scholarly journals Targeting self-renewal of cancer stem cells in colorectal cancer—a future treatment option?

2013 ◽  
Vol 11 (2) ◽  
pp. 75-75 ◽  
Author(s):  
Isobel Leake
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Treatment Option ◽  
Self Renewal ◽  
Future Treatment ◽  
Future Treatment Option

scholarly journals RNAi mediated silencing of Nanog expression suppresses the growth of human colorectal cancer stem cells

2020 ◽  
Author(s):  
Chen Zhang ◽  
Yuanyuan Zhao ◽  
Yongjing Yang ◽  
Chunlian Zhong ◽  
Tianju Ji ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Small Interfering Rna ◽  
Embryonic Stem ◽  
Self Renewal ◽  
Nanog Expression ◽  
Hct 116 ◽  
Hct 116 Cells ◽  
Interfering Rna

Abstract Background: Colorectal cancer (CRC) is the third most common cancer in the world known for its poor recurrence-free prognosis. Previous studies have shown that it is closely linked with cancer stem cells (CSCs), which have self-renewal potential and the capacity to differentiate into diverse populations. Nanog is an important transcription factor that functions to maintain the self-renewal and proliferation of embryonic stem cells; however, many recent studies have shown that Nanog is also highly expressed in many cancer stem cells.Methods: To investigate whether Nanog plays a crucial role in maintaining the stemness of colorectal CSCs (CCSCs), RNA interference was used to downregulate Nanog expression in the CRC stem cell line, EpCAM+CD44+HCT-116. We examined the anti-tumor function of Nanog in vitro and in vivo, using small interfering RNA.Results: Our results revealed that the Nanog mRNA expression level in CCSCs was higher than that in HCT-116 cells. We found that the depletion of Nanog inhibited proliferation and promoted apoptosis in EpCAM+CD44+HCT-116 cells. In addition, the invasive ability of EpCAM+CD44+HCT-116 cells was markedly restricted when Nanog was silenced by small interfering RNA. Furthermore, we found that the silencing of Nanog decreased tumor size and weight and improved the survival rate of tumor-bearing mice.Conclusions: In conclusion, these findings collectively demonstrate that Nanog, which is highly expressed in CRC stem cells, is a key factor in the development of tumor growth, and it may serve as a potential marker of prognosis and a novel and effective therapeutic target for the treatment of CRC.

scholarly journals G9a controls pluripotent-like identity and tumor-initiating function in human colorectal cancer

Oncogene ◽  
2020 ◽  
Author(s):  
Christopher J. Bergin ◽  
Aïcha Zouggar ◽  
Joshua R. Haebe ◽  
Angelique N. Masibag ◽  
François M. Desrochers ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Embryonic Stem ◽  
Transcriptome Profiling ◽  
Histone Methyltransferase ◽  
Cell Phenotype ◽  
Regulation Mechanism ◽  
Self Renewal ◽  
Undifferentiated State

AbstractColorectal tumors are hierarchically organized and governed by populations of self-renewing cancer stem cells, representing one of the deadliest types of cancers worldwide. Emergence of cancer stemness phenotype depends on epigenetic reprogramming, associated with profound transcriptional changes. As described for pluripotent reprogramming, epigenetic modifiers play a key role in cancer stem cells by establishing embryonic stem-like transcriptional programs, thus impacting the balance between self-renewal and differentiation. We identified overexpression of histone methyltransferase G9a as a risk factor for colorectal cancer, associated with shorter relapse-free survival. Moreover, using human transformed pluripotent cells as a surrogate model for cancer stem cells, we observed that G9a activity is essential for the maintenance of embryonic-like transcriptional signature promoting self-renewal, tumorigenicity, and undifferentiated state. Such a role was also applicable to colorectal cancer, where inhibitors of G9a histone methyltransferase function induced intestinal differentiation while restricting tumor-initiating activity in patient-derived colorectal tumor samples. Finally, by integrating transcriptome profiling with G9a/H3K9me2 loci co-occupancy, we identified the canonical Wnt pathway, epithelial-to-mesenchyme transition, and extracellular matrix organization as potential targets of such a chromatin regulation mechanism in colorectal cancer stem cells. Overall, our findings provide novel insights on the role of G9a as a driver of cancer stem cell phenotype, promoting self-renewal, tumorigenicity, and undifferentiated state.

scholarly journals Lgr5+CD44+EpCAM+ Strictly Defines Cancer Stem Cells in Human Colorectal Cancer

2018 ◽  
Vol 46 (2) ◽  
pp. 860-872 ◽  
Author(s):  
Zhengwei Leng ◽  
Qinghua Xia ◽  
Jinhuang Chen ◽  
Yong Li ◽  
Jiqian Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Colony Formation ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Xenograft ◽  
Self Renewal ◽  
Mesenchymal Transition

