A Novel Combination Cancer Therapy with Iron Chelator Targeting Cancer Stem Cells via Suppressing Stemness

Excess iron causes cancer and is thought to be related to carcinogenesis and cancer progression including stemness, but the details remain unclear. Here, we hypothesized that stemness in cancer is related to iron metabolism and that regulating iron metabolism in cancer stem cells (CSCs) may be a novel therapy. In this study, we used murine induced pluripotent stem cells that expressed specific stem cell genes such as Nanog, Oct3/4, Sox2, Klf4, and c-Myc, and two human cancer cell lines with similar stem cell gene expression. Deferasirox, an orally available iron chelator, suppressed expression of stemness markers and spherogenesis of cells with high stemness status in vitro. Combination therapy had a marked antitumor effect compared with deferasirox or cisplatin alone. Iron metabolism appears important for maintenance of stemness in CSCs. An iron chelator combined with chemotherapy may be a novel approach via suppressing stemness for CSC targeted therapy.

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Gastric Cancer Stem Cells

Journal of Clinical Oncology ◽

10.1200/jco.2007.15.2603 ◽

2008 ◽

Vol 26 (17) ◽

pp. 2876-2882 ◽

Cited By ~ 123

Author(s):

Shigeo Takaishi ◽

Tomoyuki Okumura ◽

Timothy C. Wang

Keyword(s):

Gastric Cancer ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Cancer Stem Cell ◽

Cell Biology ◽

Cancer Biology ◽

Human Cancer ◽

Immunodeficient Mice

Cancer stem cells are defined as the unique subpopulation in the tumors that possess the ability to initiate tumor growth and sustain self-renewal as well as metastatic potential. Accumulating evidence in recent years strongly indicate the existence of cancer stem cells in solid tumors of a wide variety of organs. In this review, we will discuss the possible existence of a gastric cancer stem cell. Our recent data suggest that a subpopulation with a defined marker shows spheroid colony formation in serum-free media in vitro, as well as tumorigenic ability in immunodeficient mice in vivo. We will also discuss the possible origins of the gastric cancer stem cell from an organ-specific stem cell versus a recently recognized new candidate bone marrow–derived cell (BMDC). We have previously shown that BMDC contributed to malignant epithelial cells in the mouse model of Helicobacter-associated gastric cancer. On the basis of these findings from animal model, we propose that a similar phenomenon may also occur in human cancer biology, particularly in the cancer origin of other inflammation-associated cancers. The expanding research field of cancer stem-cell biology may offer a novel clinical apparatus to the diagnosis and treatment of cancer.

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Translational models of 3-D organoids and cancer stem cells in gastric cancer research

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02521-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Kenly Wuputra ◽

Chia-Chen Ku ◽

Kohsuke Kato ◽

Deng-Chyang Wu ◽

Shigeo Saito ◽

...

Keyword(s):

Gastric Cancer ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Genetic Manipulation ◽

Current Knowledge ◽

Cancer Microenvironment

AbstractIt is postulated as a general concept of cancer stem cells (CSCs) that they can produce cancer cells overtly and repopulate cancer progenitor cells indefinitely. The CSC niche is part of a specialized cancer microenvironment that is important to keep the phenotypes of CSCs. Stem cell- and induced pluripotent stem cell (iPSC)-derived organoids with genetic manipulation are beneficial to the investigation of the regulation of the microenvironment of CSCs. It would be useful to assess the efficiency of the cancer microenvironment on initiation and progression of cancers. To identify CSCs in cancer tissues, normal cell organoids and gastric cancer organoids from the cancerous areas, as well as iPSCs, were established several years ago. However, many questions remain about the extent to which these cultures recapitulate the development of the gastrointestinal tract and the mechanism of Helicobacter pylori-induced cancer progression. To clarify the fidelity of human organoid models, we have noted several key issues for the cultivation of, and differences between, normal and cancerous organoids. We developed precise culture conditions for gastric organoids in vitro to improve the accuracy of the generation of organoid models for therapeutic and medical applications. In addition, the current knowledge on gastrointestinal CSC research, including the topic of CSC markers, cancer cell reprogramming, and application to target cancer cell plasticity through niches, should be reinforced. We discuss the progression of cancers derived from human gastric organoids and the identification of CSCs.

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Metformin’s Modulatory Effects on miRNAs Function in Cancer Stem Cells—A Systematic Review

Cells ◽

10.3390/cells9061401 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1401

Author(s):

