Anlotinib exerts anti‐cancer efficiency on lung cancer stem cells in vitro and in vivo through reducing NF‐κB activity

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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The Role and Molecular Mechanism of SLC34A2 in Stemness Maintenance of CD44+CD166+ Lung Cancer Stem Cells (LCSCs) with AT-II cells’ characteristics

10.21203/rs.3.rs-368100/v1 ◽

2021 ◽

Author(s):

Yan Yang ◽

Qiang Pu ◽

Hu Liao ◽

Yue Yuan ◽

Xueting Hu ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Malignant Transformation ◽

Lung Tumor ◽

Alveolar Epithelium ◽

Migration And Invasion ◽

Lung Cancer Stem Cells

Abstract Background Evidence showed some non-small cell lung cancers (NSCLCs) had the type II alveolar epithelium cells’(AT-II cells) characteristics, and AT-II cells were a kind of original stem cells of NSCLCs. But how AT-II cells malignantly transformed into NSCLCs was unclear. Recent evidence indicated SLC34A2 was critical in the development of AT-II cells, and SLC34A2 might be a new gene in the initiation of NSCLCs. However, whether SLC34A2 participated in the malignant transformation of AT-II cells remained unknown. The exact role and mechanism of SLC34A2 in the initiation of NSCLCs needed to be further investigated. Methods The expression of Napi-IIb (encoded by SLC34A2) in the NSCLC cells was compared with that in AT-II cells using immunohistochemistry (IHC). Also coexpression of CD44 and CD166 was detected in these NSCLCs tissues by IHC. Then the CD44+CD166+ cells were sorted from lung tumor spheres by FACS. They were assessed by sphere, proliferation and tumorgenicity assay. Besides, their expression of surfactants C(SP-C) was stained by IHC. Next, the role and mechanism of SLC34A2 in CD44+CD166+ lung cancer stem cells were explored by siRNA-mediated SLC34A2 knockdown, related pathway pharmacological inhibition or activation. In vitro findings were furtherly validated in vivo and NSCLCs samples. Results The expression of SLC34A2 was downregulated in NSCLCs cells compared with AT-II cells in clinic samples. Then the CD44+CD166+ population was identified as CD44+CD166+ lung cancer stem cells (LCSCs). And LCSCs showed abundant expression of SP-C, the hallmark of AT-II cells. Higher expression of SLC34A2 was found in LCSCs compared to their origin NSCLC cells. Additionally, the expression of SLC34A2 was decreased after LCSCs were differentiated, and the morphology of the differentiated cells from LCSCs was similar to their origin NSCLC cells. Knockdown SLC34A2 made declined abilities of self-renewal, drug-resistance, migration and invasion in vitro as well as tumorigenicity in vivo in LCSCs. And SLC34A2 could maintain stemness of LCSCs via PI3K/AKT/STAT3/Sox2 axis. Besides, the connection between SLC34A2 maintaining stemness of lung cancer stem cells and PI3K/AKT/STAT3/Sox2 axis was also validated in vivo and in clinic samples. Conclusions For the first time, we illustrated the expression of SLC34A2 was downregulated in NSCLCs cells compared with AT-II cells. We discovered the downregulated expression of SLC34A2 performed a vital role in the malignant transformation of AT-II cells into NSCLCs. And SLC34A2 could maintain stemness of CD44+CD166+ lung cancer stem cells, which were with AT-II cell’s characteristic, via PI3K/AKT/STAT3/Sox2 axis. It had important significance in the revelation of a new mechanism for the initiation of NSCLCs.

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Reck-Notch1 Signaling Mediates miR-221/222 Regulation of Lung Cancer Stem Cells in NSCLC

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.663279 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yuefan Guo ◽

Guangxue Wang ◽

Zhongrui Wang ◽

Xin Ding ◽

Lu Qian ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cell Proliferation ◽