Background/Aims: Although EpCAM+CD44+ cells exhibit more stem-like properties than did EpCAM-CD44- cells, the specificity of EpCAM combined with CD44 in defining CSCs needs further improvement. Lgr5 is used as a biomarker to isolate cancer stem cells (CSCs) in colorectal cancer. However, it remains unclear whether Lgr5, along with EpCAM and CD44, can further identify and define CSCs in colorectal cancer. Methods: Lgr5+CD44+EpCAM+, Lgr5+CD44+EpCAM-, Lgr5+CD44-EpCAM+, Lgr5-CD44+EpCAM+, and Lgr5-CD44-EpCAM-cells were separately isolated using fluorescence-activated cell sorting (FACS). Colony formation, self-renewal, differentiation, and tumorigenic properties of these cells were investigated through in vitro experiments and in vivo tumor xenograft models. The expression of stemness genes and CSC- and epithelial-mesenchymal transition (EMT)-related genes, such as KLF4, Oct4, Sox2, Nanog, CD133, CD44, CD166, ALDH1, Lgr5, E-cadherin, ZO-1, Vimentin, Snail, Slug, and Twist, was examined using real-time PCR. Results: Lgr5-positive subpopulations exhibited higher capacities for colony formation, self-renewal, differentiation, and tumorigenicity as well as higher expression of stemness genes and mesenchymal genes and lower expression of epithelial genes than did Lgr5-negative subpopulations. Conclusion: Our data revealed that tumorigenic cells were highly restricted to Lgr5-positive subpopulations. Most importantly, Lgr5+CD44+EpCAM+ cells exhibited more pronounced CSC-like traits than did any other subpopulation, indicating that Lgr5 combined with CD44 and EpCAM can further improve the stem-like traits of CSCs in colorectal cancer.

scholarly journals Adenylate kinase hCINAP determines self-renewal of colorectal cancer stem cells by facilitating LDHA phosphorylation

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Yapeng Ji ◽  
Chuanzhen Yang ◽  
Zefang Tang ◽  
Yongfeng Yang ◽  
Yonglu Tian ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Adenylate Kinase ◽  
Drug Target ◽  
Therapeutic Strategy ◽  
Metabolic Reprogramming ◽  
Self Renewal ◽  
Colorectal Cancer Stem Cells ◽  
Metabolic Advantage

Abstract Targeting the specific metabolic phenotypes of colorectal cancer stem cells (CRCSCs) is an innovative therapeutic strategy for colorectal cancer (CRC) patients with poor prognosis and relapse. However, the context-dependent metabolic traits of CRCSCs remain poorly elucidated. Here we report that adenylate kinase hCINAP is overexpressed in CRC tissues. Depletion of hCINAP inhibits invasion, self-renewal, tumorigenesis and chemoresistance of CRCSCs with a loss of mesenchymal signature. Mechanistically, hCINAP binds to the C-terminal domain of LDHA, the key regulator of glycolysis, and depends on its adenylate kinase activity to promote LDHA phosphorylation at tyrosine 10, resulting in the hyperactive Warburg effect and the lower cellular ROS level and conferring metabolic advantage to CRCSC invasion. Moreover, hCINAP expression is positively correlated with the level of Y10-phosphorylated LDHA in CRC patients. This study identifies hCINAP as a potent modulator of metabolic reprogramming in CRCSCs and a promising drug target for CRC invasion and metastasis.

Differentiated cancer cell-originated lactate promotes the self-renewal of cancer stem cells in patient-derived colorectal cancer organoids

2020 ◽  
Vol 493 ◽  
pp. 236-244
Author(s):  
Hui Zhao ◽  
Chang Yan ◽  
Yibing Hu ◽  
Lei Mu ◽  
Shuang Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Cell ◽  
The Self ◽  
Self Renewal

scholarly journals RNAi mediated silencing of Nanog expression suppresses the growth of human colorectal cancer stem cells

2020 ◽  
Author(s):  
Chen Zhang ◽  
Yuanyuan Zhao ◽  
Yongjing Yang ◽  
Chunlian Zhong ◽  
Tianju Ji ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Small Interfering Rna ◽  
Embryonic Stem ◽  
Self Renewal ◽  
Nanog Expression ◽  
Hct 116 ◽  
Hct 116 Cells ◽  
Interfering Rna

Abstract Background: Colorectal cancer (CRC) is the third most common cancer in the world known for its poor recurrence-free prognosis. Previous studies have shown that it is closely linked with cancer stem cells (CSCs), which have self-renewal potential and the capacity to differentiate into diverse populations. Nanog is an important transcription factor that functions to maintain the self-renewal and proliferation of embryonic stem cells; however, many recent studies have shown that Nanog is also highly expressed in many cancer stem cells. Methods: To investigate whether Nanog plays a crucial role in maintaining the stemness of colorectal CSCs (CCSCs), RNA interference was used to downregulate Nanog expression in the CRC stem cell line, EpCAM + CD44 + HCT-116. We examined the anti-tumor function of Nanog in vitro and in vivo, using small interfering RNA. Results: Our results revealed that the Nanog mRNA expression level in CCSCs was higher than that in HCT-116 cells. We found that the depletion of Nanog inhibited proliferation and promoted apoptosis in EpCAM + CD44 + HCT-116 cells. In addition, the invasive ability of EpCAM + CD44 + HCT-116 cells was markedly restricted when Nanog was silenced by small interfering RNA. Furthermore, we found that the silencing of Nanog decreased tumor size and weight and improved the survival rate of tumor-bearing mice. Conclusions: In conclusion, these findings collectively demonstrate that Nanog, which is highly expressed in CRC stem cells, is a key factor in the development of tumor growth, and it may serve as a potential marker of prognosis and a novel and effective therapeutic target for the treatment of CRC.

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