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Life
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Origins, Properties, and Therapeutic Perspectives of Cancer Stem Cells
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Origins, Properties, and Therapeutic Perspectives of Cancer Stem Cells

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Medical Research".

Deadline for manuscript submissions: closed (30 December 2022) | Viewed by 22825

Special Issue Editors

Dr. Aglaia Pappa

E-Mail Website
Guest Editor
Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece
Interests: natural products; probiotics; microbiome; rhizobiome; cellular stress responses
Special Issues, Collections and Topics in MDPI journals
Dr. Georgia-Persephoni Voulgaridou

E-Mail Website
Guest Editor
Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece
Interests: DNA damage; oxidative stress; antioxidants; natural bioactive compounds; aging; cancer research; cancer stem cells; ALDHs; aldehyde dehydrogenases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is a multifactorial disease accounting for nearly 10 million deaths worldwide. One of the greatest challenges for cancer therapeutics is the high heterogeneity of cancer cells in hematological malignancies and solid tumors. Specifically, a small subpopulation of cells, named cancer stem cells (CSCs) or tumor-initiating cells (TICs), is identified in almost all cancer types. These cells exhibit a set of stem-like properties, e.g., altered cell cycle regulation, multipotency, self-renewal ability, tumorigenicity, enhanced metastatic potential, up-regulation of stem-related genes and radio/chemoresistance. However, it is yet to be clarified whether these cells originate from malignantly transformed stem cells or whether their stem-like properties arise by accumulating genetic alterations of non-stem cancer cells. Interestingly, novel findings imply a notion of plasticity, suggesting that cancer cells can reversibly “adopt” a CSC phenotype depending on their localization and tumor microenvironment.

Due to their unique characteristics, CSCs can survive through chemotherapy and/or radiation therapy, thus leading to relapse and cancer recurrence. Considering the clinical perspectives of CSCs, it is of pivotal importance to investigate their origins as well as their function during cancer transformation and progression processes. Finally, it is crucial to characterize accurate CSC biomarkers as well as to identify novel strategies for targeting these cells, thus enhancing the therapeutic outcome of conventional cancer treatments.

In this Special Issue, novel findings will be presented regarding all aspects of CSC research, including their origins, properties, biomarkers, and clinical relevance, as well as novel therapeutic approaches targeting CSCs.

Prof. Dr. Aglaia Pappa
Dr. Georgia-Persephoni Voulgaridou
Guest Editors

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 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.

Keywords

  • cancer stem cells
  • tumor-initiating cells
  • CSCs
  • TICs
  • cancer progression
  • cancer initiation
  • CSC plasticity
  • CSC-targeting therapies
  • self-renewal
  • tumor microenvironment
  • plasticity
  • cancer epigenetics
  • epithelial–mesenchymal transition
  • CSC biomarkers

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Published Papers (6 papers)

