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Metabolic Reprogramming of Cancer Stem Cells (CSCs) and the Role...
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Metabolic Reprogramming of Cancer Stem Cells (CSCs) and the Role of Tumor Microenvironment—Mechanisms and Therapeutic Opportunities

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 14966

Special Issue Editors

Dr. Angeliki Magklara

E-Mail Website
Guest Editor
1. Laboratory of Clinical Chemistry, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
2. Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology-Hellas, 45110 Ioannina, Greece
Interests: cancer epigenetics; cancer stem cells; breast cancer; tumor heterogeneity; epigenetic therapies
Special Issues, Collections and Topics in MDPI journals
Dr. Styliani Papadaki

E-Mail Website
Guest Editor
Laboratory of Clinical Chemistry, Faculty of Medicine, School of Health Sciences, University of Ioannina and Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology-Hellas, 45110 Ioannina, Greece
Interests: cancer stem cells; metabolomics; chemoresistance; tumor microenvironment

Special Issue Information

Dear Colleagues,

One of the hallmarks of cancer is metabolic reprogramming resulting in the utilization of aerobic glycolysis for the energy requirements of cancer cells. This metabolic rewiring sustains and promotes tumor growth and often mediates the development of chemoresistance leading to the failure of cancer treatments. Cancer stem cells (CSCs) have gained much attention due to their involvement in tumor initiation, progression, and metastasis, but mostly due to their association with chemoresistance and tumor recurrence. Common anti-cancer therapeutic schemes have proven unsuccessful for the elimination of this aggressive tumor subpopulation.

CSCs inhabit a distinct niche within the tumor microenvironment (TME), which is usually characterized by hypoxia, acidosis, nutrient deficiency, and immunosuppression. The interplay between components of the CSC-niche directs their metabolic reprogramming towards glycolysis or oxidative metabolism, depending on the specific biological setting. The mechanisms of CSC metabolic plasticity and its regulation by the TME remains a field not yet fully understood. An in-depth investigation of this field could provide us with clues about the metabolic “vulnerabilities” of CSCs and how these could be exploited for the development of targeted therapies. Such CSC metabolome-targeted therapies could be employed in combination with standard treatments and may be more beneficial for cancer patients.

This Special Issue’s scope is to collect original or review articles focusing on the elucidation of the role of TME in the metabolic reprogramming of CSCs and on the investigation of the potential therapeutic benefits stemming from targeting CSC metabolism.

Dr. Angeliki Magklara
Dr. Styliani Papadaki
Guest Editors

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 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. Cancers 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 2900 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.

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Published Papers (6 papers)

