scholarly journals Histone demethylase KDM4C is required for ovarian cancer stem cell maintenance

2019 ◽  
Author(s):  
Guoqing Chen ◽  
Ping Ye ◽  
Fa Zeng ◽  
Xiongshan Zhu ◽  
Lu Chen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Histone Demethylase ◽  
Ovarian Cancer Stem Cells ◽  
Stem Cell Maintenance ◽  
Platinum Based Chemotherapy ◽  
Current Therapies

Abstract Ovarian cancer is a highly deadly disease, which is often diagnosed at a late stage with metastases. However, most ovarian cancers relapse after surgery combined with platinum based chemotherapy. Cancer stem cells (CSCs) are stem-like cells that possess high tumorigenic capability and display higher resistant capability against current therapies. However, our knowledge of ovarian CSCs and their molecular mechanism remain sparse. In current study, we found that KDM4C, a histone demethylase, was required for ovarian cancer stem cells (CSCs) maintenance. Depletion of KDM4C significantly reduced the CSCs population and sphere formation in vitro. Moreover, we found that KDM4C can regulate the expression of stem cell factor OCT-4 via binding to its promoter. These data indicate that KDM4C is relevant for ovarian CSCs maintenance and underscore its importance as a potential therapeutic target.

scholarly journals Histone Demethylase KDM4C Is Required for Ovarian Cancer Stem Cell Maintenance

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Guo-Qing Chen ◽  
Ping Ye ◽  
Rong-Song Ling ◽  
Fa Zeng ◽  
Xiong-Shan Zhu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Histone Demethylase ◽  
Potential Therapeutic Target ◽  
Stem Cell Maintenance ◽  
Platinum Based Chemotherapy ◽  
Current Therapies ◽  
Sphere Formation

Ovarian cancer is a highly deadly disease, which is often diagnosed at a late stage with metastases. However, most ovarian cancers relapse after surgery combined with platinum-based chemotherapy. Cancer stem cells (CSCs) are stem-like cells that possess high tumorigenic capability and display higher resistant capability against current therapies. However, our knowledge of ovarian CSCs and their molecular mechanism remains sparse. In the current study, we found that KDM4C, a histone demethylase, was required for ovarian cancer stem cell (CSC) maintenance. Depletion of KDM4C significantly reduced the CSC population and sphere formation in vitro. Moreover, we found that KDM4C can regulate the expression of stem cell factor OCT-4 via binding to its promoter. These data indicate that KDM4C is relevant for ovarian CSC maintenance and underscore its importance as a potential therapeutic target.

scholarly journals HER2 decreases drug sensitivity of ovarian cancer cells via inducing stem cell-like property in an NFκB-dependent way

2019 ◽  
Vol 39 (3) ◽  
Author(s):  
Wenxiang Wang ◽  
Yuxia Gao ◽  
Jing Hai ◽  
Jing Yang ◽  
Shufeng Duan
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Drug Sensitivity ◽  
Ovarian Cancer Cells ◽  
Her2 Overexpression ◽  
Her2 Positive ◽  
Ovarian Cancer Stem Cells

Abstract Increasing evidence shows that cancer stem cells are responsible for drug resistance and relapse of tumors. In breast cancer, human epidermal growth factor receptor 2 (HER2) induces Herceptin resistance by inducing cancer stem cells. In the present study, we explored the effect of HER2 on cancer stem cells induction and drug sensitivity of ovarian cancer cell lines. First, we found that HER2 overexpression (HER2 OE) induced, while HER2 knockdown (HER2 KD) decreased CD44+/CD24− population. Consistently, HER2 expression was closely correlated with the sphere formation efficiency (SFE) of ovarian cancer cells. Second, we found that NFκB inhibition by specific inhibitor JSH23 or siRNA targetting subunit p65 dramatically impaired the induction of ovarian cancer stem cells by HER2, indicating that NFκB mediated HER2-induced ovarian cancer stem cells. Third, we found that HER2 KD significantly attenuated the tumorigenicity of ovarian cancer cells. Further, we found that HER2 inhibition increased drastically the sensitivity of ovarian cancer cells to doxorubicin (DOX) or paclitaxel (PTX). Finally, we examined the correlation between HER2 status and stem cell-related genes expression in human ovarian tumor tissues, and found that expressions of OCT4, COX2, and Nanog were higher in HER2 positive tumors than in HER2 negative tumors. Consistently, the 5-year tumor-free survival rate of HER2 positive patients was dramatically lower than HER2 negative patients. Taken together, our data indicate that HER2 decreases drug sensitivity of ovarian cancer cells via inducing stem cell-like property.

scholarly journals Enhanced expression of DNA polymerase eta contributes to cisplatin resistance of ovarian cancer stem cells

2015 ◽  
Vol 112 (14) ◽  
pp. 4411-4416 ◽  
Author(s):  
Amit Kumar Srivastava ◽  
Chunhua Han ◽  
Ran Zhao ◽  
Tiantian Cui ◽  
Yuntao Dai ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Dna Polymerase ◽  
Ovarian Cancer Stem Cells ◽  
Primary Tumors ◽  
Tumor Relapse ◽  
Induced Apoptosis

Cancer stem cells (CSCs) with enhanced tumorigenicity and chemoresistance are believed to be responsible for treatment failure and tumor relapse in ovarian cancer patients. However, it is still unclear how CSCs survive DNA-damaging agent treatment. Here, we report an elevated expression of DNA polymerase η (Pol η) in ovarian CSCs isolated from both ovarian cancer cell lines and primary tumors, indicating that CSCs may have intrinsically enhanced translesion DNA synthesis (TLS). Down-regulation of Pol η blocked cisplatin-induced CSC enrichment both in vitro and in vivo through the enhancement of cisplatin-induced apoptosis in CSCs, indicating that Pol η-mediated TLS contributes to the survival of CSCs upon cisplatin treatment. Furthermore, our data demonstrated a depletion of miR-93 in ovarian CSCs. Enforced expression of miR-93 in ovarian CSCs reduced Pol η expression and increased their sensitivity to cisplatin. Taken together, our data suggest that ovarian CSCs have intrinsically enhanced Pol η-mediated TLS, allowing CSCs to survive cisplatin treatment, leading to tumor relapse. Targeting Pol η, probably through enhancement of miR-93 expression, might be exploited as a strategy to increase the efficacy of cisplatin treatment.

