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Cancer Stem Cells and Resistance to Therapy
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Cancer Stem Cells and Resistance to Therapy

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

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 90789

Special Issue Editor

Dr. Amancio Carnero

E-Mail Website
Guest Editor
1. Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Avda. Manuel Siurot s/n, 41013 Seville, Spain
2. Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain
Interests: identification of new genes involved in cancer, its characterization and traslation to clinic; the identification and validation of new targets for anticancer drug
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

 In recent years, cancer stem cells (CSCs), or cancer-initiating cells (CIC), have emerged as major drivers of chemoresistance. CSCs are a subpopulation of cancer cells that possess the same self-renewal and differentiation capacities as stem cells, thus maintaining tumor growth and the ability to regenerate a heterogeneous tumor mass. Thus, CSCs have been suggested to be responsible for metastasis and tumor growth and development. Furthermore, it has been reported that traditional chemotherapy fails to target CSCs, which could account for relapse and tumor resistance. This Special Issue will review different areas that may be involved in therapy resistance dependent on CSC populations in the tumor. There are different areas such as the subpopulation heterogeneity of CSC pools in different sections of the same tumor, between primary or metastasis or the same tumor type in different patients; the difficulty to identify properly all the CIC subpopulations in the different tumor types, including the different properties of the progenitors, and, in each case, the pathways involved and the difficulty to target them pharmacologically and how the plasticity in the different aspects of metabolism may account for these differences in resistance. Finally, the relevance of the microenvironment in the response is of great relevance in the therapeutic efficacy. Any of these topics will be considered for publication, but topics of interest are not limited to this selection. Either general studies or those focusing on specific tumors could be of great interest.

Dr. Amancio Carnero
Guest Editor

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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 (15 papers)

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Research

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19 pages, 2989 KiB  
Article
Tsc1 Regulates the Proliferation Capacity of Bone-Marrow Derived Mesenchymal Stem Cells
by Maria V. Guijarro, Laura S. Danielson, Marta Cañamero, Akbar Nawab, Carolina Abrahan, Eva Hernando and Glyn D. Palmer
Cells 2020, 9(9), 2072; https://doi.org/10.3390/cells9092072 - 10 Sep 2020
Cited by 8 | Viewed by 3052
Abstract
TSC1 is a tumor suppressor that inhibits cell growth via negative regulation of the mammalian target of rapamycin complex (mTORC1). TSC1 mutations are associated with Tuberous Sclerosis Complex (TSC), characterized by multiple benign tumors of mesenchymal and epithelial origin. TSC1 modulates self-renewal and [...] Read more.
TSC1 is a tumor suppressor that inhibits cell growth via negative regulation of the mammalian target of rapamycin complex (mTORC1). TSC1 mutations are associated with Tuberous Sclerosis Complex (TSC), characterized by multiple benign tumors of mesenchymal and epithelial origin. TSC1 modulates self-renewal and differentiation in hematopoietic stem cells; however, its effects on mesenchymal stem cells (MSCs) are unknown. We investigated the impact of Tsc1 inactivation in murine bone marrow (BM)-MSCs, using tissue-specific, transgelin (Tagln)-mediated cre-recombination, targeting both BM-MSCs and smooth muscle cells. Tsc1 mutants were viable, but homozygous inactivation led to a dwarfed appearance with TSC-like pathologies in multiple organs and reduced survival. In young (28 day old) mice, Tsc1 deficiency-induced significant cell expansion of non-hematopoietic BM in vivo, and MSC colony-forming potential in vitro, that was normalized upon treatment with the mTOR inhibitor, everolimus. The hyperproliferative BM-MSC phenotype was lost in aged (1.5 yr) mice, and Tsc1 inactivation was also accompanied by elevated ROS and increased senescence. ShRNA-mediated knockdown of Tsc1 in BM-MSCs replicated the hyperproliferative BM-MSC phenotype and led to impaired adipogenic and myogenic differentiation. Our data show that Tsc1 is a negative regulator of BM-MSC proliferation and support a pivotal role for the Tsc1-mTOR axis in the maintenance of the mesenchymal progenitor pool. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Resistance to Therapy)
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17 pages, 2740 KiB  
Article
Head and Neck Cancer Stem Cell-Enriched Spheroid Model for Anticancer Compound Screening
by Larisa Goričan, Boris Gole and Uroš Potočnik
Cells 2020, 9(7), 1707; https://doi.org/10.3390/cells9071707 - 16 Jul 2020
Cited by 14 | Viewed by 3338
Abstract
Cancer stem cells (CSCs), a rare cell population in tumors, are resistant to conventional chemotherapy and thus responsible for tumor recurrence. To screen for active compounds targeting CSCs, a good CSC-enriched model compatible with high-throughput screening (HTS) is needed. Here, we describe a [...] Read more.