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Research

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13 pages, 2320 KiB  
Article
Cancer-Associated Fibroblasts Regulate the Plasticity of Breast Cancer Stemness through the Production of Leukemia Inhibitory Factor
by Nazanin Vaziri, Laleh Shariati, Ali Zarrabi, Ali Farazmand and Shaghayegh Haghjooy Javanmard
Life 2021, 11(12), 1298; https://doi.org/10.3390/life11121298 - 26 Nov 2021
Cited by 13 | Viewed by 3339
Abstract
Leukemia inhibitory factor (LIF), as a member of the interleukin-6 cytokine family, plays a complex role in solid tumors. However, the effect of LIF as a tumor microenvironment factor on plasticity control in breast cancer remains largely unknown. In this study, an in [...] Read more.
Leukemia inhibitory factor (LIF), as a member of the interleukin-6 cytokine family, plays a complex role in solid tumors. However, the effect of LIF as a tumor microenvironment factor on plasticity control in breast cancer remains largely unknown. In this study, an in vitro investigation is conducted to determine the crosstalk between breast cancer cells and fibroblasts. Based on the results, cancer-associated fibroblasts are producers of LIF in the cocultivation system with breast cancer cells. Treatment with the CAF-CM and human LIF protein significantly promoted stemness through the dedifferentiation process and regaining of stem-cell-like properties. In addition, the results indicate that activation of LIFR signaling in breast cancer cells in the existence of CAF-secreted LIF can induce Nanog and Oct4 expression and increase breast cancer stem cell markers CD24−/CD44+. In contrast, suppression of the LIF receptor by human LIF receptor inhibition antibody decreased the cancer stem cell markers. We found that LIF was frequently overexpressed by CAFs and that LIF expression is necessary for dedifferentiation of breast cancer cell phenotype and regaining of cancer stem cell properties. Our results suggest that targeting LIF/LIFR signaling might be a potent therapeutic strategy for breast cancer and the prevention of tumor recurrence. Full article
(This article belongs to the Special Issue Origins, Properties, and Therapeutic Perspectives of Cancer Stem Cells)
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19 pages, 4426 KiB  
Article
Cell Populations Expressing Stemness-Associated Markers in Lung Adenocarcinoma
by Claudia Paterson, Ethan J. Kilmister, Helen D. Brasch, Nicholas Bockett, Josie Patel, Erin Paterson, Gordon Purdie, Sean Galvin, Paul F. Davis, Tinte Itinteang and Swee T. Tan
Life 2021, 11(10), 1106; https://doi.org/10.3390/life11101106 - 18 Oct 2021
Cited by 7 | Viewed by 3480
Abstract
The stemness-associated markers OCT4, NANOG, SOX2, KLF4 and c-MYC are expressed in numerous cancer types suggesting the presence of cancer stem cells (CSCs). Immunohistochemical (IHC) staining performed on 12 lung adenocarcinoma (LA) tissue samples showed protein expression of OCT4, NANOG, SOX2, KLF4 and [...] Read more.
The stemness-associated markers OCT4, NANOG, SOX2, KLF4 and c-MYC are expressed in numerous cancer types suggesting the presence of cancer stem cells (CSCs). Immunohistochemical (IHC) staining performed on 12 lung adenocarcinoma (LA) tissue samples showed protein expression of OCT4, NANOG, SOX2, KLF4 and c-MYC, and the CSC marker CD44. In situ hybridization (ISH) performed on six of the LA tissue samples showed mRNA expression of OCT4, NANOG, SOX2, KLF4 and c-MYC. Immunofluorescence staining performed on three of the tissue samples showed co-expression of OCT4 and c-MYC with NANOG, SOX2 and KLF4 by tumor gland cells, and expression of OCT4 and c-MYC exclusively by cells within the stroma. RT-qPCR performed on five LA-derived primary cell lines showed mRNA expression of all the markers except SOX2. Western blotting performed on four LA-derived primary cell lines demonstrated protein expression of all the markers except SOX2 and NANOG. Initial tumorsphere assays performed on four LA-derived primary cell lines demonstrated 0–80% of tumorspheres surpassing the 50 µm threshold. The expression of the stemness-associated markers OCT4, SOX2, NANOG, KFL4 and c-MYC by LA at the mRNA and protein level, and the unique expression patterns suggest a putative presence of CSC subpopulations within LA, which may be a novel therapeutic target for this cancer. Further functional studies are required to investigate the possession of stemness traits. Full article
(This article belongs to the Special Issue Origins, Properties, and Therapeutic Perspectives of Cancer Stem Cells)
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Review

