scholarly journals Inhibition of insulin-like growth factor receptor/AKT/mammalian target of rapamycin axis targets colorectal cancer stem cells by attenuating mevalonate-isoprenoid pathway in vitro and in vivo

Oncotarget ◽  
2015 ◽  
Vol 6 (17) ◽  
pp. 15332-15347 ◽  
Author(s):  
Chetna Sharon ◽  
Somesh Baranwal ◽  
Nirmita J. Patel ◽  
Daniel Rodriguez-Agudo ◽  
William M. Pandak ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Growth Factor ◽  
Cancer Stem Cells ◽  
Mammalian Target Of Rapamycin ◽  
Growth Factor Receptor ◽  
Insulin Like Growth Factor ◽  
Colorectal Cancer Stem Cells

scholarly journals PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells

Gut ◽  
2021 ◽  
pp. gutjnl-2020-323553
Author(s):  
Laura Rosa Mangiapane ◽  
Annalisa Nicotra ◽  
Alice Turdo ◽  
Miriam Gaggianesi ◽  
Paola Bianca ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Cancer Stem Cells ◽  
Growth Factor Receptor ◽  
Her2 Expression ◽  
Phosphatidylinositol 3 Kinase ◽  
Epidermal Growth ◽  
Colorectal Cancer Stem Cells

ObjectiveCancer stem cells are responsible for tumour spreading and relapse. Human epidermal growth factor receptor 2 (HER2) expression is a negative prognostic factor in colorectal cancer (CRC) and a potential target in tumours carrying the gene amplification. Our aim was to define the expression of HER2 in colorectal cancer stem cells (CR-CSCs) and its possible role as therapeutic target in CRC resistant to anti- epidermal growth factor receptor (EGFR) therapy.DesignA collection of primary sphere cell cultures obtained from 60 CRC specimens was used to generate CR-CSC mouse avatars to preclinically validate therapeutic options. We also made use of the ChIP-seq analysis for transcriptional evaluation of HER2 activation and global RNA-seq to identify the mechanisms underlying therapy resistance.ResultsHere we show that in CD44v6-positive CR-CSCs, high HER2 expression levels are associated with an activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which promotes the acetylation at the regulatory elements of the Erbb2 gene. HER2 targeting in combination with phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase kinase (MEK) inhibitors induces CR-CSC death and regression of tumour xenografts, including those carrying Kras and Pik3ca mutation. Requirement for the triple targeting is due to the presence of cancer-associated fibroblasts, which release cytokines able to confer CR-CSC resistance to PI3K/AKT inhibitors. In contrast, targeting of PI3K/AKT as monotherapy is sufficient to kill liver-disseminating CR-CSCs in a model of adjuvant therapy.ConclusionsWhile PI3K targeting kills liver-colonising CR-CSCs, the concomitant inhibition of PI3K, HER2 and MEK is required to induce regression of tumours resistant to anti-EGFR therapies. These data may provide a rationale for designing clinical trials in the adjuvant and metastatic setting.

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 Superior Effect of the Combination of Carbon-Ion Beam Irradiation and 5-Fluorouracil on Colorectal Cancer Stem Cells in vitro and in vivo

2020 ◽  
Vol Volume 13 ◽  
pp. 12625-12635
Author(s):  
Woong Sub Koom ◽  
Sei Sai ◽  
Masao Suzuki ◽  
Akira Fujimori ◽  
Shigeru Yamada ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Ion Beam ◽  
Beam Irradiation ◽  
Ion Beam Irradiation ◽  
Superior Effect ◽  
Carbon Ion Beam ◽  
Colorectal Cancer Stem Cells

scholarly journals Sequencing of Type I Insulin-Like Growth Factor Receptor Inhibition Affects Chemotherapy Response In vitro and In vivo

2009 ◽  
Vol 15 (8) ◽  
pp. 2840-2849 ◽  
Author(s):  
Xianke Zeng ◽  
Deepali Sachdev ◽  
Hua Zhang ◽  
Martine Gaillard-Kelly ◽  
Douglas Yee
Keyword(s):  
Growth Factor ◽  
Growth Factor Receptor ◽  
Chemotherapy Response ◽  
Type I ◽  
Insulin Like Growth Factor ◽  
Receptor Inhibition

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.

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