Cancer stem cells (CSCs), a rare cell population in tumors, are resistant to conventional chemotherapy and thus responsible for tumor recurrence. To screen for active compounds targeting CSCs, a good CSC-enriched model compatible with high-throughput screening (HTS) is needed. Here, we describe a new head and neck cancer stem cell-enriched spheroid model (SCESM) suitable for HTS analyses of anti-CSC compounds. We used FaDu cells, round-bottom ultra-low adherent (ULA) microplates, and stem medium. The formed spheroids displayed increased expression of all stem markers tested (qRT-PCR and protein analysis) in comparison to the FaDu cells grown in a standard adherent culture or in a well-known HTS-compatible multi-cellular tumor spheroid model (MCTS). Consistent with increased stemness of the cells in the spheroid, confocal microscopy detected fast proliferating cells only at the outer rim of the SCESM spheroids, with poorly/non-proliferating cells deeper in. To confirm the sensitivity of our model, we used ATRA treatment, which strongly reduced the expression of selected stem markers. Altogether, we developed a CSC-enriched spheroid model with a simple protocol, a microplate format compatible with multimodal detection systems, and a high detection signal, making it suitable for anti-CSC compounds’ HTS. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Resistance to Therapy)
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19 pages, 3872 KiB  
Article
Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells
by Belén G. Sánchez, Alicia Bort, Diana Vara-Ciruelos and Inés Díaz-Laviada
Cells 2020, 9(6), 1441; https://doi.org/10.3390/cells9061441 - 10 Jun 2020
Cited by 30 | Viewed by 6268
Abstract
In the past few years, cell plasticity has emerged as a mode of targeted therapy evasion in prostate adenocarcinoma. When exposed to anticancer therapies, tumor cells may switch into a different histological subtype, such as the neuroendocrine phenotype which is associated with treatment [...] Read more.
In the past few years, cell plasticity has emerged as a mode of targeted therapy evasion in prostate adenocarcinoma. When exposed to anticancer therapies, tumor cells may switch into a different histological subtype, such as the neuroendocrine phenotype which is associated with treatment failure and a poor prognosis. In this study, we demonstrated that long-term androgen signal depletion of prostate LNCaP cells induced a neuroendocrine phenotype followed by re-differentiation towards a “stem-like” state. LNCaP cells incubated for 30 days in charcoal-stripped medium or with the androgen receptor antagonist 2-hydroxyflutamide developed neuroendocrine morphology and increased the expression of the neuroendocrine markers βIII-tubulin and neuron specific enolase (NSE). When cells were incubated for 90 days in androgen-depleted medium, they grew as floating spheres and had enhanced expression of the stem cell markers CD133, ALDH1A1, and the transporter ABCB1A. Additionally, the pluripotent transcription factors Nanog and Oct4 and the angiogenic factor VEGF were up-regulated while the expression of E-cadherin was inhibited. Cell viability revealed that those cells were resistant to docetaxel and 2-hidroxyflutamide. Mechanistically, androgen depletion induced the decrease in AMP-activated kinase (AMPK) expression and activation and stabilization of the hypoxia-inducible factor HIF-1α. Overexpression of AMPK in the stem-like cells decreased the expression of stem markers as well as that of HIF-1α and VEGF while it restored the levels of E-cadherin and PGC-1α. Most importantly, docetaxel sensitivity was restored in stem-like AMPK-transfected cells. Our model provides a new regulatory mechanism of prostate cancer plasticity through AMPK that is worth exploring. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Resistance to Therapy)
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21 pages, 3977 KiB  
Article
Proteins and Molecular Pathways Relevant for the Malignant Properties of Tumor-Initiating Pancreatic Cancer Cells
by Lisa Samonig, Andrea Loipetzberger, Constantin Blöchl, Marc Rurik, Oliver Kohlbacher, Fritz Aberger and Christian G. Huber
Cells 2020, 9(6), 1397; https://doi.org/10.3390/cells9061397 - 03 Jun 2020
Cited by 7 | Viewed by 3192
Abstract
Cancer stem cells (CSCs), a small subset of the tumor bulk with highly malignant properties, are deemed responsible for tumor initiation, growth, metastasis, and relapse. In order to reveal molecular markers and determinants of their tumor-initiating properties, we enriched rare stem-like pancreatic tumor-initiating [...] Read more.
