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Cancer Stem Cells (CSC)
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Cancer Stem Cells (CSC)

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: closed (1 February 2021) | Viewed by 28776

Special Issue Editor

Prof. Dr. Ira-Ida Skvortsova

E-Mail Website
Guest Editor
Head of EXTRO-Lab, Dept. of Therapeutic Radiology and Oncology, Tyrolean Cancer Research Institute, Medical University of Innsbruck, Anichstr. 35, A-6020 Innsbruck, Austria
Interests: cancer metastasis; cancer stem cells; therapy resistance; molecular mechanisms; cancer microenvironment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer stem cells (CSCs) are considered the root of primary and acquired therapy resistances associated with disease progression and poor clinical outcomes in cancer patients. Therefore, an elucidation of the key molecular mechanisms regulating CSC activities could help with the development of novel biomarkers and therapeutic targets to predict or combat the most aggressive malignant tumors in patients. The following aspects of the subject area will be highlighted in this Special Issue:

  • signalling pathways contributing to the treatment resistance and disease progression;
  • the role of CSCs in treatment failure;
  • molecular mechanisms associated with CSC aggressiveness and increased metastatic potential;
  • CSC metabolism;
  • circadian rhythms in CSCs and metronomic chemotherapy;
  • crosstalk between CSCs and microenvironmental factors (tumor stroma, immune system);
  • biological, biochemical, and pathological methods allowing CSC identification within the malignant tumors;
  • pediatric tumors and CSCs;
  • epigenetic factors in CSC formation;
  • glioblastoma stem cells;
  • development of novel biomarkers and therapeutic targets to predict and overcome therapy resistance associated with CSC activities;
  • novel therapeutic approaches to combat locally advanced, metastatic, or relapsed malignant diseases;
  • chemical agents against CSCs;
  • translational oncology: how to make bridge between basic researchers and clinicians

Prof. Dr. Ira-Ida Skvortsova
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (7 papers)

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Editorial

Jump to: Research, Review

2 pages, 189 KiB  
Editorial
Cancer Stem Cells: What Do We Know about Them?
by Ira Skvortsova
Cells 2021, 10(6), 1528; https://doi.org/10.3390/cells10061528 - 17 Jun 2021
Cited by 6 | Viewed by 2216
Abstract
During past decades, survival rates in cancer patients have drastically improved due to the successful development of novel, promising chemical compounds and therapeutic schedules [...] Full article
(This article belongs to the Special Issue Cancer Stem Cells (CSC))

