scholarly journals A Novel Therapeutic Approach for Colorectal Cancer Stem Cells: Blocking the PI3K/Akt Signaling Axis With Caffeic Acid

2020 ◽  
Vol 8 ◽  
Author(s):  
Se-Ra Park ◽  
Soo-Rim Kim ◽  
In-Sun Hong ◽  
Hwa-Yong Lee
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Caffeic Acid ◽  
Akt Signaling ◽  
Chemotherapeutic Agents ◽  
Cancer Therapies ◽  
Self Renewal ◽  
Colorectal Cancer Stem Cells

Cancer stem cells (CSCs) have been identified in a multiple of cancer types and resistant to traditional cancer therapies such as chemotherapeutic agents and radiotherapy, which may destroy bulk tumor cells but not all CSCs, contributing to reformation tumor masses and subsequent relapse. Moreover, it is very difficult to effectively identify and eliminate CSCs because they share some common phenotypic and functional characteristics of normal stem cells. Therefore, finding better therapeutic strategies to selectively target CSCs might be helpful to reduce subsequent malignancies. In the present study, we found that caffeic acid effectively suppresses self-renewal capacity, stem-like characteristics, and migratory capacity of CD44+ and CD133+ colorectal CSCs in vitro and in vivo. In addition, we also revealed that PI3K/Akt signaling may be linked to multiple colorectal CSC-associated characteristics, such as radio-resistance, stem-like property, and tumorigenic potential. To the best of our knowledge, this is the first study demonstrating that caffeic acid effectively targets colorectal CSC populations by inhibiting the growth and/or self-renewal capacity of colorectal CSCs through PI3K/Akt signaling in vitro and in vivo.

scholarly journals Chemosensitization of prostate cancer stem cells in mice by angiogenin and plexin-B2 inhibitors

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Shuping Li ◽  
Kevin A. Goncalves ◽  
Baiqing Lyu ◽  
Liang Yuan ◽  
Guo-fu Hu
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Ribosomal Rna ◽  
Protein Translation ◽  
Chemotherapeutic Agents ◽  
Self Renewal ◽  
5S Ribosomal Rna ◽  
Prostate Cancer Stem Cells

AbstractCancer stem cells (CSCs) are an obstacle in cancer therapy and are a major cause of drug resistance, cancer recurrence, and metastasis. Available treatments, targeting proliferating cancer cells, are not effective in eliminating quiescent CSCs. Identification of CSC regulators will help design therapeutic strategies to sensitize drug-resistant CSCs for chemo-eradication. Here, we show that angiogenin and plexin-B2 regulate the stemness of prostate CSCs, and that inhibitors of angiogenin/plexin-B2 sensitize prostate CSCs to chemotherapy. Prostate CSCs capable of self-renewal, differentiation, and tumor initiation with a single cell inoculation were identified and shown to be regulated by angiogenin/plexin-B2 that promotes quiescence and self-renewal through 5S ribosomal RNA processing and generation of the bioactive 3′-end fragments of 5S ribosomal RNA, which suppress protein translation and restrict cell cycling. Monoclonal antibodies of angiogenin and plexin-B2 decrease the stemness of prostate CSCs and sensitize them to chemotherapeutic agents in vitro and in vivo.

scholarly journals MicroRNA-28-5p Regulates Liver Cancer Stem Cell Expansion via IGF-1 Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Qing Xia ◽  
Tao Han ◽  
Pinghua Yang ◽  
Ruoyu Wang ◽  
Hengyu Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Critical Role ◽  
Self Renewal ◽  
Sorafenib Treatment ◽  
The Impact

Background. MicroRNAs (miRNAs) play a critical role in the regulation of cancer stem cells (CSCs). However, the role of miRNAs in liver CSCs has not been fully elucidated. Methods. Real-time PCR was used to detect the expression of miR-miR-28-5p in liver cancer stem cells (CSCs). The impact of miR-28-5p on liver CSC expansion was investigated both in vivo and in vitro. The correlation between miR-28-5p expression and sorafenib benefits in HCC was further evaluated in patient-derived xenografts (PDXs). Results. Our data showed that miR-28-5p was downregulated in sorted EpCAM- and CD24-positive liver CSCs. Biofunctional investigations revealed that knockdown miR-28-5p promoted liver CSC self-renewal and tumorigenesis. Consistently, miR-28-5p overexpression inhibited liver CSC’s self-renewal and tumorigenesis. Mechanistically, we found that insulin-like growth factor-1 (IGF-1) was a direct target of miR-28-5p in liver CSCs, and the effects of miR-28-5p on liver CSC’s self-renewal and tumorigenesis were dependent on IGF-1. The correlation between miR-28-5p and IGF-1 was confirmed in human HCC tissues. Furthermore, the miR-28-5p knockdown HCC cells were more sensitive to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrated that the miR-28-5p may predict sorafenib benefits in HCC patients. Conclusion. Our findings revealed the crucial role of the miR-28-5p in liver CSC expansion and sorafenib response, rendering miR-28-5p an optimal therapeutic target for HCC.

