The bad seed: Cancer stem cells in tumor development and resistance

Koren, Elle; Fuchs, Yaron

doi:10.1016/j.drup.2016.06.006

Cited by 97 publications

(59 citation statements)

References 163 publications

(154 reference statements)

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“…CSCs represent a subset of cancer cells that are characterized by self‐renewal capacity and drug resistance . In comparison with other cancer cells, CSCs have lower levels of intracellular ROS production and higher sensitivity to oxidant stress, which are considered beneficial for maintenance of CSC stemness .…”

Section: Discussionmentioning

confidence: 99%

Loss of Xanthine Oxidoreductase Potentiates Propagation of Hepatocellular Carcinoma Stem Cells

Sun

Zhang

et al. 2020

Hepatology

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Background and Aims Liver cancer stem cells (CSCs) exist in the tumor environment and are critically involved in the initiation and progression of hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of self‐renewal and maintenance of liver CSCs remain poorly understood. Approach and Results We identified that xanthine oxidoreductase (XOR), which was expressed at low levels in human HCC samples and liver CSCs, restrained HCC formation and chemoresistance by attenuating liver CSC propagation. Mechanistically, XOR physically interacts with ubiquitin‐specific peptidase 15 (USP15), thereby promoting deubiquitination of Kelch‐like ECH associated protein 1 (KEAP1) to stabilize its expression, which leads to degradation of Nrf2 (nuclear factor erythroid 2–related factor 2) through ubiquitination and subsequently reactive oxygen species accumulation in liver CSCs. Finally, our data reveal that XOR promotes USP15‐mediated Nrf2‐KEAP1 signaling to block liver CSCs and tumor propagation. Conclusion We identified that XOR may represent a potential therapeutic target for clinical intervention in HCC driven by liver CSCs.

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Section: Discussionmentioning

confidence: 99%

Loss of Xanthine Oxidoreductase Potentiates Propagation of Hepatocellular Carcinoma Stem Cells

Sun

Zhang

et al. 2020

Hepatology

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“…In total, 200 single viable cells were plated on ultralow attachment six-well plates (Corning) and cultured in serumfree DMEM/F12 medium (11,330,032, Gibco) supplemented with N 2 (17,502,048, Gibco), 20 ng/mL human recombinant epidermal growth factor (BMS320, eBioscience, San Diego, CA, USA), and 20 ng/mL basic fibroblast growth factor (68-8785-39, eBioscience) for approximately 2 weeks. Representative photos were taken on days 4, 8, and 12.…”

Section: Spheroid Formation Assaymentioning

confidence: 99%

“…Hence, targeting CSCs could improve current cancer treatment and help decrease the rate of ovarian cancer relapse. The most commonly used markers for the isolation of ovarian cancer CSCs are CD44, CD133, CD24, CD117 (c-Kit) and ALDH 1A1, which are often used in combination [6][7][8][9][10][11]. In addition, pluripotent stem cell markers of normal stem cells, notably OCT4, NANOG and SOX2, have also been found to play an important role in ovarian cancer development and metastasis and can be used to verify cell stemness [12].…”

Section: Introductionmentioning

confidence: 99%

A novel c-Kit/phospho-prohibitin axis enhances ovarian cancer stemness and chemoresistance via Notch3—PBX1 and β-catenin—ABCG2 signaling

