scholarly journals High Frequency of Tumor Propagating Cells in Fusion-Positive Rhabdomyosarcoma

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1373
Author(s):  
Melanie Generali ◽  
Sampoorna Satheesha ◽  
Peter K. Bode ◽  
Debora Wanner ◽  
Beat W. Schäfer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
High Frequency ◽  
Cell Clone ◽  
Hierarchical Organization ◽  
Stem Cell Markers ◽  
Worse Prognosis

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Fusion-positive RMS (FPRMS), expressing the PAX3/7-FOXO1, has a worse prognosis compared to the more common fusion-negative RMS (FNRMS). Although several studies reported hierarchical organization for FNRMS with the identification of cancer stem cells, the cellular organization of FPRMS is not yet clear. In this study we investigated the expression of key stem cell markers, developed a sphere assay, and investigated the seven most common FPRMS cell lines for subpopulations of tumor propagating cancer stem-like cells, also called cancer stem cells (CSCs). Moreover, loss- and gain-of-functions of the stem cell genes SOX2, OCT4, and NANOG were investigated in the same cells. Single-cell clonal analysis was performed in vitro as well as in vivo. We found that no stable CSC subpopulation could be enriched in FPRMS. Unlike depletion of PAX3-FOXO1, neither overexpression nor siRNA-mediated downregulation of SOX2, OCT4, and NANOG affected physiology of RMS cells. Every single subclone-derived cell clone initiated tumor growth in mice, despite displaying considerable heterogeneity in gene expression. FPRMS appears to contain a high frequency of tumor propagating stem-like cells, which could explain their higher propensity for metastasis and relapse. Their dependency on PAX3-FOXO1 activity reinforces the importance of the fusion protein as the key therapeutic target.

scholarly journals Molecular markers of cancer stem cells verified in vivo

2016 ◽  
Vol 62 (3) ◽  
pp. 228-238 ◽  
Author(s):  
Y.S. Kim ◽  
A.M. Kaidina ◽  
J.H. Chiang ◽  
K.N. Yarygin ◽  
A.Yu. Lupatov
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Molecular Markers ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
Stem Cell Markers ◽  
Cancer Stem Cell Markers ◽  
Immunodeficient Mice ◽  
Molecular Features

This systematic review aims to analyze molecular markers of cancer stem cells. Only studies that confirmed tumor-initiating capacity of this population by in vivo assay in immunodeficient mice were included. Final sample of papers that fully correspond with initial aim consists of 97 original studies. The results of their analysis reveal that markers commonly used for cancer stem cells deriving were as follows: CD133, СD44, ALDH, CD34, CD24 and EpCAM. The review also contains description of molecular features of some cancer stem cell markers, modern approaches to cancer treatment by targeting this population and brief assessment of cancer stem cell theory development.

scholarly journals Mesenchymal stem cells promote glioma neovascularization in vivo by fusing with cancer stem cells

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Chao Sun ◽  
Xingliang Dai ◽  
Dongliang Zhao ◽  
Haiyang Wang ◽  
Xiaoci Rong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Tumor Growth ◽  
Glioma Cells ◽  
Stem Cell Markers ◽  
Xenograft Tumor ◽  
Angiogenic Effect

Abstract Background and objective Tumor angiogenesis is vital for tumor growth. Recent evidence indicated that bone marrow-derived mesenchymal stem cells (BMSCs) can migrate to tumor sites and exert critical effects on tumor growth through direct and/or indirect interactions with tumor cells. However, the effect of BMSCs on tumor neovascularization has not been fully elucidated. This study aimed to investigate whether fusion cells from glioma stem cells and BMSCs participated in angiogenesis. Methods SU3-RFP cells were injected into the right caudate nucleus of NC-C57Bl/6 J-GFP nude mice, and the RFP+/GFP+ cells were isolated and named fusion cells. The angiogenic effects of SU3-RFP, BMSCs and fusion cells were compared in vivo and in vitro. Results Fusion cells showed elevated levels of CD31, CD34 and VE-Cadherin (markers of VEC) as compared to SU3-RFP and BMSCs. The MVD-CD31 in RFP+/GFP+ cell xenograft tumor was significantly greater as compared to that in SU3-RFP xenograft tumor. In addition, the expression of CD133 and stem cell markers Nanog, Oct4 and Sox2 were increased in fusion cells as compared to the parental cells. Fusion cells exhibited enhanced angiogenic effect as compared to parental glioma cells in vivo and in vitro, which may be related to their stem cell properties. Conclusion Fusion cells exhibited enhanced angiogenic effect as compared to parental glioma cells in vivo and in vitro, which may be related to their stem cell properties. Hence, cell fusion may contribute to glioma angiogenesis.