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16 pages, 1356 KiB  
Review
The Intricate Interplay between Cancer Stem Cells and Oncogenic miRNAs in Breast Cancer Progression and Metastasis
by Antonis Tsintarakis, Chara Papalouka, Christina Kontarini, Panagiotis Zoumpourlis, Konstantinos Karakostis, Maria Adamaki and Vassilis Zoumpourlis
Life 2023, 13(6), 1361; https://doi.org/10.3390/life13061361 - 9 Jun 2023
Cited by 4 | Viewed by 2066
Abstract
Complex signaling interactions between cancer cells and their microenvironments drive the clonal selection of cancer cells. Opposing forces of antitumor and tumorigenic potential regulate the survival of the fittest clones, while key genetic and epigenetic alterations in healthy cells force them to transform, [...] Read more.
Complex signaling interactions between cancer cells and their microenvironments drive the clonal selection of cancer cells. Opposing forces of antitumor and tumorigenic potential regulate the survival of the fittest clones, while key genetic and epigenetic alterations in healthy cells force them to transform, overcome cell senescence, and proliferate in an uncontrolled manner. Both clinical samples and cancer cell lines provide researchers with an insight into the complex structure and hierarchy of cancer. Intratumor heterogeneity allows for multiple cancer cell subpopulations to simultaneously coexist within tumors. One category of these cancer cell subpopulations is cancer stem cells (CSCs), which possess stem-like characteristics and are not easily detectable. In the case of breast cancer, which is the most prevalent cancer type among females, such subpopulations of cells have been isolated and characterized via specific stem cell markers. These stem-like cells, known as breast cancer stem cells (BCSCs), have been linked to major events during tumorigenesis including invasion, metastasis and patient relapse following conventional therapies. Complex signaling circuitries seem to regulate the stemness and phenotypic plasticity of BCSCs along with their differentiation, evasion of immunosurveillance, invasiveness and metastatic potential. Within these complex circuitries, new key players begin to arise, with one of them being a category of small non-coding RNAs, known as miRNAs. Here, we review the importance of oncogenic miRNAs in the regulation of CSCs during breast cancer formation, promotion and metastasis, in order to highlight their anticipated usage as diagnostic and prognostic tools in the context of patient stratification and precision medicine. Full article
(This article belongs to the Special Issue Origins, Properties, and Therapeutic Perspectives of Cancer Stem Cells)
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24 pages, 3435 KiB  
Review
The Concept of Cancer Stem Cells: Elaborating on ALDH1B1 as an Emerging Marker of Cancer Progression
by Ilias Tsochantaridis, Angelos Roupas, Sofie Mohlin, Aglaia Pappa and Georgia-Persephoni Voulgaridou
Life 2023, 13(1), 197; https://doi.org/10.3390/life13010197 - 9 Jan 2023
Cited by 6 | Viewed by 3561
Abstract
Cancer is a multifactorial, complex disease exhibiting extraordinary phenotypic plasticity and diversity. One of the greatest challenges in cancer treatment is intratumoral heterogeneity, which obstructs the efficient eradication of the tumor. Tumor heterogeneity is often associated with the presence of cancer stem cells [...] Read more.
Cancer is a multifactorial, complex disease exhibiting extraordinary phenotypic plasticity and diversity. One of the greatest challenges in cancer treatment is intratumoral heterogeneity, which obstructs the efficient eradication of the tumor. Tumor heterogeneity is often associated with the presence of cancer stem cells (CSCs), a cancer cell sub-population possessing a panel of stem-like properties, such as a self-renewal ability and multipotency potential. CSCs are associated with enhanced chemoresistance due to the enhanced efflux of chemotherapeutic agents and the existence of powerful antioxidant and DNA damage repair mechanisms. The distinctive characteristics of CSCs make them ideal targets for clinical therapeutic approaches, and the identification of efficient and specific CSCs biomarkers is of utmost importance. Aldehyde dehydrogenases (ALDHs) comprise a wide superfamily of metabolic enzymes that, over the last years, have gained increasing attention due to their association with stem-related features in a wide panel of hematopoietic malignancies and solid cancers. Aldehyde dehydrogenase 1B1 (ALDH1B1) is an isoform that has been characterized as a marker of colon cancer progression, while various studies suggest its importance in additional malignancies. Here, we review the basic concepts related to CSCs and discuss the potential role of ALDH1B1 in cancer development and its contribution to the CSC phenotype. Full article
(This article belongs to the Special Issue Origins, Properties, and Therapeutic Perspectives of Cancer Stem Cells)
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22 pages, 1272 KiB  
Review
Identification, Culture and Targeting of Cancer Stem Cells
by Alejandro Herreros-Pomares
Life 2022, 12(2), 184; https://doi.org/10.3390/life12020184 - 27 Jan 2022
Cited by 13 | Viewed by 6344
Abstract
Chemoresistance, tumor progression, and metastasis are features that are frequently seen in cancer that have been associated with cancer stem cells (CSCs). These cells are a promising target in the future of cancer therapy but remain largely unknown. Deregulation of pathways that govern [...] Read more.
Chemoresistance, tumor progression, and metastasis are features that are frequently seen in cancer that have been associated with cancer stem cells (CSCs). These cells are a promising target in the future of cancer therapy but remain largely unknown. Deregulation of pathways that govern stemness in non-tumorigenic stem cells (SCs), such as Notch, Wnt, and Hedgehog pathways, has been described in CSC pathogenesis, but it is necessary to conduct further studies to discover potential new therapeutic targets. In addition, some markers for the identification and characterization of CSCs have been suggested, but the search for specific CSC markers in many cancer types is still under development. In addition, methods for CSC cultivation are also under development, with great heterogeneity existing in the protocols used. This review focuses on the most recent aspects of the identification, characterization, cultivation, and targeting of human CSCs, highlighting the advances achieved in the clinical implementation of therapies targeting CSCs and remarking those potential areas where more research is still required. Full article
(This article belongs to the Special Issue Origins, Properties, and Therapeutic Perspectives of Cancer Stem Cells)
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Other

