scholarly journals iNOS promotes CD24+CD133+liver cancer stem cell phenotype through a TACE/ADAM17-dependent Notch signaling pathway

2018 ◽  
Vol 115 (43) ◽  
pp. E10127-E10136 ◽  
Author(s):  
Ronghua Wang ◽  
Yawen Li ◽  
Allan Tsung ◽  
Hai Huang ◽  
Qiang Du ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Notch Signaling ◽  
Cancer Progression ◽  
Tumor Formation ◽  
Cell Phenotype ◽  
Stem Cell Markers ◽  
Notch1 Signaling

The inducible nitric oxide synthase (iNOS) is associated with more aggressive solid tumors, including hepatocellular carcinoma (HCC). Notch signaling in cancer stem cells promotes cancer progression and requires Notch cleavage by ADAM (a disintegrin and metalloprotease) proteases. We hypothesized that iNOS/NO promotes Notch1 activation through TACE/ADAM17 activation in liver cancer stem cells (LCSCs), leading to a more aggressive cancer phenotype. Expression of the stem cell markers CD24 and CD133 in the tumors of patients with HCC was associated with greater iNOS expression and worse outcomes. The expression of iNOS in CD24+CD133+LCSCs, but not CD24−CD133−LCSCs, promoted Notch1 signaling and stemness characteristics in vitro and in vivo, as well as accelerating HCC initiation and tumor formation in the mouse xenograft tumor model. iNOS/NO led to Notch1 signaling through a pathway involving the soluble guanylyl cyclase/cGMP/PKG-dependent activation of TACE/ADAM17 and up-regulation of iRhom2 in LCSCs. In patients with HCC, higher TACE/ADAM17 expression and Notch1 activation correlated with poor prognosis. These findings link iNOS to Notch1 signaling in CD24+CD133+LCSCs through the activation of TACE/ADAM17 and identify a mechanism for how iNOS contributes to progression of CD24+CD133+HCC.

scholarly journals A Systematic Review to Clarify the Prognostic Values of CD44 and CD44+CD24- Phenotype in Triple-Negative Breast Cancer Patients: Lessons Learned and The Road Ahead

2021 ◽  
Vol 11 ◽  
Author(s):  
Mahdi Abdoli Shadbad ◽  
Negar Hosseinkhani ◽  
Zahra Asadzadeh ◽  
Afshin Derakhshani ◽  
Noora Karim Ahangar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cell Phenotype ◽  
Stem Cell Markers ◽  
Advanced Tumor Stage

As a unique population of tumor bulk, cancer stem cells have been implicated in tumor relapse and chemoresistance in triple-negative breast cancer (TNBC). Therefore, understanding the phenotype of cancer stem cells can pave the way for introducing novel molecular targeted therapies for treating TNBC patients. Preclinical studies have identified CD44+CD24-/low as a cancer stem cell phenotype; however, clinical studies have reported seemingly controversial results regarding the prognostic values of CD44 and CD44+CD24-/low phenotype in TNBC patients. To critically review the clinicopathological significance and prognostic values of CD44 and CD44+CD24-/low phenotype in TNBC patients, the Scopus, Embase, PubMed, and Web of Science databases were systematically searched to obtain the relevant records published before 20 October 2020. Based on nine included studies, CD44 and CD44+CD24-/low phenotype are associated with inferior prognosis in TNBC patients. Moreover, these cancer stem cell markers have been associated with advanced tumor stage, tumor size, higher tumor grade, tumor metastasis, and lymphatic involvement in TNBC patients. Our evidence has also indicated that, unlike the treatment-naïve TNBC patients, the tumoral cells of chemoradiotherapy-treated TNBC patients can upregulate the CD44+CD24-/low phenotype and establish an inverse association with androgen receptor (AR), leading to the inferior prognosis of affected patients. In summary, CD44 and CD44+CD24-/low phenotype can be utilized to determine TNBC patients’ prognosis in the pathology department as a routine practice, and targeting these phenotypes can substantially improve the prognosis of TNBC patients.