Cancer stem cells (CSCs), a small subset of the tumor bulk with highly malignant properties, are deemed responsible for tumor initiation, growth, metastasis, and relapse. In order to reveal molecular markers and determinants of their tumor-initiating properties, we enriched rare stem-like pancreatic tumor-initiating cells (TICs) by harnessing their clonogenic growth capacity in three-dimensional multicellular spheroid cultures. We compared pancreatic TICs isolated from three-dimensional tumor spheroid cultures with nontumor-initiating cells (non-TICs) enriched in planar cultures. Employing differential proteomics (PTX), we identified more than 400 proteins with significantly different expression in pancreatic TICs and the non-TIC population. By combining the unbiased PTX with mRNA expression analysis and literature-based predictions of pro-malignant functions, we nominated the two calcium-binding proteins S100A8 (MRP8) and S100A9 (MRP14) as well as galactin-3-binding protein LGALS3BP (MAC-2-BP) as putative determinants of pancreatic TICs. In silico pathway analysis followed by candidate-based RNA interference mediated loss-of-function analysis revealed a critical role of S100A8, S100A9, and LGALS3BP as molecular determinants of TIC proliferation, migration, and in vivo tumor growth. Our study highlights the power of combining unbiased proteomics with focused gene expression and functional analyses for the identification of novel key regulators of TICs, an approach that warrants further application to identify proteins and pathways amenable to drug targeting. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Resistance to Therapy)
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Review

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24 pages, 879 KiB  
Review
Cellular Immunotherapy Targeting Cancer Stem Cells: Preclinical Evidence and Clinical Perspective
by Chiara Donini, Ramona Rotolo, Alessia Proment, Massimo Aglietta, Dario Sangiolo and Valeria Leuci
Cells 2021, 10(3), 543; https://doi.org/10.3390/cells10030543 - 04 Mar 2021
Cited by 14 | Viewed by 3483
Abstract
The term “cancer stem cells” (CSCs) commonly refers to a subset of tumor cells endowed with stemness features, potentially involved in chemo-resistance and disease relapses. CSCs may present peculiar immunogenic features influencing their homeostasis within the tumor microenvironment. The susceptibility of CSCs to [...] Read more.
The term “cancer stem cells” (CSCs) commonly refers to a subset of tumor cells endowed with stemness features, potentially involved in chemo-resistance and disease relapses. CSCs may present peculiar immunogenic features influencing their homeostasis within the tumor microenvironment. The susceptibility of CSCs to recognition and targeting by the immune system is a relevant issue and matter of investigation, especially considering the multiple emerging immunotherapy strategies. Adoptive cellular immunotherapies, especially those strategies encompassing the genetic redirection with chimeric antigen receptors (CAR), hold relevant promise in several tumor settings and might in theory provide opportunities for selective elimination of CSC subsets. Initial dedicated preclinical studies are supporting the potential targeting of CSCs by cellular immunotherapies, indirect evidence from clinical studies may be derived and new studies are ongoing. Here we review the main issues related to the putative immunogenicity of CSCs, focusing on and highlighting the existing evidence and opportunities for cellular immunotherapy approaches with T and non-T antitumor lymphocytes. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Resistance to Therapy)
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29 pages, 2829 KiB  
Review
Role of Mitochondria in Cancer Stem Cell Resistance
by José Manuel García-Heredia and Amancio Carnero
Cells 2020, 9(7), 1693; https://doi.org/10.3390/cells9071693 - 15 Jul 2020
Cited by 58 | Viewed by 5992
Abstract
Cancer stem cells (CSC) are associated with the mechanisms of chemoresistance to different cytotoxic drugs or radiotherapy, as well as with tumor relapse and a poor prognosis. Various studies have shown that mitochondria play a central role in these processes because of the [...] Read more.
