Overcoming Challenges of Ovarian Cancer Stem Cells: Novel Therapeutic Approaches

Aguilar-Gallardo, Cristóbal; Rutledge, E.C.; Martínez-Arroyo, Ana M.; Hidalgo, Juan J.; Domingo, Santiago; Simón, Carlos

doi:10.1007/s12015-011-9344-5

Cited by 47 publications

(35 citation statements)

References 158 publications

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“…To determine if MORAB-003–induced autophagy links with cell death, we employed inhibitors of late-stage autophagy, including bafilomycin A1 (39) or hydroxychloroquine (HCQ) (40), to block the autophagic vacuolization and fusion. We found that both bafilomycin A1 and HCQ reversed the MORAB-003–induced reduction of cell viability in the SKOV3ip1 3-D spheroids (Fig.…”

Section: Resultsmentioning

confidence: 99%

Immunotherapy Targeting Folate Receptor Induces Cell Death Associated with Autophagy in Ovarian Cancer

Wen

Graybill

Previs

et al. 2015

Clinical Cancer Research

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Purpose Cancer cells are highly dependent on folate metabolism, making them susceptible to drugs that inhibit folate receptor activities. Targeting overexpressed folate receptor alpha (FRα) in cancer cells offers a therapeutic opportunity. We investigated the functional mechanisms of MORAB-003 (farletuzumab), a humanized monoclonal antibody against FRα, in ovarian cancer models. Experimental Design We first examined FRα expression in an array of human ovarian cancer cell lines and then assessed the in vivo effect of MORAB-003 on tumor growth and progression in several orthotopic mouse models of ovarian cancer derived from these cell lines. Molecular mechanisms of tumor cell death induced by MORAB-003 were investigated by cDNA and protein expression profiling analysis. Mechanistic studies were performed to determine the role of autophagy in MORAB-003–induced cell death. Results MORAB-003 significantly decreased tumor growth in the high-FRα IGROV1 and SKOV3ip1 models but not in the low-FRα A2780 model. MORAB-003 reduced proliferation but had no significant effect on apoptosis. Protein expression and cDNA microarray analyses showed that MORAB-003 regulated an array of autophagy-related genes. It also significantly increased expression of LC3 isoform II and enriched autophagic vacuolization. Blocking autophagy with hydroxychloroquine or bafilomycin A1 reversed the growth inhibition induced by MORAB-003. In add, alteration of FOLR1 gene copy number significantly correlated with shorter disease-free survival in patients with ovarian serous cystadenocarcinoma. Conclusions MORAB-003 displays prominent antitumor activity in ovarian cancer models expressing FRα at high levels. Blockade of folate receptor by MORAB-003 induced sustained autophagy and suppressed cell proliferation.

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Section: Resultsmentioning

confidence: 99%

Immunotherapy Targeting Folate Receptor Induces Cell Death Associated with Autophagy in Ovarian Cancer

Wen

Graybill

Previs

et al. 2015

Clinical Cancer Research

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“…After the first description of stem cells in ovarian tumors nearly eight years ago [24], significant progress has been made towards identifying, characterizing and understanding CSCs and their role in ovarian cancer [32,47,48]. However, despite these advances, ovarian cancer patients are still faced with incurable chemoresistant disease that may be attributed to a population of CSC-like cells [34].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the JAK2/STAT3 pathway in ovarian cancer results in the loss of cancer stem cell-like characteristics and a reduced tumor burden