et al. 2020

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Background: The underlying mechanism involved in ovarian cancer stemness and chemoresistance remains largely unknown. Here, we explored whether the regulation of c-Kit and plasma membrane prohibitin (PHB) affects ovarian cancer stemness and chemotherapy resistance.Methods: Mass spectrum analysis and an in vitro kinase assay were conducted to examine the phosphorylation of PHB at tyrosine 259 by c-Kit. The in vitro effects of c-Kit on membrane raft-PHB in ovarian cancer were determined using tissue microarray (TMA)-based immunofluorescence, western blotting, immunoprecipitation, colony and spheroid formation, cell migration and cell viability assays. In vivo tumor initiation and carboplatin treatment were conducted in nude mice.Results: We found that c-Kit and PHB colocalized in the raft domain and were positively correlated in human ovarian serous carcinoma. c-Kit interacted with PHB and facilitated the phosphorylation of PHB at tyrosine 259 (phospho-PHB Y259 ) in the membrane raft to enhance ovarian cancer cell motility. The generation of SKOV3GL-G4, a metastatic phenotype of SKOV3 green fluorescent protein and luciferase (GL) ovarian cancer cells, in xenograft murine ascites showed a correlation between metastatic potential and stem cell characteristics, as indicated by the expression of c-Kit, Notch3, Oct4, Nanog and SOX2. Further study revealed that after activation by c-Kit, raft-phospho-PHB Y259 interacted with Notch3 to stabilize Notch3 and increase the downstream target PBX1. Downregulation of raft-phospho-PHB Y259 increased the protein degradation of Notch3 through a lysosomal pathway and inhibited the β-catenin-ABCG2 signaling pathway. Moreover, raft-phospho-PHB Y259 played an important role in ovarian cancer stemness and tumorigenicity as well as resistance to platinum drug treatment in vitro and in vivo.Conclusions: These findings thus reveal a hitherto unreported interrelationship between c-Kit and PHB as well as the effects of raft-phospho-PHB Y259 on ovarian cancer stemness and tumorigenicity mediated by the Notch3 and β-catenin signaling pathways. Targeting the c-Kit/raft-phospho-PHB Y259 axis may provide a new therapeutic strategy for treating patients with ovarian cancer.

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“…Surgery and radiotherapy remain curative treatments for localized cases and chemotherapy is applied as initial treatment for metastatic ones 3,4 . Cancer stem cells (CSCs) exert special properties to initiate, maintain, as well as to repopulate different tumors, whereby facilitating tumor metastasis and contributing to drug resistance and tumorigenicity 5 . Targeting CSCs may serve as a promising strategy of the therapeutic intervention for PCa treatment.…”

Section: Introductionmentioning

confidence: 99%

THBS4 silencing regulates the cancer stem cell‐like properties in prostate cancer via blocking the PI3K/Akt pathway

Hou

Huo

2020

The Prostate

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Background: Although thrombospondins 4 (THBS4) participates in controlling the biology of prostate cancer (PCa), the mechanism underlying this regulation remains unknown. Hence, this study aims to identify the regulatory effects of THBS4 on the PCa stem cell-like properties and the potential mechanism associated with the phosphatidylinositol 3′-kinase (PI3K)/protein kinase B (Akt) pathway.Methods: PCa stem cells were sorted and identified using flow cytometry and THBS4 expression in the identified PCa stem cells was measured using Western blot assay.THBS4 was overexpressed or silenced in PCa stem cells, following which, self-renewal, proliferation, cell cycle distribution, and apoptosis of PCa stem cells were assessed as well as tumorigenicity in vivo was evaluated. PI3K/Akt pathway inhibitor was applied to identify its involvement in the regulatory roles of THBS4 in PCa stem cells.Results: THBS4 was expressed at a higher level in PCa stem cells than in PCa cells. The overexpression of THBS4 promoted the self-renewal and proliferation, curbed the apoptosis of PCa stem cells, and enhanced the in vivo tumorigenicity, which was achieved by activating the PI3K/Akt pathway. On the contrary, short-hairpin RNAmediated silencing of THBS4 exhibited suppressive effects on those cancer stem cell (CSC)-like properties and promotive effects on their apoptosis. Conclusion: THBS4 silencing can impede the CSC-like properties in PCa via blockade of the PI3K/Akt pathway, which provides patients with PCa a new therapeutic target. K E Y W O R D S cancer stem cells, PI3K/Akt pathway, prostate cancer, self-renewal, THBS4, tumorigenicity

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The bad seed: Cancer stem cells in tumor development and resistance

Cited by 97 publications

References 163 publications

Loss of Xanthine Oxidoreductase Potentiates Propagation of Hepatocellular Carcinoma Stem Cells

Loss of Xanthine Oxidoreductase Potentiates Propagation of Hepatocellular Carcinoma Stem Cells

A novel c-Kit/phospho-prohibitin axis enhances ovarian cancer stemness and chemoresistance via Notch3—PBX1 and β-catenin—ABCG2 signaling

THBS4 silencing regulates the cancer stem cell‐like properties in prostate cancer via blocking the PI3K/Akt pathway

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