Research

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25 pages, 7043 KiB  
Article
Continuous Inflammatory Stimulation Leads via Metabolic Plasticity to a Prometastatic Phenotype in Triple-Negative Breast Cancer Cells
by Dina Morein, Linor Rubinstein-Achiasaf, Hadar Brayer, Orly Dorot, Edward Pichinuk, Hagar Ben-Yaakov, Tsipi Meshel, Metsada Pasmanik-Chor and Adit Ben-Baruch
Cells 2021, 10(6), 1356; https://doi.org/10.3390/cells10061356 - 31 May 2021
Cited by 8 | Viewed by 3706
Abstract
Chronic inflammation promotes cancer progression by affecting the tumor cells and their microenvironment. Here, we demonstrate that a continuous stimulation (~6 weeks) of triple-negative breast tumor cells (TNBC) by the proinflammatory cytokines tumor necrosis factor α (TNFα) + interleukin 1β (IL-1β) changed the [...] Read more.
Chronic inflammation promotes cancer progression by affecting the tumor cells and their microenvironment. Here, we demonstrate that a continuous stimulation (~6 weeks) of triple-negative breast tumor cells (TNBC) by the proinflammatory cytokines tumor necrosis factor α (TNFα) + interleukin 1β (IL-1β) changed the expression of hundreds of genes, skewing the cells towards a proinflammatory phenotype. While not affecting stemness, the continuous TNFα + IL-1β stimulation has increased tumor cell dispersion and has induced a hybrid metabolic phenotype in TNBC cells; this phenotype was indicated by a transcription-independent elevation in glycolytic activity and by increased mitochondrial respiratory potential (OXPHOS) of TNBC cells, accompanied by elevated transcription of mitochondria-encoded OXPHOS genes and of active mitochondria area. The continuous TNFα + IL-1β stimulation has promoted in a glycolysis-dependent manner the activation of p65 (NF-κB), and the transcription and protein expression of the prometastatic and proinflammatory mediators sICAM-1, CCL2, CXCL8 and CXCL1. Moreover, when TNBC cells were stimulated continuously by TNFα + IL-1β in the presence of a glycolysis inhibitor, their conditioned media had reduced ability to recruit monocytes and neutrophils in vivo. Such inflammation-induced metabolic plasticity, which promotes prometastatic cascades in TNBC, may have important clinical implications in treatment of TNBC patients. Full article
(This article belongs to the Special Issue Cancer Stem Cells (CSC))
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17 pages, 5718 KiB  
Article
Transcriptional CDK Inhibitors CYC065 and THZ1 Induce Apoptosis in Glioma Stem Cells Derived from Recurrent GBM
by Viktorija Juric, Heiko Düssmann, Martine L. M. Lamfers, Jochen H. M. Prehn, Markus Rehm and Brona M. Murphy
Cells 2021, 10(5), 1182; https://doi.org/10.3390/cells10051182 - 12 May 2021
Cited by 5 | Viewed by 3223
Abstract
Glioma stem cells (GSCs) are tumour initiating cells which contribute to treatment resistance, temozolomide (TMZ) chemotherapy and radiotherapy, in glioblastoma (GBM), the most aggressive adult brain tumour. A major contributor to the uncontrolled tumour cell proliferation in GBM is the hyper activation of [...] Read more.
Glioma stem cells (GSCs) are tumour initiating cells which contribute to treatment resistance, temozolomide (TMZ) chemotherapy and radiotherapy, in glioblastoma (GBM), the most aggressive adult brain tumour. A major contributor to the uncontrolled tumour cell proliferation in GBM is the hyper activation of cyclin-dependent kinases (CDKs). Due to resistance to standard of care, GBMs relapse in almost all patients. Targeting GSCs using transcriptional CDK inhibitors, CYC065 and THZ1 is a potential novel treatment to prevent relapse of the tumour. TCGA-GBM data analysis has shown that the GSC markers, CD133 and CD44 were significantly upregulated in GBM patient tumours compared to non-tumour tissue. CD133 and CD44 stem cell markers were also expressed in gliomaspheres derived from recurrent GBM tumours. Light Sheet Florescence Microscopy (LSFM) further revealed heterogeneous expression of these GSC markers in gliomaspheres. Gliomaspheres from recurrent tumours were highly sensitive to transcriptional CDK inhibitors, CYC065 and THZ1 and underwent apoptosis while being resistant to TMZ. Apoptotic cell death in GSC subpopulations and non-stem tumour cells resulted in sphere disruption. Collectively, our study highlights the potential of these novel CKIs to induce cell death in GSCs from recurrent tumours, warranting further clinical investigation. Full article
(This article belongs to the Special Issue Cancer Stem Cells (CSC))
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10 pages, 1175 KiB  
Article
The mRNA Distribution of Cancer Stem Cell Marker CD90/Thy-1 Is Comparable in Hepatocellular Carcinoma of Eastern and Western Populations
by An B. Luong, Huy Q. Do, Paola Tarchi, Deborah Bonazza, Cristina Bottin, Loraine Kay D. Cabral, Long D. C. Tran, Thao P. T. Doan, Lory S. Crocè, Hoa L. T. Pham, Claudio Tiribelli and Caecilia H. C. Sukowati
Cells 2020, 9(12), 2672; https://doi.org/10.3390/cells9122672 - 12 Dec 2020
Cited by 4 | Viewed by 2164
Abstract
Epidemiology of hepatocellular carcinoma (HCC) showed a correlation between incidence and geographical-relevant risk factors. This study aims to compare the distributions of cancer stem cells (CSC) in two distant populations in Asia and Europe. We analyzed 52 and 43 selected HCC patients undergoing [...] Read more.
Epidemiology of hepatocellular carcinoma (HCC) showed a correlation between incidence and geographical-relevant risk factors. This study aims to compare the distributions of cancer stem cells (CSC) in two distant populations in Asia and Europe. We analyzed 52 and 43 selected HCC patients undergoing hepatectomy in Ho Chi Minh City (Vietnam) and Trieste (Italy). Each patient sample consisted of HCC, peri-HCC, and non-tumoral (distal) tissue. Demographic data were recorded together with clinical findings. The protocol for the collection of tissue samples and RNA was standardized in both laboratories and gene expression analysis was performed in a single laboratory with identical PCR conditions. Baseline data showed comparable laboratory findings between the two cohorts. mRNA distribution showed a comparable pattern of all CSC markers analyzed with the expression of CD90 progressively increasing from distal and peri-HCC to be highest in HCC (p < 0.001), confirmed by immunofluorescence data. CD90 mRNA distribution was related to HBV-related HCC and a tumor diameter less than 5 cm. Patients with high tumoral CD90 mRNA had a shorter time (p < 0.05) to tumor recurrence compared to patients with lower CD90. This comparative study showed that CD90 mRNA expressions are comparable between Eastern and Western HCC cases. Full article