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Research

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20 pages, 5597 KiB  
Article
Down-Regulation of lncRNA MBNL1-AS1 Promotes Tumor Stem Cell-like Characteristics and Prostate Cancer Progression through miR-221-3p/CDKN1B/C-myc Axis
by Ji Liu, Maskey Niraj, Hong Wang, Wentao Zhang, Ruiliang Wang, Aimaitiaji Kadier, Wei Li and Xudong Yao
Cancers 2022, 14(23), 5783; https://doi.org/10.3390/cancers14235783 - 24 Nov 2022
Cited by 3 | Viewed by 1631
Abstract
The recurrence, progression, and drug resistance of prostate cancer (PC) is closely related to the cancer stem cells (CSCs). Therefore, it is necessary to find the key regulators of prostate cancer stem cells (PCSCs). Here, we analyzed the results of a single-class logistic [...] Read more.
The recurrence, progression, and drug resistance of prostate cancer (PC) is closely related to the cancer stem cells (CSCs). Therefore, it is necessary to find the key regulators of prostate cancer stem cells (PCSCs). Here, we analyzed the results of a single-class logistic regression machine learning algorithm (OCLR) to identify the PCSC-associated lncRNA MBNL1-AS1. The effects of MBNL1-AS1 on the stemness of CSCs was assessed using qPCR, western blot and sphere-forming assays. The role of MBNL1-AS1 in mediating the proliferation and invasion of the PC cell lines was examined using Transwell, wounding-healing, CCK-8, EdU and animal assays. Dual-luciferase and ChIRP assays were used to examine the molecular mechanism of MBNL1-AS1 in PCSCs. MBNL1-AS1 was shown to be negatively correlated with stemness index (mRNAsi), and even prognosis, tumor progression, recurrence, and drug resistance in PC patients. The knockdown of MBNL1-AS1 significantly affected the stemness of the PC cells, and subsequently their invasive and proliferative abilities. Molecular mechanism studies suggested that MBNL1-AS1 regulates CDKN1B through competitive binding to miR-221-3p, which led to the inhibition of the Wnt signaling pathway to affect PCSCs. In conclusion, our study identified MBNL1-AS1 as a key regulator of PCSCs and examined its mechanism of action in the malignant progression of PC. Full article
(This article belongs to the Special Issue Metabolic Reprogramming of Cancer Stem Cells (CSCs) and the Role of Tumor Microenvironment—Mechanisms and Therapeutic Opportunities)
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17 pages, 6424 KiB  
Article
WNT/β-Catenin-Mediated Resistance to Glucose Deprivation in Glioblastoma Stem-like Cells
by Suad Yusuf, Philippe Aretz, Ann-Christin Nickel, Philipp Westhoff, Amit Sharma, Nan Qin, Marc Remke, Hans-Jakob Steiger, Daniel Hänggi, Hongjia Liu, Hongde Liu, Silke Neumann, Guido Reifenberger and Jarek Maciaczyk
Cancers 2022, 14(13), 3165; https://doi.org/10.3390/cancers14133165 - 28 Jun 2022
Cited by 6 | Viewed by 2556
Abstract
Isocitrate dehydrogenase (IDH)-wildtype glioblastoma is the most common primary malignant brain tumor. It is associated with a particularly poor prognosis, as reflected by an overall median survival of only 15 months in patients who undergo a supramarginal surgical reduction of the tumor mass [...] Read more.
Isocitrate dehydrogenase (IDH)-wildtype glioblastoma is the most common primary malignant brain tumor. It is associated with a particularly poor prognosis, as reflected by an overall median survival of only 15 months in patients who undergo a supramarginal surgical reduction of the tumor mass followed by combined chemoradiotherapy. The highly malignant nature of IDH-wildtype glioblastoma is thought to be driven by glioblastoma stem-like cells (GSCs) that harbor the ability of self-renewal, survival, and adaptability to challenging environmental conditions. The wingless (WNT) signaling pathway is a phylogenetically highly conserved stemness pathway, which promotes metabolic plasticity and adaptation to a nutrient-limited tumor microenvironment. To unravel the reciprocal regulation of the WNT pathway and the nutrient-limited microenvironment, glioblastoma cancer stem-like cells were cultured in a medium