Cancer stem cells (CSC) are associated with the mechanisms of chemoresistance to different cytotoxic drugs or radiotherapy, as well as with tumor relapse and a poor prognosis. Various studies have shown that mitochondria play a central role in these processes because of the ability of this organelle to modify cell metabolism, allowing survival and avoiding apoptosis clearance of cancer cells. Thus, the whole mitochondrial cycle, from its biogenesis to its death, either by mitophagy or by apoptosis, can be targeted by different drugs to reduce mitochondrial fitness, allowing for a restored or increased sensitivity to chemotherapeutic drugs. Once mitochondrial misbalance is induced by a specific drug in any of the processes of mitochondrial metabolism, two elements are commonly boosted: an increment in reactive nitrogen/oxygen species and, subsequently, activation of the intrinsic apoptotic pathway. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Resistance to Therapy)
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36 pages, 1211 KiB  
Review
CSC Radioresistance: A Therapeutic Challenge to Improve Radiotherapy Effectiveness in Cancer
by María Auxiliadora Olivares-Urbano, Carmen Griñán-Lisón, Juan Antonio Marchal and María Isabel Núñez
Cells 2020, 9(7), 1651; https://doi.org/10.3390/cells9071651 - 09 Jul 2020
Cited by 105 | Viewed by 8641
Abstract
Radiotherapy (RT) is a modality of oncologic treatment that can be used to treat approximately 50% of all cancer patients either alone or in combination with other treatment modalities such as surgery, chemotherapy, immunotherapy, and therapeutic targeting. Despite the technological advances in RT, [...] Read more.
Radiotherapy (RT) is a modality of oncologic treatment that can be used to treat approximately 50% of all cancer patients either alone or in combination with other treatment modalities such as surgery, chemotherapy, immunotherapy, and therapeutic targeting. Despite the technological advances in RT, which allow a more precise delivery of radiation while progressively minimizing the impact on normal tissues, issues like radioresistance and tumor recurrence remain important challenges. Tumor heterogeneity is responsible for the variation in the radiation response of the different tumor subpopulations. A main factor related to radioresistance is the presence of cancer stem cells (CSC) inside tumors, which are responsible for metastases, relapses, RT failure, and a poor prognosis in cancer patients. The plasticity of CSCs, a process highly dependent on the epithelial–mesenchymal transition (EMT) and associated to cell dedifferentiation, complicates the identification and eradication of CSCs and it might be involved in disease relapse and progression after irradiation. The tumor microenvironment and the interactions of CSCs with their niches also play an important role in the response to RT. This review provides a deep insight into the characteristics and radioresistance mechanisms of CSCs and into the role of CSCs and tumor microenvironment in both the primary tumor and metastasis in response to radiation, and the radiobiological principles related to the CSC response to RT. Finally, we summarize the major advances and clinical trials on the development of CSC-based therapies combined with RT to overcome radioresistance. A better understanding of the potential therapeutic targets for CSC radiosensitization will provide safer and more efficient combination strategies, which in turn will improve the live expectancy and curability of cancer patients. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Resistance to Therapy)
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25 pages, 1098 KiB  
Review
Linking Cancer Stem Cell Plasticity to Therapeutic Resistance-Mechanism and Novel Therapeutic Strategies in Esophageal Cancer
by Chenghui Zhou, Ningbo Fan, Fanyu Liu, Nan Fang, Patrick S. Plum, René Thieme, Ines Gockel, Sascha Gromnitza, Axel M. Hillmer, Seung-Hun Chon, Hans A. Schlösser, Christiane J. Bruns and Yue Zhao
Cells 2020, 9(6), 1481; https://doi.org/10.3390/cells9061481 - 17 Jun 2020
Cited by 20 | Viewed by 4986
Abstract
Esophageal cancer (EC) is an aggressive form of cancer, including squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) as two predominant histological subtypes. Accumulating evidence supports the existence of cancer stem cells (CSCs) able to initiate and maintain EAC or ESCC. In this review, [...] Read more.