scholarly journals Stage-specific embryonic antigen-3 (SSEA-3) and β3GalT5 are cancer specific and significant markers for breast cancer stem cells

2015 ◽  
Vol 113 (4) ◽  
pp. 960-965 ◽  
Author(s):  
Sarah K. C. Cheung ◽  
Po-Kai Chuang ◽  
Han-Wen Huang ◽  
Wendy W. Hwang-Verslues ◽  
Candy Hsin-Hua Cho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Embryonic Stem ◽  
Cancer Therapies ◽  
New Cancer Therapies ◽  
Globo Series

The discovery of cancer stem cells (CSCs), which are responsible for self-renewal and tumor growth in heterogeneous cancer tissues, has stimulated interests in developing new cancer therapies and early diagnosis. However, the markers currently used for isolation of CSCs are often not selective enough to enrich CSCs for the study of this special cell population. Here we show that the breast CSCs isolated with CD44+CD24-/loSSEA-3+ or ESAhiPROCRhiSSEA-3+ markers had higher tumorigenicity than those with conventional markers in vitro and in vivo. As few as 10 cells with CD44+CD24-/loSSEA-3+ formed tumor in mice, compared with more than 100 cells with CD44+CD24-/lo. Suppression of SSEA-3 expression by knockdown of the gene encoding β-1,3-galactosyltransferase 5 (β3GalT5) in the globo-series pathway, led to apoptosis in cancer cells specifically but had no effect on normal cells. This finding is further supported by the analysis of SSEA-3 and the two related globo-series epitopes SSEA4 and globo-H in stem cells (embryonic stem cells and induced pluripotent stem cells) and various normal and cancer cells, and by the antibody approach to target the globo-series glycans and the late-stage clinical trials of a breast cancer vaccine.

scholarly journals Aptamer-mediated survivin RNAi enables 5-fluorouracil to eliminate colorectal cancer stem cells

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Hadi AlShamaileh ◽  
Tao Wang ◽  
Dongxi Xiang ◽  
Wang Yin ◽  
Phuong Ha-Lien Tran ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Xenograft Model ◽  
Chemotherapeutic Agents ◽  
Mouse Xenograft Model ◽  
Colorectal Cancer Cells ◽  
Colorectal Cancer Stem Cells ◽  
Molecular Therapeutic

AbstractThe development of chemoresistance and inability in elimination of cancer stem cells are among the key limitations of cancer chemotherapy. Novel molecular therapeutic strategies able to overcome such limitations are urgently needed for future effective management of cancer. In this report, we show that EpCAM-aptamer-guided survivin RNAi effectively downregulated survivin both in colorectal cancer cells in vitro and in a mouse xenograft model for colorectal cancer. When combined with the conventional chemotherapeutic agents, the aptamer-guided survivin RNAi was able to enhance the sensitivity towards 5-FU or oxaliplatin in colorectal cancer stem cells, increase apoptosis, inhibit tumour growth and improve the overall survival of mice bearing xenograft colorectal cancer. Our results indicate that survivin is one of the key players responsible for the innate chemoresistance of colorectal cancer stem cells. Thus, aptamer-mediated targeting of survivin in cancer stem cells in combination with chemotherapeutic drugs constitutes a new avenue to improve treatment outcome in oncologic clinics.

scholarly journals Long non-coding RNA NORAD promotes pancreatic cancer stem cell proliferation and self-renewal by blocking microRNA-202-5p-mediated ANP32E inhibition

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yu-Shui Ma ◽  
Xiao-Li Yang ◽  
Yu-Shan Liu ◽  
Hua Ding ◽  
Jian-Jun Wu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cell Viability ◽  
Luciferase Reporter ◽  
Cell Cycle Distribution ◽  
Loss Of Function ◽  
Self Renewal