with either standard or reduced glucose concentrations for various time points (24, 48, and 72 h). Glucose depletion reduced cell viability and facilitated the survival of a small population of starvation-resistant tumor cells. The surviving cells demonstrated increased clonogenic and invasive properties as well as enhanced chemosensitivity to pharmacological inhibitors of the WNT pathway (LGK974, berberine). Glucose depletion partially led to the upregulation of WNT target genes such as CTNNB1, ZEB1, and AXIN2 at the mRNA and corresponding protein levels. LGK974 treatment alone or in combination with glucose depletion also altered the metabolite concentration in intracellular compartments, suggesting WNT-mediated metabolic regulation. Taken together, our findings suggest that WNT-mediated metabolic plasticity modulates the survival of GSCs under nutrient-restricted environmental conditions. Full article
(This article belongs to the Special Issue Metabolic Reprogramming of Cancer Stem Cells (CSCs) and the Role of Tumor Microenvironment—Mechanisms and Therapeutic Opportunities)
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17 pages, 3762 KiB  
Article
Overexpression of Cystine/Glutamate Antiporter xCT Correlates with Nutrient Flexibility and ZEB1 Expression in Highly Clonogenic Glioblastoma Stem-like Cells (GSCs)
by Katharina Koch, Rudolf Hartmann, Abigail Kora Suwala, Dayana Herrera Rios, Marcel Alexander Kamp, Michael Sabel, Hans-Jakob Steiger, Dieter Willbold, Amit Sharma, Ulf Dietrich Kahlert and Jarek Maciaczyk
Cancers 2021, 13(23), 6001; https://doi.org/10.3390/cancers13236001 - 29 Nov 2021
Cited by 9 | Viewed by 2893
Abstract
Cancer stem-like cells mediate tumor initiation, progression, and therapy resistance; however, their identification and selective eradication remain challenging. Herein, we analyze the metabolic dependencies of glioblastoma stem-like cells (GSCs) with high-resolution proton nuclear magnetic resonance (1H-NMR) spectroscopy. We stratify our in [...] Read more.
Cancer stem-like cells mediate tumor initiation, progression, and therapy resistance; however, their identification and selective eradication remain challenging. Herein, we analyze the metabolic dependencies of glioblastoma stem-like cells (GSCs) with high-resolution proton nuclear magnetic resonance (1H-NMR) spectroscopy. We stratify our in vitro GSC models into two subtypes primarily based on their relative amount of glutamine in relationship to glutamate (Gln/Glu). Gln/GluHigh GSCs were found to be resistant to glutamine deprivation, whereas Gln/GluLow GSCs respond with significantly decreased in vitro clonogenicity and impaired cell growth. The starvation resistance appeared to be mediated by an increased expression of the glutamate/cystine antiporter SLC7A11/xCT and efficient cellular clearance of reactive oxygen species (ROS). Moreover, we were able to directly correlate xCT-dependent starvation resistance and high Gln/Glu ratios with in vitro clonogenicity, since targeted differentiation of GSCs with bone morphogenic protein 4 (BMP4) impaired xCT expression, decreased the Gln/Glu ratio, and restored the sensitivity to glutamine starvation. Moreover, significantly reduced levels of the oncometabolites lactate (Lac), phosphocholine (PC), total choline (tCho), myo-inositol (Myo-I), and glycine (Gly) were observed in differentiated GSCs. Furthermore, we found a strong association between high Gln/Glu ratios and increased expression of Zinc finger E-box-binding homeobox 1 (ZEB1) and xCT in primary GBM tumor tissues. Our analyses suggest that the inhibition of xCT represents a potential therapeutic target in glioblastoma; thus, we could further extend its importance in GSC biology and stress responses. We also propose that monitoring of the intracellular Gln/Glu ratio can be used to predict nutrient stress resistance. Full article
(This article belongs to the Special Issue Metabolic Reprogramming of Cancer Stem Cells (CSCs) and the Role of Tumor Microenvironment—Mechanisms and Therapeutic Opportunities)
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Review