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

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.

scholarly journals Moonlighting Role of PEDF in Breast Cancer

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.

scholarly journals Notch pathway inhibition targets chemoresistant insulinoma cancer stem cells

2018 ◽  
Vol 25 (2) ◽  
pp. 131-144 ◽  
Author(s):  
Y Capodanno ◽  
F O Buishand ◽  
L Y Pang ◽  
J Kirpensteijn ◽  
J A Mol ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Targeted Therapies ◽  
Notch Pathway ◽  
Notch Signalling ◽  
Treatment Modalities ◽  
Stem Cell Markers ◽  
Gamma Secretase

Insulinomas (INS) are the most common neuroendocrine pancreatic tumours in humans and dogs. The long-term prognosis for malignant INS is still poor due to a low success rate of the current treatment modalities, particularly chemotherapy. A better understanding of the molecular processes underlying the development and progression of INS is required to develop novel targeted therapies. Cancer stem cells (CSCs) are thought to be critical for the engraftment and chemoresistance of many tumours, including INS. This study was aimed to characterise and target INS CSCs in order to develop novel targeted therapies. Highly invasive and tumourigenic human and canine INS CSC-like cells were successfully isolated. These cells expressed stem cell markers (OCT4,SOX9, SOX2, CD133 and CD34), exhibited greater resistance to 5-fluorouracil (5-FU) and demonstrated a more invasive and tumourigenic phenotypein vivocompared to bulk INS cells. Here, we demonstrated that Notch-signalling-related genes (NOTCH2andHES1)were overexpressed in INS CSC-like cells. Protein analysis showed an active NOTCH2-HES1 signalling in INS cell lines, especially in cells resistant to 5-FU. Inhibition of the Notch pathway, using a gamma secretase inhibitor (GSI), enhanced the sensitivity of INS CSC-like cells to 5-FU. When used in combination GSI and 5-FU, the clonogenicityin vitroand the tumourigenicityin vivoof INS CSC-like cells were significantly reduced. These findings suggested that the combined strategy of Notch signalling inhibition and 5-FU synergistically attenuated enriched INS CSC populations, providing a rationale for future therapeutic exploitation.

scholarly journals Stem cells in genetically-engineered mouse models of prostate cancer

2015 ◽  
Vol 22 (6) ◽  
pp. T199-T208 ◽  
Author(s):  
Maho Shibata ◽  
Michael M Shen
Keyword(s):  
Prostate Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
Cell Model ◽  
Genetically Engineered ◽  
Hierarchical Organization ◽  
Tumorigenic Cells

The cancer stem cell model proposes that tumors have a hierarchical organization in which tumorigenic cells give rise to non-tumorigenic cells, with only a subset of stem-like cells able to propagate the tumor. In the case of prostate cancer, recent analyses of genetically engineered mouse (GEM) models have provided evidence supporting the existence of cancer stem cells in vivo. These studies suggest that cancer stem cells capable of tumor propagation exist at various stages of tumor progression from prostatic intraepithelial neoplasia (PIN) to advanced metastatic and castration-resistant disease. However, studies of stem cells in prostate cancer have been limited by available approaches for evaluating their functional properties in cell culture and transplantation assays. Given the role of the tumor microenvironment and the putative cancer stem cell niche, future studies using GEM models to analyze cancer stem cells in their native tissue microenvironment are likely to be highly informative.

scholarly journals β-Tubulin Isotype, TUBB4B, Regulates The Maintenance of Cancer Stem Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Dhrishya Dharmapal ◽  
Athira Jyothy ◽  
Amrutha Mohan ◽  
P. G. Balagopal ◽  
Nebu Abraham George ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Oral Cancer ◽  
Cancer Stem Cells ◽  
Membrane Trafficking ◽  
Adult Stem Cell ◽  
Membrane Expression ◽  
Tcga Dataset