scholarly journals Efficacy of Using Cancer Stem Cell Markers in Isolating and Characterizing Liver Cancer Stem Cells

2013 ◽  
Vol 22 (19) ◽  
pp. 2655-2664 ◽  
Author(s):  
George S. Wilson ◽  
Zenan Hu ◽  
Wei Duan ◽  
Aiping Tian ◽  
Xin M. Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Cancer Stem Cell ◽  
Stem Cell Markers ◽  
Cell Markers ◽  
Cancer Stem Cell Markers ◽  
Liver Cancer Stem Cells

scholarly journals A Novel Function for KLF4 in Modulating the De-Differentiation of EpCAM−/CD133− nonStem Cells into EpCAM+/CD133+ Liver Cancer Stem Cells in HCC Cell Line HuH7

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1198 ◽  
Author(s):  
Zeynep Firtina Karagonlar ◽  
Soheil Akbari ◽  
Mustafa Karabicici ◽  
Eren Sahin ◽  
Sanem Tercan Avci ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Cell Line ◽  
Tumor Cells ◽  
Cell Phenotype ◽  
High Plasticity ◽  
Liver Cancer Stem Cells

The complex and heterogeneous nature of hepatocellular carcinoma (HCC) hampers the identification of effective therapeutic strategies. Cancer stem cells (CSCs) represent a fraction of cells within tumors with the ability to self-renew and differentiate, and thus significantly contribute to the formation and maintenance of heterogeneous tumor mass. Increasing evidence indicates high plasticity in tumor cells, suggesting that non-CSCs could acquire stem cell properties through de-differentiation or reprogramming processes. In this paper, we reveal KLF4 as a transcription factor that can induce a CSC-like phenotype in non-CSCs through upregulating the EpCAM and E-CAD expression. Our studies indicated that KLF4 could directly bind to the promoter of EpCAM and increase the number of EpCAM+/CD133+ liver cancer stem cells (LCSCs) in the HuH7 HCC cell line. When KLF4 was overexpressed in EpCAM−/CD133− non-stem cells, the expressions of hepatic stem/progenitor cell genes such as CK19, EpCAM and LGR5 were significantly increased. KLF4 overexpressing non-stem cells exhibited greater cell viability upon sorafenib treatment, while the cell migration and invasion capabilities of these cells were suppressed. Importantly, we detected an increased membranous expression and colocalization of β-CAT, E-CAD and EpCAM in the KLF4-overexpressing EpCAM−/CD133− non-stem cells, suggesting that this complex might be required for the cancer stem cell phenotype. Moreover, our in vivo xenograft studies demonstrated that with a KLF4 overexpression, EpCAM−/CD133− non-stem cells attained an in vivo tumor forming ability comparable to EpCAM+/CD133+ LCSCs, and the tumor specimens from KLF4-overexpressing xenografts had increased levels of both the KLF4 and EpCAM proteins. Additionally, we identified a correlation between the KLF4 and EpCAM protein expressions in human HCC tissues independent of the tumor stage and differentiation status. Collectively, our data suggest a novel function for KLF4 in modulating the de-differentiation of tumor cells and the induction of EpCAM+/CD133+ LCSCs in HuH7 HCC cells.

scholarly journals Current Strategies for Identification of Glioma Stem Cells: Adequate or Unsatisfactory?

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Paola Brescia ◽  
Cristina Richichi ◽  
Giuliana Pelicci
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Cell Phenotype ◽  
Multiple Tumor ◽  
Early Results ◽  
Tumorigenic Potential ◽  
Tumor Types

Cancer stem cells (CSCs) were isolated in multiple tumor types, including human glioblastomas, and although the presence of surface markers selectively expressed on CSCs can be used to isolate them, no marker/pattern of markers are sufficiently robust to definitively identify stem cells in tumors. Several markers were evaluated for their prognostic value with promising early results, however none of them was proven to be clinically useful in large-scale studies, leading to outstanding efforts to identify new markers. Given the heterogeneity of human glioblastomas further investigations are necessary to identify both cancer stem cell-specific markers and the molecular mechanisms sustaining the tumorigenic potential of these cells to develop tailored treatments. Markers for glioblastoma stem cells such as CD133, CD15, integrin-α6, L1CAM might be informative to identify these cells but cannot be conclusively linked to a stem cell phenotype. Overlap of expression, functional state and morphology of different subpopulations lead to carefully consider the techniques employed so far to isolate these cells. Due to a dearth of methods and markers reliably identifying the candidate cancer stem cells, the isolation/enrichment of cancer stem cells to be therapeutically targeted remains a major challenge.

