title: 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.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Suping
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Bing
authors.initials: B
authors.lastname: Cui
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Hsien
authors.initials: H
authors.lastname: Lai
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Grace
authors.initials: G
authors.lastname: Liu
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Emanuela M
authors.initials: EM
authors.lastname: Ghia
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: George F
authors.initials: GF
authors.lastname: Widhopf
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Zhuhong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Christina C N
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Liguang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Wu
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Richard
authors.initials: R
authors.lastname: Schwab
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093 tkipps@ucsd.edu dcarson@ucsd.edu.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Carson
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093 tkipps@ucsd.edu dcarson@ucsd.edu.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D053208:Kaplan-Meier Estimate; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D018613:Microscopy, Confocal; D058990:Molecular Targeted Therapy / Q000379:methods*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D011379:Prognosis; D034622:RNA Interference; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; C078716:ROR1 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors
keywords: PDX mice model; ROR1; monoclonal antibody; ovarian cancer stem cell