Esophageal cancer (EC) is an aggressive form of cancer, including squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) as two predominant histological subtypes. Accumulating evidence supports the existence of cancer stem cells (CSCs) able to initiate and maintain EAC or ESCC. In this review, we aim to collect the current evidence on CSCs in esophageal cancer, including the biomarkers/characterization strategies of CSCs, heterogeneity of CSCs, and the key signaling pathways (Wnt/β-catenin, Notch, Hedgehog, YAP, JAK/STAT3) in modulating CSCs during esophageal cancer progression. Exploring the molecular mechanisms of therapy resistance in EC highlights DNA damage response (DDR), metabolic reprogramming, epithelial mesenchymal transition (EMT), and the role of the crosstalk of CSCs and their niche in the tumor progression. According to these molecular findings, potential therapeutic implications of targeting esophageal CSCs may provide novel strategies for the clinical management of esophageal cancer. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Resistance to Therapy)
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21 pages, 929 KiB  
Review
Cancer Stem Cells in Soft-Tissue Sarcomas
by Paula Martínez-Delgado, Serena Lacerenza, Antonia Obrador-Hevia, Maria Lopez-Alvarez, José L. Mondaza-Hernandez, Elena Blanco-Alcaina, Paloma Sanchez-Bustos, Nadia Hindi, David S. Moura and Javier Martin-Broto
Cells 2020, 9(6), 1449; https://doi.org/10.3390/cells9061449 - 10 Jun 2020
Cited by 12 | Viewed by 4879
Abstract
Soft tissue sarcomas (STS) are a rare group of mesenchymal solid tumors with heterogeneous genetic profiles and clinical features. Systemic chemotherapy is the backbone treatment for advanced STS; however, STS frequently acquire resistance to standard therapies, which highlights the need to improve treatments [...] Read more.
Soft tissue sarcomas (STS) are a rare group of mesenchymal solid tumors with heterogeneous genetic profiles and clinical features. Systemic chemotherapy is the backbone treatment for advanced STS; however, STS frequently acquire resistance to standard therapies, which highlights the need to improve treatments and identify novel therapeutic targets. Increases in the knowledge of the molecular pathways that drive sarcomas have brought to light different molecular alterations that cause tumor initiation and progression. These findings have triggered a breakthrough of targeted therapies that are being assessed in clinical trials. Cancer stem cells (CSCs) exhibit mesenchymal stem cell (MSC) features and represent a subpopulation of tumor cells that play an important role in tumor progression, chemotherapy resistance, recurrence and metastasis. In fact, CSCs phenotypes have been identified in sarcomas, allied to drug resistance and tumorigenesis. Herein, we will review the published evidence of CSCs in STS, discussing the molecular characteristic of CSCs, the commonly used isolation techniques and the new possibilities of targeting CSCs as a way to improve STS treatment and consequently patient outcome. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Resistance to Therapy)
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23 pages, 1481 KiB  
Review
Targeting Cancer Stem Cells to Overcome Therapy Resistance in Ovarian Cancer
by Sandra Muñoz-Galván and Amancio Carnero
Cells 2020, 9(6), 1402; https://doi.org/10.3390/cells9061402 - 04 Jun 2020
Cited by 43 | Viewed by 5037
Abstract
Ovarian cancer is the most lethal gynecological malignancy due to its late detection and high recurrence rate. Resistance to conventional platinum-based therapies and metastasis are attributed to a population of cells within tumors called cancer stem cells, which possess stem-like features and are [...] Read more.