The effect of BMI-1 inhibition on brain cancer stem cells.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13543-e13543
Author(s):  
Monal Mehta ◽  
Atif J. Khan ◽  
Hatem E. Sabaawy ◽  
Bruce George Haffty
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cell Lines ◽  
Brain Cancer ◽  
Insertion Site ◽  
Stem Cell Markers ◽  
Primary Cells ◽  
Self Renewal

e13543 Background: Glioblastoma (GBM) is the most frequent and deadly brain cancer. Despite tolerance doses of radiation, control of tumor growth within the brain remains a formidable failure. Since the identification of brain cancer stem cells (BCSCs), efforts are underway to target the pathways regulating these cells. The role of Bmi-1 (B-cell specific MMLV insertion site-1), a polycomb member of chromatin-remodeling complex, in BCSCs self-renewal was elucidated. Here we utilize shRNA targeting or pharmacological inhibition of Bmi-1 in GBM cell lines and primary cells as a radiosensitizer to examine the effects of combination therapy on cell death and BCSCs differentiation. Methods: Cells were pre-treated with a Bmi-1 inhibitor before being irradiated. Serial neurosphere assay, a measure of self-renewal potential, was employed to study the effects of radiation, Bmi-1 inhibition, or the combination on BCSCs. The efficacy of this combination on cell death was assessed with MTT and clonogenic assays. Next, the abilities of the inhibitor and radiation to induce differentiation in GBM cell lines and primary cells were quantified. Further, by utilizing a novel zebrafish orthotropic xenograft model, small molecules targeting Bmi-1 and other BCSC pathways can be identified, and used to predict response to combination therapies. Results: Targeting of Bmi-1 in combination with radiation, specifically as a radiosensitizer, induced significant cell death in GBM cells, and was five-fold more effective than radiation only. Importantly, the neurosphere forming ability of BCSCs was severely compromised when the cells were treated with the combination, indicating a potent effect on the stem cell constituency. These effects may be due to loss of BCSC self-renewal potential, increased differentiation, and/or apoptosis as cells treated with the combination exhibited decreased expression of neural stem cell markers and abnormal phenotypes compared to single treatment. Conclusions: Targeting of Bmi-1 may eliminate the subpopulation of radioresistant BCSCs. Bmi-1 inhibition when combined with radiotherapy might provide an effective therapy for GBM patients specifically through its effect on BCSCs by affecting their survival, proliferation, and stem cell features.

scholarly journals The Expression of Markers Related to Ovarian Germline Stem Cells in the Mouse Ovarian Surface Epithelium and the Correlation with Notch Signaling Pathway

2015 ◽  
Vol 37 (6) ◽  
pp. 2311-2322 ◽  
Author(s):  
Zezheng Pan ◽  
Mengli Sun ◽  
Jia Li ◽  
Fangyue Zhou ◽  
Xia Liang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Ovarian Surface Epithelium ◽  
Notch Signaling Pathway ◽  
Surface Epithelium ◽  
Stem Cell Markers ◽  
Germline Stem Cells ◽  
Ovarian Surface