Mammosphere Formation ◽

Notch1 Signaling ◽

Cancer Initiation ◽

Direct Target Gene ◽

Lung Cancer Stem Cells

Cancer stem cells (CSCs) contribute to the cancer initiation, metastasis and drug resistance in non-small cell lung cancer (NSCLC). Herein, we identified a miR-221/222 cluster as a novel regulator of CSCs in NSCLC. Targeted overexpression or knockdown of miR-221/222 in NSCLC cells revealed the essential roles of miR-221/222 in regulation of lung cancer cell proliferation, mammosphere formation, subpopulation of CD133+ CSCs and the expression of stemness genes including OCT4, NANOG and h-TERT. The in vivo animal study showed that overexpression of miR-221/222 significantly enhanced the capacity of lung cancer cells to develop tumor and grow faster, indicating the importance of miR-221/222 in tumorigenesis and tumor growth. Mechanistically, Reck was found to be a key direct target gene of miR-221/222 in NSCLC. Overexpression of miR-221/222 significantly suppressed Reck expression, activated Notch1 signaling and increased the level of NICD. As an activated form of Notch1, NICD leads to enhanced stemness in NSCLC cells. In addition, knockdown of Reck by siRNA not only mimicked miR-221/222 effects, but also demonstrated involvement of Reck in the miR-221/222-induced activation of Notch1 signaling, verifying the essential roles of the miR-221/222-Reck-Notch1 axis in regulating stemness of NSCLC cells. These findings uncover a novel mechanism by which lung CSCs are significantly manipulated by miR-221/222, and provide a potential therapeutic target for the treatment of NSCLC.

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AS602801, an Anti-Cancer Stem Cell Drug Candidate, Suppresses Gap-junction Communication Between Lung Cancer Stem Cells and Astrocytes

Anticancer Research ◽

10.21873/anticanres.12829 ◽

2018 ◽

Vol 38 (9) ◽

pp. 5093-5099 ◽

Cited By ~ 7

Author(s):

KENTA KURAMOTO ◽

MASAHIRO YAMAMOTO ◽

SHUHEI SUZUKI ◽

TOMOMI SANOMACHI ◽

KEITA TOGASHI ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Cancer Stem Cell ◽

Gap Junction ◽

Drug Candidate ◽

Gap Junction Communication ◽

Anti Cancer ◽

Lung Cancer Stem Cells

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miR-21 modulates the effect of EZH2 on the biological behavior of human lung cancer stem cells in vitro

Oncotarget ◽

10.18632/oncotarget.20006 ◽

2017 ◽

Vol 8 (49) ◽

pp. 85442-85451 ◽

Cited By ~ 7

Author(s):

Hui Xia ◽

Wen Zhang ◽

Baoshi Zhang ◽

Yingnan Zhao ◽

Yunlong Zhao ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Human Lung ◽

Biological Behavior ◽

Human Lung Cancer ◽

Lung Cancer Stem Cells

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TRAIL Is Active Against Leukemia Stem Cells and Leukemia-Initiating Cells of Children with Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v118.21.2953.2953 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2953-2953

Author(s):

Catarina Castro Alves ◽

Leticia Quintanilla-Martinez ◽

Irmela Jeremias

Keyword(s):

Stem Cells ◽

Acute Lymphoblastic Leukemia ◽

Cancer Stem Cells ◽

Tumor Cells ◽

Lymphoblastic Leukemia ◽

Leukemia Stem Cells ◽

Nsg Mice ◽

Anti Cancer

Abstract Abstract 2953 Cancer stem cells represent the most important target cells for anti-tumor therapy as they are uniquely capable to maintain tumor growth and to induce relapse. For sustained anti-tumor activity, anti-cancer therapy has to address and eliminate cancer stem cells. Unfortunately in acute lymphoblastic leukemia (ALL), cancer stem cells / leukemia stem cells (LSCs) can not be reliably defined by cell surface markers complicating studies on cancer stem cells. To overcome this obstacle, we used the functional definition of CSCs as surrogate and studied leukemia-initiating cells (LICs) by their name-defining capability to initiate leukemia in immune-compromised mice. TRAIL (TNF-related apoptosis-inducing ligand) is a member of the TNF family which induces apoptosis in a wide variety of tumor cells while sparing normal cells. TRAIL represents an important candidate anti-cancer agent which is currently tested in phase I and II clinical trials, yet its ability to target cancer stem cells is currently unknown. Here we tested the effect of TRAIL on LSCs and LICs using tumor cells from children with precursor B-cell acute lymphoblastic leukemia (pre-B ALL). Primary ALL cells were engrafted and passaged in NSG mice. Cells were freshly isolated from NSG mice and stimulated with TRAIL in vitro for 2 days and afterwards re-engrafted into mice in dilution curves upon limiting dilution transplantation assay comparing non-treated with TRAIL-treated cells and using about 25 mice per stimulation. After 12–16 weeks, mice were evaluated for leukemic engraftment by staining for leukemia cells in organs like bone marrow, spleen, liver and blood using FACscan analysis and immune histochemistry. In all 3 pre-B ALL samples tested, in vitro treatment with TRAIL prior to transplantation of cells into mice significantly reduced their engraftment capability. TRAIL disabled leukemic engraftment by > 95 % in all 3 samples. Accordingly, in vitro TRAIL treatment significantly increased the time to engraftment and completely disabled engraftment below a defined threshold. In a second, additive approach, TRAIL was used in a preclinical mouse model. Pre-B ALL samples were engrafted in NSG mice and leukemia-bearing mice were treated with TRAIL systemically at 7.5 mg / kg daily i.p. for 10 days. In this preclinical in vivo model, TRAIL treatment completely cured a proportion of animals harbouring patient-derived pre-B ALL xenografts. Taken together, TRAIL significantly disabled the leukemia-initiating function of LICs from patient-derived pre-B ALL xenografts in vitro and that TRAIL eliminated leukemia together with its LSCs in vivo. Although the methods used do not allow the study of signalling mechanisms, TRAIL might most probably have induced apoptosis in LICs and LSCs. Our data show that it is feasible, although technically demanding, to test the apoptosis sensitivity of LICs and LSCs. We conclude from these data that TRAIL constitutes an attractive future drug for treatment of ALL. Disclosures: No relevant conflicts of interest to declare.

