Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance

Alvero, Ayesha B.; Chen, Rui; Fu, Han-Hsuan; Montagna, Michele K.; Schwartz, Peter E.; Rutherford, Thomas J.; Silasi, Dan‐Arin; Steffensen, Karina Dahl; Waldstrøm, Marianne; Visintin, Irene; Mor, Gil

doi:10.4161/cc.8.1.7533

Cited by 454 publications

(544 citation statements)

References 36 publications

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“…These studies suggest that treatment with this anti-ROR1 mAb could impair the self-renewal capacity of CSC cells in vivo. As such, these studies demonstrate that UC-961 might inhibit the maintenance and/or self-renewal of ovarian CSCs, which otherwise may be resistant to chemotherapy and responsible for relapse after conventional anticancer treatment (4)(5)(6).…”

Section: Discussionmentioning

confidence: 81%

“…ROR1 | ovarian cancer stem cell | monoclonal antibody | PDX mice model A lthough most patients with advanced ovarian cancer initially respond well to paclitaxel-and cisplatin-based therapies (1,2), ∼85% of patients relapse within a few years after systemic chemotherapy and cytoreductive surgery, including those who had an apparent complete response to therapy (3). Cancer recurrence is thought to reflect the survival of a small percentage of ovarian cancer stem cells (CSCs), which are relatively resistant to chemotherapy, can repopulate the tumor, and can spread to distal sites (4)(5)(6).…”

mentioning

confidence: 99%

“…Furthermore, ovarian CSCs may express various surface antigens, such as CD44, CD117, or CD133 (7,8,(17)(18)(19). Functionally, human ovarian CSCs apparently can form nonadherent cellular spheres, called "spheroids," which in turn are enriched for ovarian cancer cells that have high ALDH1 activity, are relatively resistant to chemotherapeutic drugs, and have enhanced potential for seeding metastatic sites or engrafting immune-deficient mice (5,17,18,(20)(21)(22).…”

mentioning

confidence: 99%

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

Zhang

Cui

Lai

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

161

156

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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

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Section: Discussionmentioning

confidence: 81%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Zhang

Cui

Lai

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

161

156

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“…The existence of CSCs, or tumor-initiating cells, was first reported by Lapidot and colleagues (93). Since then, CSCs have been identified in numerous solid tumors, including breast, colon, endometrial, pancreas, prostate, ovary, and brain tumors (94)(95)(96)(97)(98)(99)(100)(101)(102). High tumorigenicity was shown in CSCs.…”

Section: Emt Met and Cancer Stem Cellsmentioning

confidence: 96%

Mechanism of the Mesenchymal–Epithelial Transition and Its Relationship with Metastatic Tumor Formation

Yao

Dai

Peng

2011

Molecular Cancer Research

384

296

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Cancer metastasis consists of a sequential series of events, and the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are recognized as critical events for metastasis of carcinomas. A current area of focus is the histopathological similarity between primary and metastatic tumors, and MET at sites of metastases has been postulated to be part of the process of metastatic tumor formation. Here, we summarize accumulating evidence from experimental studies that directly supports the role of MET in cancer metastasis, and we analyze the main mechanisms that regulate MET or reverse EMT in carcinomas. Given the critical role of MET in metastatic tumor formation, the potential to effectively target the MET process at sites of metastasis offers new hope for inhibiting metastatic tumor formation.

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“…The diversity of stem cell marker staining observed in the IGROV1 cell line studied here supports the emerging concept that CSC-like properties may contribute to the phenotypic heterogeneity observed in EOC. The high frequency of the development of drug resistance and concomitant disease recurrence in EOC patients (Vasey, 2008;Alvero et al, 2009) further suggests the possible presence of such CSCs in these tumors.…”

Section: Sub-population Of Eoc Cells Co-expresses Lin28 and Oct4mentioning

confidence: 99%

Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer

2010

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Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance

Cited by 454 publications

References 36 publications

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

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

Mechanism of the Mesenchymal–Epithelial Transition and Its Relationship with Metastatic Tumor Formation

Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer

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