Ovarian cancer is the most lethal gynecological malignancy due to its late detection and high recurrence rate. Resistance to conventional platinum-based therapies and metastasis are attributed to a population of cells within tumors called cancer stem cells, which possess stem-like features and are able to recapitulate new tumors. Recent studies have deepened the understanding of the biology of ovarian cancer stem cells and their special properties and have identified multiple markers and signaling pathways responsible for their self-renewal abilities. Targeting cancer stem cells represents the most promising strategy for overcoming therapy resistance and reducing mortality in ovarian cancer, but further efforts must be made to improve our understanding of the mechanisms involved in therapy resistance. In this review, we summarize our current knowledge about ovarian cancer stem cells, their involvement in metastasis and their interactions with the tumor microenvironment; we also discuss the therapeutic approaches that are being developed to target them to prevent tumor relapse. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Resistance to Therapy)
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17 pages, 1532 KiB  
Review
Metformin’s Modulatory Effects on miRNAs Function in Cancer Stem Cells—A Systematic Review
by Bartosz Malinowski, Nikola Musiała and Michał Wiciński
Cells 2020, 9(6), 1401; https://doi.org/10.3390/cells9061401 - 04 Jun 2020
Cited by 6 | Viewed by 2553
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Resistance to Therapy)
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22 pages, 2229 KiB  
Review
The Roles of Cancer Stem Cells and Therapy Resistance in Colorectal Carcinoma
by Plabon Kumar Das, Farhadul Islam and Alfred K. Lam
Cells 2020, 9(6), 1392; https://doi.org/10.3390/cells9061392 - 03 Jun 2020
Cited by 124 | Viewed by 7256
Abstract
Cancer stem cells (CSCs) are the main culprits involved in therapy resistance and disease recurrence in colorectal carcinoma (CRC). Results using cell culture, animal models and tissues from patients with CRC suggest the indispensable roles of colorectal CSCs in therapeutic failure. Conventional therapies [...] Read more.
Cancer stem cells (CSCs) are the main culprits involved in therapy resistance and disease recurrence in colorectal carcinoma (CRC). Results using cell culture, animal models and tissues from patients with CRC suggest the indispensable roles of colorectal CSCs in therapeutic failure. Conventional therapies target proliferating and mature cancer cells, while CSCs are mostly quiescent and poorly differentiated, thereby they can easily survive chemotherapeutic insults. The aberrant activation of Wnt/β-catenin, Notch, Hedgehog, Hippo/YAP (Yes-associated protein) and phosphatidylinositol 3-kinase/protein kinase B facilitates CSCs with excessive self-renewal and therapy resistance property in CRC. CSCs survive the chemo-radiotherapies by escaping therapy mediated DNA damage via altering the cell cycle checkpoints, increasing DNA damage repair capacity and by an efficient scavenging of reactive oxygen species. Furthermore, dysregulations of miRNAs e.g., miR-21, miR-93, miR-203, miR-215, miR-497 etc., modulate the therapeutic sensitivity of colorectal CSCs by regulating growth and survival signalling. In addition, a reversible quiescent G0 state and the re-entering cell cycle capacity of colorectal CSCs can accelerate tumour regeneration after treatment. Moreover, switching to favourable metabolic signatures during a therapeutic regimen will add more complexity in therapeutic outcomes against CSCs. Therapeutic strategies targeting these underlying mechanisms of CSCs’ therapy resistance could provide a promising outcome, however, deep understanding and concerted research are necessary to design novel therapies targeting CSCs. To conclude, the understanding of these mechanisms of CSC in CRC could lead to the improved management of patients with CRC. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Resistance to Therapy)
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29 pages, 1372 KiB  
Review
Cancer Stem Cell Functions in Hepatocellular Carcinoma and Comprehensive Therapeutic Strategies
by Yu-Chin Liu, Chau-Ting Yeh and Kwang-Huei Lin
Cells 2020, 9(6), 1331; https://doi.org/10.3390/cells9061331 - 26 May 2020
Cited by 146 | Viewed by 9481
Abstract
Hepatocellular carcinoma (HCC) is a significant cause of cancer-related mortality owing to resistance to traditional treatments and tumor recurrence after therapy, which leads to poor therapeutic outcomes. Cancer stem cells (CSC) are a small subset of tumor cells with the capability to influence [...] Read more.