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13 pages, 288 KiB  
Commentary
The Concept of “Cancer Stem Cells” in the Context of Classic Carcinogenesis Hypotheses and Experimental Findings
by James E. Trosko
Life 2021, 11(12), 1308; https://doi.org/10.3390/life11121308 - 27 Nov 2021
Cited by 7 | Viewed by 2354
Abstract
In this Commentary, the operational definition of cancer stem cells or cancer initiating cells includes the ability of certain cells, found in a heterogeneous mixture of cells within a tumor, which are able to sustain growth of that tumor. However, that concept [...] Read more.
In this Commentary, the operational definition of cancer stem cells or cancer initiating cells includes the ability of certain cells, found in a heterogeneous mixture of cells within a tumor, which are able to sustain growth of that tumor. However, that concept of cancer stem cells does not resolve the age-old controversy of two opposing hypotheses of the origin of the cancer, namely the stem cell hypothesis versus the de-differentiation or re-programming hypothesis. Moreover, this cancer stem concept has to take into account classic experimental observations, techniques, and concepts, such as the multi-stage, multi-mechanism process of carcinogenesis; roles of mutagenic, cytotoxic and epigenetic mechanisms; the important differences between errors of DNA repair and errors of DNA replication in forming mutations; biomarkers of known characteristics of normal adult organ-specific stem cells and of cancer stem cells; and the characteristics of epigenetic mechanisms involved in the carcinogenic process. In addition, vague and misleading terms, such as carcinogens, immortal and normal cells have to be clarified in the context of current scientific facts. The ultimate integration of all of these historic factors to provide a current understanding of the origin and characteristics of a cancer stem cell, which is required for a rational strategy for prevention and therapy for cancer, does not follow a linear path. Lastly, it will be speculated that there exists evidence of two distinct types of cancer stem cells, one that has its origin in an organ-specific adult stem cell that is ‘initiated’ in the stem cell stage, expressing the Oct4A gene and not expressing any connexin gene or having functional gap junctional intercellular communication (GJIC). The other cancer stem cell is derived from a stem cell that is initiated early after the Oct4A gene is suppressed and the connexin gene is expressed, which starts early differentiation, but it is blocked from terminal differentiation. Full article
(This article belongs to the Special Issue Origins, Properties, and Therapeutic Perspectives of Cancer Stem Cells)
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