indicating that targeting ROR1 may affect CSC self-renewal. Collectively, these studies indicate that ovarian CSCs express ROR1, which contributes to their capacity to form tumors, making ROR1 a potential target for the therapy of patients with ovarian cancer.

• Authors: Suping Zhang, Bing Cui, Hsien Lai, Grace Liu, Emanuela M Ghia, George F Widhopf 2nd, Zhuhong Zhang, Christina C N Wu, Liguang Chen, Rongrong Wu, Richard Schwab, Dennis A Carson, Thomas J Kipps
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 48 Pg. 17266-71 (Dec 02 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 25411317 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antibodies, Monoclonal
• ROR1 protein, human
• Receptor Tyrosine Kinase-like Orphan Receptors

Topics

• Animals
• Antibodies, Monoclonal (immunology, pharmacology)
• Cell Line, Tumor
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Immunoblotting
• Kaplan-Meier Estimate
• Mice, Inbred NOD
• Mice, Knockout
• Mice, SCID
• Microscopy, Confocal
• Molecular Targeted Therapy (methods)
• Neoplastic Stem Cells (metabolism, pathology)
• Ovarian Neoplasms (genetics, metabolism, prevention & control)
• Prognosis
• RNA Interference
• Receptor Tyrosine Kinase-like Orphan Receptors (genetics, immunology, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Spheroids, Cellular (drug effects, metabolism)
• Transplantation, Heterologous