Hepatocellular carcinoma (HCC) is a significant cause of cancer-related mortality owing to resistance to traditional treatments and tumor recurrence after therapy, which leads to poor therapeutic outcomes. Cancer stem cells (CSC) are a small subset of tumor cells with the capability to influence self-renewal, differentiation, and tumorigenesis. A number of surface markers for liver cancer stem cell (LCSC) subpopulations (EpCAM, CD133, CD44, CD13, CD90, OV-6, CD47, and side populations) in HCC have been identified. LCSCs play critical roles in regulating HCC stemness, self-renewal, tumorigenicity, metastasis, recurrence, and therapeutic resistance via genetic mutations, epigenetic disruption, signaling pathway dysregulation, or alterations microenvironment. Accumulating studies have shown that biomarkers for LCSCs contribute to diagnosis and prognosis prediction of HCC, supporting their utility in clinical management and development of therapeutic strategies. Preclinical and clinical analyses of therapeutic approaches for HCC using small molecule inhibitors, oncolytic measles viruses, and anti-surface marker antibodies have demonstrated selective, efficient, and safe targeting of LCSC populations. The current review focuses on recent reports on the influence of LCSCs on HCC stemness, tumorigenesis, and multiple drug resistance (MDR), along with LCSC-targeted therapeutic strategies for HCC. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Resistance to Therapy)
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35 pages, 3315 KiB  
Review
Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods
by Nuzhat Ahmed, Elif Kadife, Ali Raza, Mary Short, Paul T. Jubinsky and George Kannourakis
Cells 2020, 9(3), 719; https://doi.org/10.3390/cells9030719 - 14 Mar 2020
Cited by 39 | Viewed by 5540
Abstract
Epithelial ovarian cancer (EOC) constitutes 90% of ovarian cancers (OC) and is the eighth most common cause of cancer-related death in women. The cancer histologically and genetically is very complex having a high degree of tumour heterogeneity. The pathogenic variability in OC causes [...] Read more.
Epithelial ovarian cancer (EOC) constitutes 90% of ovarian cancers (OC) and is the eighth most common cause of cancer-related death in women. The cancer histologically and genetically is very complex having a high degree of tumour heterogeneity. The pathogenic variability in OC causes significant impediments in effectively treating patients, resulting in a dismal prognosis. Disease progression is predominantly influenced by the peritoneal tumour microenvironment rather than properties of the tumor and is the major contributor to prognosis. Standard treatment of OC patients consists of debulking surgery, followed by chemotherapy, which in most cases end in recurrent chemoresistant disease. This review discusses the different origins of high-grade serous ovarian cancer (HGSOC), the major sub-type of EOC. Tumour heterogeneity, genetic/epigenetic changes, and cancer stem cells (CSC) in facilitating HGSOC progression and their contribution in the circumvention of therapy treatments are included. Several new treatment strategies are discussed including our preliminary proof of concept study describing the role of mitochondria-associated granulocyte macrophage colony-stimulating factor signaling protein (Magmas) in HGSOC and its unique potential role in chemotherapy-resistant disease. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Resistance to Therapy)
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19 pages, 1474 KiB  
Review
Recent Progress of Stem Cell Therapy in Cancer Treatment: Molecular Mechanisms and Potential Applications
by Dinh-Toi Chu, Tiep Tien Nguyen, Nguyen Le Bao Tien, Dang-Khoa Tran, Jee-Heon Jeong, Pham Gia Anh, Vo Van Thanh, Dang Tien Truong and Thien Chu Dinh
Cells 2020, 9(3), 563; https://doi.org/10.3390/cells9030563 - 28 Feb 2020
Cited by 98 | Viewed by 15931
Abstract
The insufficient and unspecific target of traditional therapeutic approaches in cancer treatment often leads to therapy resistance and cancer recurrence. Over the past decades, accumulating discoveries about stem cell biology have provided new potential approaches to cure cancer patients. Stem cells possess unique [...] Read more.
The insufficient and unspecific target of traditional therapeutic approaches in cancer treatment often leads to therapy resistance and cancer recurrence. Over the past decades, accumulating discoveries about stem cell biology have provided new potential approaches to cure cancer patients. Stem cells possess unique biological actions, including self-renewal, directional migration, differentiation, and modulatory effects on other cells, which can be utilized as regenerative medicine, therapeutic carriers, drug targeting, and generation of immune cells. In this review, we emphasize the mechanisms underlying the use of various types of stem cells in cancer treatment. In addition, we summarize recent progress in the clinical applications of stem cells, as well as common risks of this therapy. We finally give general directions for future studies, aiming to improve overall outcomes in the fight against cancer. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Resistance to Therapy)
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