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STEM-26. SMALL MOLECULE DRUG CBL0137 INHIBITS THE FACT COMPLEX AND SENSITIZES GLIOBLASTOMA CANCER STEM CELLS TO RADIOTHERAPY

Neuro-Oncology ◽

10.1093/neuonc/noaa215.843 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii201-ii202

Author(s):

Miranda Tallman ◽

Abigail Zalenski ◽

Amanda Deighen ◽

Morgan Schrock ◽

Sherry Mortach ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

High Rate ◽

Orthotopic Model ◽

In Vivo Models ◽

Specific Cytotoxicity ◽

Treatment Paradigm ◽

Cancer Agent

Abstract Glioblastoma (GBM) is a malignant brain tumor with nearly universal recurrence. GBM cancer stem cells (CSCs), a subpopulation of radio- and chemo-resistant cancer cells capable of self-renewal, contribute to the high rate of recurrence. The anti-cancer agent, CBL0137, inhibits the FACT (facilitates chromatin transcription) complex leading to cancer cell specific cytotoxicity. Here, we show that CBL0137 sensitized GBM CSCs to radiotherapy using both in vitro and in vivo models. Treatment of CBL0137 combined with radiotherapy led to increased DNA damage in GBM patient specimens and failure to resolve the damage led to decreased cell viability. Using clonogenic assays, we confirmed that CBL0137 radiosensitized the CSCs. To validate that combination therapy impacted CSCs, we used an in vivo subcutaneous model and showed a decrease in the frequency of cancer stem cells present in tumors as well as decreased tumor volume. Using an orthotopic model of GBM, we confirmed that treatment with CBL0137 followed by radiotherapy led to significantly increased survival compared to either treatment alone. Radiotherapy remains a critical component of patient care for GBM, even though there exists a resistant subpopulation. Radio-sensitizing agents, including CBL0137, pose an exciting treatment paradigm to increase the efficacy of irradiation, especially by inclusively targeting CSCs.

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Targeting multiple genes containing long mononucleotide A-T repeats in lung cancer stem cells

Journal of Translational Medicine ◽

10.1186/s12967-021-02902-6 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Narumol Bhummaphan ◽

Piyapat Pin-on ◽

Preeyaporn Plaimee Phiboonchaiyanan ◽

Jirattha Siriluksana ◽

Chatchawit Aporntewan ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cell ◽

Transcriptional Control ◽

Single Gene ◽

Repeat Sequence ◽

Control Activity ◽

Multiple Genes ◽

Lung Cancer Stem Cells

Abstract Background Intratumour heterogeneous gene expression among cancer and cancer stem cells (CSCs) can cause failure of current targeted therapies because each drug aims to target the function of a single gene. Long mononucleotide A-T repeats are cis-regulatory transcriptional elements that control many genes, increasing the expression of numerous genes in various cancers, including lung cancer. Therefore, targeting A-T repeats may dysregulate many genes driving cancer development. Here, we tested a peptide nucleic acid (PNA) oligo containing a long A-repeat sequence [A(15)] to disrupt the transcriptional control of the A-T repeat in lung cancer and CSCs. Methods First, we separated CSCs from parental lung cancer cell lines. Then, we evaluated the role of A-T repeat gene regulation by counting the number of repeats in differentially regulated genes between CSCs and the parental cells of the CSCs. After testing the dosage and effect of PNA-A15 on normal and cancer cell toxicity and CSC phenotypes, we analysed genome-wide expression to identify dysregulated genes in CSCs. Results The number of A-T repeats in genes differentially regulated between CSCs and parental cells differed. PNA-A15 was toxic to lung cancer cells and CSCs but not to noncancer cells. Finally, PNA-A15 dysregulated a number of genes in lung CSCs. Conclusion PNA-A15 is a promising novel targeted therapy agent that targets the transcriptional control activity of multiple genes in lung CSCs.

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