Bartosz Malinowski ◽

Nikola Musiała ◽

Michał Wiciński

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Solid Tumors ◽

Cancer Progression ◽

Mechanism Of Action ◽

Eligibility Criteria ◽

Major Function ◽

Mirnas Expression ◽

Meta Analyses

Cancer stem cells (CSCs) have been reported in various hematopoietic and solid tumors, therefore, are considered to promote cancer progression, metastasis, recurrence and drug resistance. However, regulation of CSCs at the molecular level is not fully understood. microRNAs (miRNAs) have been identified as key regulators of CSCs by modulating their major functions: self-renewal capacity, invasion, migration and proliferation. Various studies suggest that metformin, an anti-diabetic drug, has an anti-tumor activity but its precise mechanism of action has not been understood. The present article was written in accordance to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We systematically reviewed evidence for metformin’s ability to eradicate CSCs through modulating the expression of miRNAs in various solid tumors. PubMed and MEDLINE were searched from January 1990 to January 2020 for in vitro studies. Two authors independently selected and reviewed articles according to predefined eligibility criteria and assessed risk of bias of included studies. Four papers met the inclusion criteria and presented low risk bias. All of the included studies reported a suppression of CSCs’ major function after metformin dosage. Moreover, it was showed that metformin anti-tumor mechanism of action is based on regulation of miRNAs expression. Metformin inhibited cell survival, clonogenicity, wound-healing capacity, sphere formation and promotes chemosensitivity of tumor cells. Due to the small number of publications, aforementioned evidences are limited but may be consider as background for clinical studies.

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LncRNA ASAP1-IT1 enhances cancer cell stemness via regulating miR-509-3p/YAP1 axis in NSCLC

Cancer Cell International ◽

10.1186/s12935-021-02270-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yantao Liu ◽

Yuping Yang ◽

Lingli Zhang ◽

Jiaqiang Lin ◽

Bin Li ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Growth ◽

Cancer Stem Cells ◽

Tumor Growth ◽

Cancer Cell ◽

Qrt Pcr

Abstract Background Non-small cell lung cancer (NSCLC) is a major cause of cancer-related death worldwide, and cancer stem cell is responsible for the poor clinical outcome of NSCLC. Previous reports indicated that long noncoding RNAs (lncRNAs) play important roles in maintaining cancer stemness, however, the underlying mechanisms remain unclear. This study investigates the role of ASAP1 Intronic Transcript 1 (ASAP1-IT1) in cancer cell stemness of NSCLC. Methods The expression of ASAP1-IT1, microRNA-509-3p (miR-509-3p) and apoptosis-/stemness-related genes was analyzed by qRT-PCR in NSCLC tissues, cancer cells and spheres of cancer stem cells. Knockdown of ASAP1-IT1 or overexpression of miR-509-3p in NSCLC cells by infection or transfection of respective plasmids. Sphere formation and colony formation were used to detect NSCLC stem cell-like properties and tumor growth in vitro. Luciferase reporter assays, RNA immunoprecitation (RIP) and qRT-PCR assays were used to analyze the interaction between lncRNA and miRNA. The expression of expression of regulated genes of ASAP1-IT1/miR-509-3p axis was evaluated by qRT-PCR and Western blot. The NSCLC xenograft mouse model was used to validate the role of ASAP1-IT1 in NSCLC stemness and tumor growth in vivo. Results ASAP1-IT1 was up-regulated in NSCLC tissues, cancer cells, and in spheres of A549-derived cancer stem cells. Downregulation of ASAP1-IT1 or overexpression of miR-509-3p significantly decreased cell colony formation and stem cell-like properties of A549-dereived stem cells with decreased expression of stem cell biomarkers SOX2, CD34, and CD133, and suppressing the expression of cell growth-related genes, Cyclin A1, Cyclin B1, and PCNA. Furthermore, knockdown of ASAP1-IT1 or overexpression of miR-509-3p repressed tumor growth in nude mice via reducing expression of tumorigenic genes. ASAP1-IT1 was found to interact with miR-509-3p. Moreover, overexpression of ASAP1-IT1 blocked the inhibition by miR-509-3p on stem cell-like properties and cell growth of A549-dereived stem cells both in vitro and in vivo. Finally, the level of YAP1 was regulated by ASAP1-IT1 and miR-509-3p. Conclusions YAP1-involved ASAP1-IT1/miR-509-3p axis promoted NSCLC progression by regulating cancer cell stemness, and targeting this signaling pathway could be is a promising therapeutic strategy to overcome NSCLC stemness.

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Moonlighting Role of PEDF in Breast Cancer

10.21203/rs.3.rs-93992/v1 ◽

2020 ◽

Author(s):

Carmen Gil-Gas ◽

Marta Sánchez-Díez ◽

Paloma Honrubia-Gómez ◽

Jose Luis Sánchez-Sánchez ◽

Carmen Belen Alvarez-Simón ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Cancer Patient ◽