Recent advancements in cancer research have shown that cancer stem cell (CSC) niche is a crucial factor modulating tumor progression and treatment outcomes. It sustains CSCs by orchestrated regulation of several cytokines, growth factors, and signaling pathways. Although the features defining adult stem cell niches are well-explored, the CSC niche is poorly characterized. Since membrane trafficking proteins have been shown to be essential for the localization of critical proteins supporting CSCs, we investigated the role of TUBB4B, a probable membrane trafficking protein that was found to be overexpressed in the membranes of stem cell enriched cultures, in sustaining CSCs in oral cancer. Here, we show that the knockdown of TUBB4B downregulates the expression of pluripotency markers, depletes ALDH1A1+ population, decreases in vitro sphere formation, and diminishes the tumor initiation potential in vivo. As TUBB4B is not known to have any role in transcriptional regulation nor cell signaling, we suspected that its membrane trafficking function plays a role in constituting a CSC niche. The pattern of its expression in tissue sections, forming a gradient in and around the CSCs, reinforced the notion. Later, we explored its possible cooperation with a signaling protein, Ephrin-B1, the abrogation of which reduces the self-renewal of oral cancer stem cells. Expression and survival analyses based on the TCGA dataset of head and neck squamous cell carcinoma (HNSCC) samples indicated that the functional cooperation of TUBB4 and EFNB1 results in a poor prognosis. We also show that TUBB4B and Ephrin-B1 cohabit in the CSC niche. Moreover, depletion of TUBB4B downregulates the membrane expression of Ephrin-B1 and reduces the CSC population. Our results imply that the dynamics of TUBB4B is decisive for the surface localization of proteins, like Ephrin-B1, that sustain CSCs by their concerted signaling.

scholarly journals LncRNA ASAP1-IT1 Enhances Cancer Cell Stemness via Regulating miR-509-3p/YAP1 Axis in NSCLC

2021 ◽  
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 Cells ◽  
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 mainly responsible for the poor clinical outcome of NSCLC. Although previous reports indicated long noncoding RNAs (lncRNAs) play important roles in cancer stemness maintain, the underlying causes mechanisms remain is still mysterious. Our study aims to investigate the role of ASAP1 Intronic Transcript 1 (ASAP1-IT1) in cancer cell stemness of NSCLC. Methods: qRT-PCR analysis the expression of ASAP1-IT1 and microRNA-509-3p (miR-509-3p) in NSCLC tissues, cancer cells and spheres of cancer cells-derived cancer stem cells. Knockdown of ASAP1-IT1 or overexpression of miR-509-3p in NSCLC cells by infection or transfection. Sphere formation and colony formation detects NSCLC stem cell-like properties and tumor growth in vitro. Luciferase reporter assays, RNA immunoprecitation (RIP) and qRT-PCR assays analyzed the interaction between lncRNA and miRNA, qRT-PCR and Western blot detect ASAP1-IT1/miR-509-3p axis's regulation on the expression of regulated genes. NSCLC xenograft mice model validates ASAP1-IT1 role 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. Downregulated ASAP1-IT1 or 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 miR-509-3p mediated regulation of stem cell-like properties, cell growth, and cell apoptosis 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 related signaling is a promising therapeutic strategy to overcome NSCLC stemness.

scholarly journals LncRNA ASAP1-IT1 Enhances Cancer Cell Stemness via Regulating miR-509-3p/YAP1 Axis in NSCLC

2021 ◽  
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 Cells ◽  
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 mainly responsible for the poor clinical outcome of NSCLC. Although previous reports indicated long noncoding RNAs (lncRNAs) play important roles in cancer stemness maintain, the underlying causes mechanisms remain is still mysterious. Our study aims to investigate the role of ASAP1 Intronic Transcript 1 (ASAP1-IT1) in cancer cell stemness of NSCLC. Methods: qRT-PCR analysis the expression of ASAP1-IT1 and microRNA-509-3p (miR-509-3p) in NSCLC tissues, cancer cells and spheres of cancer cells-derived cancer stem cells. Knockdown of ASAP1-IT1 or overexpression of miR-509-3p in NSCLC cells by infection or transfection. Sphere formation and colony formation detects NSCLC stem cell-like properties and tumor growth in vitro. Luciferase reporter assays, RNA immunoprecitation (RIP) and qRT-PCR assays analyzed the interaction between lncRNA and miRNA, qRT-PCR and Western blot detect ASAP1-IT1/miR-509-3p axis's regulation on the expression of regulated genes. NSCLC xenograft mice model validates ASAP1-IT1 role 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. Downregulated ASAP1-IT1 or 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 miR-509-3p mediated regulation of stem cell-like properties, cell growth, and cell apoptosis 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 related signaling is a promising therapeutic strategy to overcome NSCLC stemness.

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