et al. 2014

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BackgroundCurrent treatment of ovarian cancer patients with chemotherapy leaves behind a residual tumor which results in recurrent ovarian cancer within a short time frame. We have previously demonstrated that a single short-term treatment of ovarian cancer cells with chemotherapy in vitro resulted in a cancer stem cell (CSC)-like enriched residual population which generated significantly greater tumor burden compared to the tumor burden generated by control untreated cells. In this report we looked at the mechanisms of the enrichment of CSC-like residual cells in response to paclitaxel treatment.MethodsThe mechanism of survival of paclitaxel-treated residual cells at a growth inhibitory concentration of 50% (GI50) was determined on isolated tumor cells from the ascites of recurrent ovarian cancer patients and HEY ovarian cancer cell line by in vitro assays and in a mouse xenograft model.ResultsTreatment of isolated tumor cells from the ascites of ovarian cancer patients and HEY ovarian cancer cell line with paclitaxel resulted in a CSC-like residual population which coincided with the activation of Janus activated kinase 2 (JAK2) and signal transducer and activation of transcription 3 (STAT3) pathway in paclitaxel surviving cells. Both paclitaxel-induced JAK2/STAT3 activation and CSC-like characteristics were inhibited by a low dose JAK2-specific small molecule inhibitor CYT387 (1 μM) in vitro. Subsequent, in vivo transplantation of paclitaxel and CYT387-treated HEY cells in mice resulted in a significantly reduced tumor burden compared to that seen with paclitaxel only-treated transplanted cells. In vitro analysis of tumor xenografts at protein and mRNA levels demonstrated a loss of CSC-like markers and CA125 expression in paclitaxel and CYT387-treated cell-derived xenografts, compared to paclitaxel only-treated cell-derived xenografts. These results were consistent with significantly reduced activation of JAK2 and STAT3 in paclitaxel and CYT387-treated cell-derived xenografts compared to paclitaxel only-treated cell derived xenografts.ConclusionsThis proof of principle study demonstrates that inhibition of the JAK2/STAT3 pathway by the addition of CYT387 suppresses the ‘stemness’ profile in chemotherapy-treated residual cells in vitro, which is replicated in vivo, leading to a reduced tumor burden. These findings have important implications for ovarian cancer patients who are treated with taxane and/or platinum-based therapies.

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“…In ovarian cancer, the CSC model has been postulated to drive tumor progression [2, 3, 38]. Numerous markers have been used to distinguish and characterize ovarian CSCs including CD133, CD44, CD117, epithelial cell adhesion molecule (EpCAM), CD24 and aldehyde dehydrogenase (ALDH) [2, 39–42].…”

Section: Discussionmentioning

confidence: 99%

Autocrine interleukin-23 promotes self-renewal of CD133+ ovarian cancer stem-like cells

et al. 2016

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Cancer stem cells (CSCs) are a group of cells which possess the ability of self-renewing and unlimited proliferation. And these CSCs are thought to be the cause of metastasis, recurrence and resistance. Recent study has found that pro-inflammatory cytokine and chemotactic factor mediate the self-renewing and differentiation of most of CSCs. Thus we speculate that ovarian cancer stem cells (OCSCs) can also maintain the ability of self-renewing and differentiation by releasing inflammatory factor. This report we discuss the biological characteristics and the specific molecular mechanism mediated by interleukin-23 (IL-23) and its receptor on the self-renewing of OCSCs. We found that OCSCs had high expression of IL-23 and IL-23R. IL-23 could promote the self-renewal ability of OCSCs and played a very important role to maintain the stable expression of stem cell markers in vitro. Moreover, we verified that IL-23 could maintain the potential tumorigenic of OCSCs in vivo and mediate the self-renewal ability and the formation of tumor in OCSCs by activating the signal pathways of STAT3 and NF-κB. In addition, human low differentiation tissues showed overexpression of IL-23. And IL-23 positively correlated to the expression level of CD133, Nanog and Oct4. In conclusion, Our discoveries demonstrate that autocrine IL-23 contribute to ovarian cancer malignancy through promoting the self-renewal of CD133+ ovarian cancer stem-like cells, and this suggests that IL-23 and its signaling pathway might serve as therapeutic targets for the treatment of ovarian cancer.

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Overcoming Challenges of Ovarian Cancer Stem Cells: Novel Therapeutic Approaches

Cited by 47 publications

References 158 publications

Immunotherapy Targeting Folate Receptor Induces Cell Death Associated with Autophagy in Ovarian Cancer

Immunotherapy Targeting Folate Receptor Induces Cell Death Associated with Autophagy in Ovarian Cancer

Inhibition of the JAK2/STAT3 pathway in ovarian cancer results in the loss of cancer stem cell-like characteristics and a reduced tumor burden

Autocrine interleukin-23 promotes self-renewal of CD133+ ovarian cancer stem-like cells

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