In Vitro Culture ◽

Screening Tests ◽

Stem Cell Markers ◽

Self Renewal

Abstract Background: Breast cancer is the leading cause of death among females in developed countries. Although the implementation of screening tests and the development of new therapies has increased the probability of remission, relapse rates still remain high. Numerous studies have indicated the connection between cancer initiating cells and slow cellular cycle cells, identified by their capacity to retain long labelling (LT+). Methods: We have designed a transgenic protein consisting in the C-terminal part of this protein, which acts by blocking endogenous PEDF in culture cell assays. Present work is based in doses-response in vitro assays as well as flow cytometry analysis of surface markers and cell cycle kinetic study of the tumour initiating cells.Results: In this study we show that this type of cells is present not only in cancer cell lines but also in cancer cells from patients with metastatic and advanced stage tumours. We also present new assays showing how stem cell self-renewal modulating proteins, such as PEDF, can modify the properties, expression of markers, and carcinogenicity of cancer stem cells. This protein has been involved in self-renewal in adult stem cells and has been described as anti-tumoral because of its anti-angiogenic effect. However, we show that PEDF enhances resistance in breast cancer patient cells in vitro culture by favoring a slow cellular cycle population (LT+). The PEDF signalling pathway could be a useful tool for controlling cancer stem cells self-renewal, and therefore control patient relapse. Conclusions: We demonstrate that it is possible to interfere with the self-renewal capacity of cancer stem cells, induce anoikis in vivo, and reduce resistance against Docetaxel treatment in cancer patient cells in vitro culture. We have also demonstrated that this PEDF modified protein produces a significant decrease in cancer stem cell markers. All these properties make this protein a potential application in clinical cancer therapies via co-administration with chemotherapy for relapse cancer treatment.

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Chemical Genetic Screen in Drosophila Germline Uncovers Small Molecule Drugs That Sensitize Stem Cells to Insult-Induced Apoptosis

Cells ◽

10.3390/cells10102771 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2771

Author(s):

Julien Roy Ishibashi ◽

Riya Keshri ◽

Tommy Henry Taslim ◽

Daniel Kennedy Brewer ◽

Tung Ching Chan ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Small Molecule ◽

Adult Stem Cells ◽

Genetic Interactions ◽

Germline Stem Cells ◽

Drug Candidates ◽

Chemical Genetic

Cancer stem cells, in contrast to their more differentiated daughter cells, can endure genotoxic insults, escape apoptosis, and cause tumor recurrence. Understanding how normal adult stem cells survive and go to quiescence may help identify druggable pathways that cancer stem cells have co-opted. In this study, we utilize a genetically tractable model for stem cell survival in the Drosophila gonad to screen drug candidates and probe chemical-genetic interactions. Our study employs three levels of small molecule screening: (1) a medium-throughput primary screen in male germline stem cells (GSCs), (2) a secondary screen with irradiation and protein-constrained food in female GSCs, and (3) a tertiary screen in breast cancer organoids in vitro. Herein, we uncover a series of small molecule drug candidates that may sensitize cancer stem cells to apoptosis. Further, we have assessed these small molecules for chemical-genetic interactions in the germline and identified the NF-κB pathway as an essential and druggable pathway in GSC quiescence and viability. Our study demonstrates the power of the Drosophila stem cell niche as a model system for targeted drug discovery.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1722100115 ◽

2018 ◽

Vol 115 (43) ◽

pp. E10127-E10136 ◽

Cited By ~ 37

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.

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Targeting Lung Cancer Stem Cells with Antipsychological Drug Thioridazine

BioMed Research International ◽

10.1155/2016/6709828 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 14

Author(s):

Haiying Yue ◽

Dongning Huang ◽

Li Qin ◽

Zhiyong Zheng ◽

Li Hua ◽

...

Keyword(s):

Lung Cancer ◽

Cell Cycle ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Progression ◽

Cell Cycle Distribution ◽

Lung Cancer Stem Cells ◽

Sphere Formation

Lung cancer stem cells are a subpopulation of cells critical for lung cancer progression, metastasis, and drug resistance. Thioridazine, a classical neurological drug, has been reported with anticancer ability. However, whether thioridazine could inhibit lung cancer stem cells has never been studied. In our current work, we used different dosage of thioridazine to test its effect on lung cancer stem cells sphere formation. The response of lung cancer stem cells to chemotherapy drug with thioridazine treatment was measured. The cell cycle distribution of lung cancer stem cells after thioridazine treatment was detected. The in vivo inhibitory effect of thioridazine was also measured. We found that thioridazine could dramatically inhibit sphere formation of lung cancer stem cells. It sensitized the LCSCs to chemotherapeutic drugs 5-FU and cisplatin. Thioridazine altered the cell cycle distribution of LCSCs and decreased the proportion of G0 phase cells in lung cancer stem cells. Thioridazine inhibited lung cancer stem cells initiated tumors growth in vivo. This study showed that thioridazine could inhibit lung cancer stem cells in vitro and in vivo. It provides a potential drug for lung cancer therapy through targeting lung cancer stem cells.

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Pro-apoptotic and pro-differentiation induction by 8-quinolinecarboxaldehyde selenosemicarbazone and its Co(iii) complex in human cancer cell lines

MedChemComm ◽

10.1039/c6md00199h ◽

2016 ◽

Vol 7 (8) ◽

pp. 1604-1616 ◽

Cited By ~ 6

Author(s):

Nenad R. Filipović ◽

Snežana Bjelogrlić ◽

Gustavo Portalone ◽

Sveva Pelliccia ◽

Romano Silvestri ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cytotoxic Activity ◽

Cell Lines ◽

Cancer Cell ◽

Plasmid Dna ◽

Human Cancer ◽

Human Cancer Cell ◽

Human Cancer Cell Lines ◽

Differentiation Induction

The ligand initiated reprogramming of cancer stem cells phenotype in AsPC-1 cells. The complex digested plasmid DNA which might be the cause of its cytotoxic activity.

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