Abstract Background Cancer stem cells (CSCs) are key regulators in the processes of tumor initiation, progression, and recurrence. The mechanism that maintains their stemness remains enigmatic, although the role of several long noncoding RNAs (lncRNAs) has been highlighted in the pancreatic cancer stem cells (PCSCs). In this study, we first established that PCSCs overexpressing lncRNA NORAD, and then investigated the effects of NORAD on the maintenance of PCSC stemness. Methods Expression of lncRNA NORAD, miR-202-5p and ANP32E in PC tissues and cell lines was quantified after RNA isolation. Dual-luciferase reporter assay, RNA pull-down and RIP assays were performed to verify the interactions among NORAD, miR-202-5p and ANP32E. We then carried out gain- and loss-of function of miR-202-5p, ANP32E and NORAD in PANC-1 cell line, followed by measurement of the aldehyde dehydrogenase activity, cell viability, apoptosis, cell cycle distribution, colony formation, self-renewal ability and tumorigenicity of PC cells. Results LncRNA NORAD and ANP32E were upregulated in PC tissues and cells, whereas the miR-202-5p level was down-regulated. LncRNA NORAD competitively bound to miR-202-5p, and promoted the expression of the miR-202-5p target gene ANP32E thereby promoting PC cell viability, proliferation, and self-renewal ability in vitro, as well as facilitating tumorigenesis of PCSCs in vivo. Conclusion Overall, lncRNA NORAD upregulates ANP32E expression by competitively binding to miR-202-5, which accelerates the proliferation and self-renewal of PCSCs.

scholarly journals IL-17B/IL-17RB signaling cascade contributes to self-renewal and tumorigenesis of cancer stem cells by regulating Beclin-1 ubiquitination

Oncogene ◽  
2021 ◽  
Author(s):  
Qingli Bie ◽  
Hui Song ◽  
Xinke Chen ◽  
Xiao Yang ◽  
Shuo Shi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Molecular Mechanisms ◽  
Tumor Necrosis Factor Receptor ◽  
Beclin 1 ◽  
Signaling Cascade ◽  
Interleukin 17 ◽  
Self Renewal

AbstractCancer stem cells (CSCs) are characterized by robust self-renewal and tumorigenesis and are responsible for metastasis, drug resistance, and angiogenesis. However, the molecular mechanisms for the regulation of CSC homeostasis are incompletely understood. This study demonstrated that the interleukin-17 (IL-17)B/IL-17RB signaling cascade promotes the self-renewal and tumorigenesis of CSCs by inducing Beclin-1 ubiquitination. We found that IL-17RB expression was significantly upregulated in spheroid cells and Lgr5-positive cells from the same tumor tissues of patients with gastric cancer (GC), which was closely correlated with the degree of cancer cell differentiation. Recombinant IL-17B (rIL-17B) promoted the sphere-formation ability of CSCs in vitro and enhanced tumor growth and metastasis in vivo. Interestingly, IL-17B induced autophagosome formation and cleavage-mediated transformation of LC3 in CSCs and 293T cells. Furthermore, inhibition of autophagy activation by ATG7 knockdown reversed rIL-17B-induced self-renewal of GC cells. In addition, we showed that IL-17B also promoted K63-mediated ubiquitination of Beclin-1 by mediating the binding of tumor necrosis factor receptor-associated factor 6 to Beclin-1. Silencing IL-17RB expression abrogated the effects of IL-17B on Beclin-1 ubiquitination and autophagy activation in GC cells. Finally, we showed that IL-17B level in the serum of GC patients was positively correlated with IL-17RB expression in GC tissues, and IL-17B could induce IL-17RB expression in GC cells. Overall, the results elucidate the novel functions of IL-17B for CSCs and suggest that the intervention of the IL-17B/IL-17RB signaling pathway may provide new therapeutic targets for the treatment of cancer.

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 The Efficacy of PI3Kγ and EGFR Inhibitors on the Suppression of the Characteristics of Cancer Stem Cells

2021 ◽  
Author(s):  
Yanning Xu ◽  
Said M. Afify ◽  
Juan Du ◽  
Bingbing Liu ◽  
Qing Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Recurrence ◽  
Significant Inhibition ◽  
Migration And Invasion ◽  
Antitumor Effects ◽  
Self Renewal ◽  
Egfr Signaling Pathway

Abstract Cancer stem cells (CSCs) are capable of continuous proliferation, self-renewal and are proposed to play significant roles in oncogenesis, tumor growth, metastasis and cancer recurrence. We have established a model of CSCs that was originally developed from mouse induced pluripotent stem cells (miPSCs) by proposing miPSCs to the conditioned medium (CM) of cancer derived cells, which is a mimic of carcinoma microenvironment. Further research found that not only PI3K-Akt but also EGFR signaling pathway was activated during converting miPSCs into CSCs. In this study, we tried to observe both of PI3Kγ inhibitor Eganelisib and EGFR inhibitor Gefitinib antitumor effects on the models of CSCs derived from miPSCs (miPS-CSC) in vitro and in vivo. As the results, targeting these two pathways exhibited significant inhibition of cell proliferation, self-renewal, migration and invasion abilities in vitro. Both Eganelisib and Gefitinib showed antitumor effects in vivo while Eganelisib displayed more significant therapeutic efficacy and less side effects than Gefitinib on all miPS-CSC models. Thus, these data suggest that the inhibitiors of PI3K and EGFR, especially PI3Kγ, might be a promising therapeutic strategy against CSCs defeating cancer in the near future

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