(This article belongs to the Special Issue Cancer Stem Cells (CSC))
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22 pages, 2933 KiB  
Article
BR-BCSC Signature: The Cancer Stem Cell Profile Enriched in Brain Metastases that Predicts a Worse Prognosis in Lymph Node-Positive Breast Cancer
by Maria Rita Dionísio, André F. Vieira, Rita Carvalho, Inês Conde, Mónica Oliveira, Madalena Gomes, Marta T. Pinto, Pedro Pereira, José Pimentel, Cristiano Souza, Márcia M. C. Marques, Vinícius Duval da Silva, Alison Barroso, Daniel Preto, Jorge F. Cameselle-Teijeiro, Fernando Schmitt, Ana Sofia Ribeiro and Joana Paredes
Cells 2020, 9(11), 2442; https://doi.org/10.3390/cells9112442 - 09 Nov 2020
Cited by 9 | Viewed by 2942
Abstract
Brain metastases remain an unmet clinical need in breast oncology, being frequently found in HER2-overexpressing and triple-negative carcinomas. These tumors were reported to be highly cancer stem-like cell-enriched, suggesting that brain metastases probably arise by the seeding of cancer cells with stem features. [...] Read more.
Brain metastases remain an unmet clinical need in breast oncology, being frequently found in HER2-overexpressing and triple-negative carcinomas. These tumors were reported to be highly cancer stem-like cell-enriched, suggesting that brain metastases probably arise by the seeding of cancer cells with stem features. Accordingly, we found that brain-tropic breast cancer cells show increased stem cell activity and tumorigenic capacity in the chick embryo choriallantoic membrane when compared to the parental cell line. These observations were supported by a significant increase in their stem cell frequency and by the enrichment for the breast cancer stem cell (BCSC) phenotype CD44+CD24−/low. Based on this data, the expression of BCSC markers (CD44, CD49f, P-cadherin, EpCAM, and ALDH1) was determined and found to be significantly enriched in breast cancer brain metastases when compared to primary tumors. Therefore, a brain (BR)-BCSC signature was defined (3–5 BCSC markers), which showed to be associated with decreased brain metastases-free and overall survival. Interestingly, this signature significantly predicted a worse prognosis in lymph node-positive patients, acting as an independent prognostic factor. Thus, an enrichment of a BCSC signature was found in brain metastases, which can be used as a new prognostic factor in clinically challenging breast cancer patients. Full article
(This article belongs to the Special Issue Cancer Stem Cells (CSC))
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19 pages, 3965 KiB  
Article
A Novel Function for KLF4 in Modulating the De-Differentiation of EpCAM−/CD133− nonStem Cells into EpCAM+/CD133+ Liver Cancer Stem Cells in HCC Cell Line HuH7
by Zeynep Firtina Karagonlar, Soheil Akbari, Mustafa Karabicici, Eren Sahin, Sanem Tercan Avci, Nevin Ersoy, Kıvılcım Eren Ates, Tugsan Balli, Bilge Karacicek, Kubra Nur Kaplan, Canan Celiker, Nese Atabey and Esra Erdal
Cells 2020, 9(5), 1198; https://doi.org/10.3390/cells9051198 - 12 May 2020
Cited by 39 | Viewed by 4911
Abstract
The complex and heterogeneous nature of hepatocellular carcinoma (HCC) hampers the identification of effective therapeutic strategies. Cancer stem cells (CSCs) represent a fraction of cells within tumors with the ability to self-renew and differentiate, and thus significantly contribute to the formation and maintenance [...] Read more.
The complex and heterogeneous nature of hepatocellular carcinoma (HCC) hampers the identification of effective therapeutic strategies. Cancer stem cells (CSCs) represent a fraction of cells within tumors with the ability to self-renew and differentiate, and thus significantly contribute to the formation and maintenance of heterogeneous tumor mass. Increasing evidence indicates high plasticity in tumor cells, suggesting that non-CSCs could acquire stem cell properties through de-differentiation or reprogramming processes. In this paper, we reveal KLF4 as a transcription factor that can induce a CSC-like phenotype in non-CSCs through upregulating the EpCAM and E-CAD expression. Our studies indicated that KLF4 could directly bind to the promoter of EpCAM and increase the number of EpCAM+/CD133+ liver cancer stem cells (LCSCs) in the HuH7 HCC cell line. When KLF4 was overexpressed in EpCAM−/CD133− non-stem cells, the expressions of hepatic stem/progenitor cell genes such as CK19, EpCAM and LGR5 were significantly increased. KLF4 overexpressing non-stem cells exhibited greater cell viability upon sorafenib treatment, while the cell migration and invasion capabilities of these cells were suppressed. Importantly, we detected an increased membranous expression and colocalization of β-CAT, E-CAD and EpCAM in the KLF4-overexpressing EpCAM−/CD133− non-stem cells, suggesting that this complex might be required for the cancer stem cell phenotype. Moreover, our in vivo xenograft studies demonstrated that with a KLF4 overexpression, EpCAM−/CD133− non-stem cells attained an in vivo tumor forming ability comparable to EpCAM+/CD133+ LCSCs, and the tumor specimens from KLF4-overexpressing xenografts had increased levels of both the KLF4 and EpCAM proteins. Additionally, we identified a correlation between the KLF4 and EpCAM protein expressions in human HCC tissues independent of the tumor stage and differentiation status. Collectively, our data suggest a novel function for KLF4 in modulating the de-differentiation of tumor cells and the induction of EpCAM+/CD133+ LCSCs in HuH7 HCC cells. Full article
(This article belongs to the Special Issue Cancer Stem Cells (CSC))
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Review

