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

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2014-12, Vol.111 (48), p.17266-17271
Main Authors: Zhang, Suping, Cui, Bing, Lai, Hsien, Liu, Grace, Ghia, Emanuela M., Widhopf, George F., Zhang, Zhuhong, Wu, Christina C. N., Chen, Liguang, Wu, Rongrong, Schwab, Richard, Carson, Dennis A., Kipps, Thomas J.
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - immunology
Antibodies, Monoclonal - pharmacology
Biological Sciences
Cancer
Cancer therapies
Cell Line, Tumor
Cell lines
Cellular immunity
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Heterologous transplantation
Humans
Immunoblotting
Kaplan-Meier Estimate
Mice
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Microscopy, Confocal
Molecular Targeted Therapy - methods
Neoplastic Stem Cells - metabolism
Neoplastic Stem Cells - pathology
Ovarian cancer
Ovarian Neoplasms - genetics
Ovarian Neoplasms - metabolism
Ovarian Neoplasms - prevention & control
Prognosis
Receptor Tyrosine Kinase-like Orphan Receptors - genetics
Receptor Tyrosine Kinase-like Orphan Receptors - immunology
Receptor Tyrosine Kinase-like Orphan Receptors - metabolism
Reverse Transcriptase Polymerase Chain Reaction
RNA Interference
Rodents
Signatures
Spheroids
Spheroids, Cellular - drug effects
Spheroids, Cellular - metabolism
Stem cells
Transplantation, Heterologous
Tumors
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Summary: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. Significance This study demonstrates that the oncoembryonic surface antigen, receptor tyrosine kinase-like orphan receptor 1 (ROR1), is expressed on human ovarian cancer stem cells (CSCs), on which it seems to play a functional role in promoting migration/invasion or spheroid formation in vitro and tumor engraftment in immune-deficient mice. Treatment with a humanized mAb specific for ROR1 (UC-961) could inhibit the capacity of ovarian cancer cells to migrate, form spheroids, or engraft immune-deficient mice. Moreover, such treatment inhibited the growth of tumor xenografts, which in turn had a reduced capacity to engraft immune-deficient mice and were rel
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1419599111