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22 pages, 962 KiB  
Review
The Emerging Role of Tumor Microenvironmental Stimuli in Regulating Metabolic Rewiring of Liver Cancer Stem Cells
by Margherita Correnti, Eleonora Binatti, Elena Gammella, Pietro Invernizzi and Stefania Recalcati
Cancers 2023, 15(1), 5; https://doi.org/10.3390/cancers15010005 - 20 Dec 2022
Cited by 5 | Viewed by 1986
Abstract
Primary liver cancer (PLC) is one of the most devastating cancers worldwide. Extensive phenotypical and functional heterogeneity is a cardinal hallmark of cancer, including PLC, and is related to the cancer stem cell (CSC) concept. CSCs are responsible for tumor growth, progression, relapse [...] Read more.
Primary liver cancer (PLC) is one of the most devastating cancers worldwide. Extensive phenotypical and functional heterogeneity is a cardinal hallmark of cancer, including PLC, and is related to the cancer stem cell (CSC) concept. CSCs are responsible for tumor growth, progression, relapse and resistance to conventional therapies. Metabolic reprogramming represents an emerging hallmark of cancer. Cancer cells, including CSCs, are very plastic and possess the dynamic ability to constantly shift between different metabolic states depending on various intrinsic and extrinsic stimuli, therefore amplifying the complexity of understanding tumor heterogeneity. Besides the well-known Warburg effect, several other metabolic pathways including lipids and iron metabolism are altered in PLC. An increasing number of studies supports the role of the surrounding tumor microenvironment (TME) in the metabolic control of liver CSCs. In this review, we discuss the complex metabolic rewiring affecting liver cancer cells and, in particular, liver CSCs. Moreover, we highlight the role of TME cellular and noncellular components in regulating liver CSC metabolic plasticity. Deciphering the specific mechanisms regulating liver CSC–TME metabolic interplay could be very helpful with respect to the development of more effective and innovative combinatorial therapies for PLC treatment. Full article
(This article belongs to the Special Issue Metabolic Reprogramming of Cancer Stem Cells (CSCs) and the Role of Tumor Microenvironment—Mechanisms and Therapeutic Opportunities)
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24 pages, 1886 KiB  
Review
Regulation of Metabolic Plasticity in Cancer Stem Cells and Implications in Cancer Therapy
by Styliani Papadaki and Angeliki Magklara
Cancers 2022, 14(23), 5912; https://doi.org/10.3390/cancers14235912 - 30 Nov 2022
Cited by 12 | Viewed by 2902
Abstract
Cancer stem cells (CSCs), a subpopulation of tumor cells with self-renewal capacity, have been associated with tumor initiation, progression, and therapy resistance. While the bulk of tumor cells mainly use glycolysis for energy production, CSCs have gained attention for their ability to switch [...] Read more.
Cancer stem cells (CSCs), a subpopulation of tumor cells with self-renewal capacity, have been associated with tumor initiation, progression, and therapy resistance. While the bulk of tumor cells mainly use glycolysis for energy production, CSCs have gained attention for their ability to switch between glycolysis and oxidative phosphorylation, depending on their energy needs and stimuli from their microenvironment. This metabolic plasticity is mediated by signaling pathways that are also implicated in the regulation of CSC properties, such as the Wnt/β-catenin, Notch, and Hippo networks. Two other stemness-associated processes, autophagy and hypoxia, seem to play a role in the metabolic switching of CSCs as well. Importantly, accumulating evidence has linked the metabolic plasticity of CSCs to their increased resistance to treatment. In this review, we summarize the metabolic signatures of CSCs and the pathways that regulate them; we especially highlight research data that demonstrate the metabolic adaptability of these cells and their role in stemness and therapy resistance. As the development of drug resistance is a major challenge for successful cancer treatment, the potential of specific elimination of CSCs through targeting their metabolism is of great interest and it is particularly examined. Full article
(This article belongs to the Special Issue Metabolic Reprogramming of Cancer Stem Cells (CSCs) and the Role of Tumor Microenvironment—Mechanisms and Therapeutic Opportunities)
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14 pages, 1132 KiB  
Review
Metabolic Plasticity of Cancer Stem Cells in Response to Microenvironmental Cues
by Yunong Xie, Stephanie Ma and Man Tong
Cancers 2022, 14(21), 5345; https://doi.org/10.3390/cancers14215345 - 29 Oct 2022
Cited by 8 | Viewed by 2068
Abstract
An increasing body of evidence suggests that cancer stem cells (CSCs) utilize reprogrammed metabolic strategies to adapt to a hostile tumor microenvironment (TME) for survival and stemness maintenance. Such a metabolic alteration in CSCs is facilitated by microenvironmental cues including metabolites such as [...] Read more.
An increasing body of evidence suggests that cancer stem cells (CSCs) utilize reprogrammed metabolic strategies to adapt to a hostile tumor microenvironment (TME) for survival and stemness maintenance. Such a metabolic alteration in CSCs is facilitated by microenvironmental cues including metabolites such as glucose, amino acids and lipids, and environmental properties such as hypoxic and acidic TME. Similarly, metabolites uptake from the diet exerts critical imprints to the metabolism profile of CSCs and directly influence the maintenance of the CSC population. Moreover, CSCs interact with tumor-infiltrating cells inside the CSC niche to promote cancer stemness, ultimately contributing to tumor development and progression. Understanding the underlying mechanisms of how CSCs employ metabolic plasticity in response to different microenvironmental cues represents a therapeutic opportunity for better cancer treatment. Full article
(This article belongs to the Special Issue Metabolic Reprogramming of Cancer Stem Cells (CSCs) and the Role of Tumor Microenvironment—Mechanisms and Therapeutic Opportunities)
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