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20 pages, 2412 KiB  
Review
Cancer Stem Cells: Significance in Origin, Pathogenesis and Treatment of Glioblastoma
by Karina Biserova, Arvids Jakovlevs, Romans Uljanovs and Ilze Strumfa
Cells 2021, 10(3), 621; https://doi.org/10.3390/cells10030621 - 11 Mar 2021
Cited by 74 | Viewed by 8219
Abstract
Cancer stem cells (CSCs), known also as tumor-initiating cells, are quiescent, pluripotent, self-renewing neoplastic cells that were first identified in hematologic tumors and soon after in solid malignancies. CSCs have attracted remarkable research interest due to their role in tumor resistance to chemotherapy [...] Read more.
Cancer stem cells (CSCs), known also as tumor-initiating cells, are quiescent, pluripotent, self-renewing neoplastic cells that were first identified in hematologic tumors and soon after in solid malignancies. CSCs have attracted remarkable research interest due to their role in tumor resistance to chemotherapy and radiation treatment as well as recurrence. Extensive research has been devoted to the role of CSCs in glioblastoma multiforme (GBM), the most common primary brain tumor in adults, which is characterized by a dismal prognosis because of its aggressive course and poor response to treatment. The aim of the current paper is to provide an overview of current knowledge on the role of cancer stem cells in the pathogenesis and treatment resistance of glioblastoma. The six regulatory mechanisms of glioma stem cells (GSCs)—tumor microenvironment, niche concept, metabolism, immunity, genetics, and epigenetics—are reviewed. The molecular markers used to identify GSCs are described. The role of GSCs in the treatment resistance of glioblastoma is reviewed, along with future treatment options targeting GSCs. Stem cells of glioblastoma thus represent both a driving mechanism of major treatment difficulties and a possible target for more effective future approaches. Full article
(This article belongs to the Special Issue Cancer Stem Cells (CSC))
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