Background/Aims: Ovarian germline stem cells (OGSCs) have been shown to mainly exist in the ovarian surface epithelium (OSE), but the activity changes of germline stem cells during different reproductive stages and the potential regulatory signaling pathway are still unknown. The Notch signaling pathway plays a key role in cell development, primordial follicles and stem cell proliferation. However, whether it plays a role in the proliferation of OGSCs is unknown. Here, we analyzed the activity changes of germline stem cells and the correlation between germline stem cells and the Notch signaling pathway. Methods: The expression of germline stem cell markers Mvh, Ooc4 and the Notch molecules Notch1, Hes1, and Hes5 were detected during 3 days (3d), and 2, 12, 20 months (2m, 12m, 20m) mouse ovarian surface epithelium samples. DAPT, a specific inhibitor of the Notch pathway, was used to observe the influence of Notch signaling in the germline stem cells. Results: The results showed that the levels of MVH and OCT4 decreased substantially with reproductive age in ovarian surface epithelium, and the same tendency was detected in the Notch signaling molecules Notch1, Hes1 and Hes5. Dual-IF results showed that the germline stem cell markers were co-expressed with Notch molecules in the ovarian surface epithelium. While, the expression of MVH and OCT4 were reduced when the ovaries were treated with DAPT and the levels were attenuated with increasing dose of DAPT. Conclusion: Taken together, our results indicate that the viability of OGSCs decreased with the age of the mouse ovaries, and the activity of OGSCs in the ovarian surface epithelium may be related to the Notch signaling pathway.

scholarly journals Gastric Cancer Stem Cells Survive in Stress Environments via Their Autophagy System

2020 ◽  
Author(s):  
Shingo Togano ◽  
Masakazu Yashiro ◽  
Go Masuda ◽  
Atsushi Sugimoto ◽  
Yuichiro Miki ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Electron Microscope ◽  
Cancer Stem Cells ◽  
Western Blot ◽  
Stem Cell Markers ◽  
Cell Markers ◽  
Autophagy Inhibitor ◽  
Stress Environments

Abstract Background: It has been reported that cancer stem cells (CSCs) play an important role in the progression of carcinoma and have a high potential for survival in various stress environments such as starvation and hypoxia. However, the mechanisms responsible for the capacity of CSCs to survive under stresses have been unclear. The aim of this study was to clarify the significance of the autophagy systems of CSCs under stress environments.Methods: Four human gastric cancer cell line, OCUM-12, OCUM-2MD3, MKN-45 and MKN-74 were used. Side population (SP) cells were sorted from the parent OCUM-12 and OCUM-2MD3, as CSC rich cells. The expression of stem cell markers was examined by RT-PCR. The viability of cancer cells under starvation and hypoxia (1%O2) was evaluated by MTT assay with or without the autophagy inhibitor, chloroquine. The expression level of the autophagy molecule LC3-II was examined by western blot. The numbers of autophagosomes and autolysosomes were counted by electron microscope.Results: SP cells of OCUM-12 showed a higher expression of stem cell markers and higher viability in starvation and hypoxia. Western blot and electron microscope examinations indicated that the autophagy was more induced in SP cells than in parent cells. The autophagy inhibitor significantly decreased the viability and the proportion of SP cells under the stress environments.Conclusions: Cancer stem cells of gastric cancer might maintain their viability under stress environments of starvation and hypoxia via the autophagy system. Autophagy inhibitors might be a promising therapeutic agent for gastric cancer.

scholarly journals Molecular markers of cancer stem cells verified in vivo

2016 ◽  
Vol 62 (3) ◽  
pp. 228-238 ◽  
Author(s):  
Y.S. Kim ◽  
A.M. Kaidina ◽  
J.H. Chiang ◽  
K.N. Yarygin ◽  
A.Yu. Lupatov
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Molecular Markers ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
Stem Cell Markers ◽  
Cancer Stem Cell Markers ◽  
Immunodeficient Mice ◽  
Molecular Features

This systematic review aims to analyze molecular markers of cancer stem cells. Only studies that confirmed tumor-initiating capacity of this population by in vivo assay in immunodeficient mice were included. Final sample of papers that fully correspond with initial aim consists of 97 original studies. The results of their analysis reveal that markers commonly used for cancer stem cells deriving were as follows: CD133, СD44, ALDH, CD34, CD24 and EpCAM. The review also contains description of molecular features of some cancer stem cell markers, modern approaches to cancer treatment by targeting this population and brief assessment of cancer stem cell theory development.

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