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.ROR1 | ovarian cancer stem cell | monoclonal antibody | PDX mice model

High-level ROR1 associates with accelerated disease progression in chronic lymphocytic leukemia

“…A variety of different cancers have been found to express ROR1. 23 To date, high-level expression of ROR1 has been found to have adverse prognostic significance for patients with breast cancer, [24][25][26][27] ovarian cancer, 28,29 melanoma, 30 or Ewing sarcoma. 31 Moreover, high-level expression of ROR1 also has been associated with higher levels of AKT activation, 24,30,32,33 consistent with the notion that ROR1 signaling leading to activation of AKT may serve as a driver, not just in CLL, but also in other malignancies.…”

Estradiol, TGF-β1 and hypoxia promote breast cancer stemness and EMT-mediated breast cancer migration

“…Anticancer therapies at present emphasize killing CSCs or inhibiting the induction of the CSC population (32,33). However, CSC-targeted cancer therapies are problematic due to the characteristics of CSCs, including radio-and chemoresistance (34,35).…”

Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation

“…Cancer-cell expression of ROR1 or ROR2 has been associated with enhanced cancer-cell migration, epithelialmessenchymal transition (EMT), increased associated risk for relapse and metastasis, and unfavorable prognosis (20,21). More recently, ROR1 was identified on ovarian cancer stem cells, which have enhanced capacity for migration/spheroid formation in vitro and engraftment/metastasis in vivo (22).…”