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

2014 ◽  
Vol 111 (48) ◽  
pp. 17266-17271 ◽  
Author(s):  
Suping Zhang ◽  
Bing Cui ◽  
Hsien Lai ◽  
Grace Liu ◽  
Emanuela M. Ghia ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cell Therapy ◽  
Cancer Stem Cell ◽  
Stem Cell Therapy ◽  
Ovarian Cancer Stem Cells ◽  
Anti Cancer

scholarly journals Role of the Microenvironment in Ovarian Cancer Stem Cell Maintenance

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Jennifer Pasquier ◽  
Arash Rafii
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Biology ◽  
Tumor Stroma ◽  
Cellular Component ◽  
Cytokine Network ◽  
Ovarian Cancer Stem Cells ◽  
Stem Cell Maintenance

Despite recent progresses in cancer therapy and increased knowledge in cancer biology, ovarian cancer remains a challenging condition. Among the latest concepts developed in cancer biology, cancer stem cells and the role of microenvironment in tumor progression seem to be related. Indeed, cancer stem cells have been described in several solid tumors including ovarian cancers. These particular cells have the ability to self-renew and reconstitute a heterogeneous tumor. They are characterized by specific surface markers and display resistance to therapeutic regimens. During development, specific molecular cues from the tumor microenvironment can play a role in maintaining and expanding stemness of cancer cells. The tumor stroma contains several compartments: cellular component, cytokine network, and extracellular matrix. These different compartments interact to form a permissive niche for the cancer stem cells. Understanding the molecular cues underlying this crosstalk will allow the design of new therapeutic regimens targeting the niche. In this paper, we will discuss the mechanisms implicated in the interaction between ovarian cancer stem cells and their microenvironment.

scholarly journals Ovarian Cancer Stemness: Biological and Clinical Implications for Metastasis and Chemotherapy Resistance

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 907 ◽  
Author(s):  
Takeshi Motohara ◽  
Hidetaka Katabuchi
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Chemotherapy Resistance ◽  
Clinical Implications ◽  
Ovarian Cancer Stem Cells

Epithelial ovarian cancer is a highly lethal gynecological malignancy that is characterized by the early development of disseminated metastasis. Though ovarian cancer has been generally considered to preferentially metastasize via direct transcoelomic dissemination instead of the hematogenous route, emerging evidence has indicated that the hematogenous spread of cancer cells plays a larger role in ovarian cancer metastasis than previously thought. Considering the distinctive biology of ovarian cancer, an in-depth understanding of the biological and molecular mechanisms that drive metastasis is critical for developing effective therapeutic strategies against this fatal disease. The recent “cancer stem cell theory” postulates that cancer stem cells are principally responsible for tumor initiation, metastasis, and chemotherapy resistance. Even though the hallmarks of ovarian cancer stem cells have not yet been completely elucidated, metastasized ovarian cancer cells, which have a high degree of chemoresistance, seem to manifest cancer stem cell properties and play a key role during relapse at metastatic sites. Herein, we review our current understanding of the cell-biological mechanisms that regulate ovarian cancer metastasis and chemotherapy resistance, with a pivotal focus on ovarian cancer stem cells, and discuss the potential clinical implications of evolving cancer stem cell research and resultant novel therapeutic approaches.

scholarly journals The Metabolic Inhibitor CPI-613 Negates Treatment Enrichment of Ovarian Cancer Stem Cells

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1678 ◽  
Author(s):  
Chiara Bellio ◽  
Celeste DiGloria ◽  
David R. Spriggs ◽  
Rosemary Foster ◽  
Whitfield B. Growdon ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Treatment Strategies ◽  
Tca Cycle ◽  
Metabolic Inhibitor ◽  
Ovarian Cancer Stem Cells ◽  
Platinum Resistant

One of the most significant therapeutic challenges in the treatment of ovarian cancer is the development of recurrent platinum-resistant disease. Cancer stem cells (CSCs) are postulated to contribute to recurrent and platinum-resistant ovarian cancer (OvCa). Drugs that selectively target CSCs may augment the standard of care cytotoxics and have the potential to prevent and/or delay recurrence. Increased reliance on metabolic pathway modulation in CSCs relative to non-CSCs offers a possible therapeutic opportunity. We demonstrate that treatment with the metabolic inhibitor CPI-613 (devimistat, an inhibitor of tricarboxylic acid (TCA) cycle) in vitro decreases CD133+ and CD117+ cell frequency relative to untreated OvCa cells, with negligible impact on non-CSC cell viability. Additionally, sphere-forming capacity and tumorigenicity in vivo are reduced in the CPI-613 treated cells. Collectively, these results suggest that treatment with CPI-613 negatively impacts the ovarian CSC population. Furthermore, CPI-613 impeded the unintended enrichment of CSC following olaparib or carboplatin/paclitaxel treatment. Collectively, our results suggest that CPI-613 preferentially targets ovarian CSCs and could be a candidate to augment current treatment strategies to extend either progression-free or overall survival of OvCa.

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