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Signalling Pathways of Cancer Stem Cells

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 16618

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Special Issue Editor

Dr. Moorthy P. Ponnusamy

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Guest Editor

Assistant Professor, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198-5870, USA
Interests: cancer stem cells

Special Issue Information

Dear Colleagues,

Cancer cells with stem-like properties, known as cancer stem cells (CSCs), are responsible for tumor initiation, drug resistance, metastasis of several cancers. CSCs differentiate into self-renewing cells and differentiated cells that make up the entire bulk of the tumor. This Special Issue of Cancers is dedicated to Signaling Pathways of Cancer Stem Cells. Although several studies focused on the specific markers of cancer stem cells, the mechanism of maintenance and target of cancer stem cells is poorly understood. To further improve the understanding of cancer stem cell maintenance and target, we have to focus on specific signaling involved in cancer stem cell maintenance. We expect submissions for this endeavor from researchers, molecular pathologists, and oncologists who can better understand cancer stem cells in different cancers.

Dr. Moorthy P. Ponnusamy
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. 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.

Keywords

cancer stem cells
self-renewal
drug-resistance
metastasis
asymmetric division
origin of cancer stem cells
metabolomic reprograming of cancer stem cells
de-differentiation of cancer stem cells
cancer stem cell markers
phenotype of cancer stem cells
mutation in cancer stem cells

Published Papers (7 papers)

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Research

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17 pages, 2801 KiB

Open AccessArticle

Histidine Enhances the Anticancer Effect of Gemcitabine against Pancreatic Cancer via Disruption of Amino Acid Homeostasis and Oxidant—Antioxidant Balance

by Narendra Kumar, Satyanarayana Rachagani, Gopalakrishnan Natarajan, Alexandra Crook, Thiyagarajan Gopal, Vinothkumar Rajamanickam, Jyoti B. Kaushal, Sirpu N. Nagabhishek, Robert Powers, Surinder K. Batra and Viswanathan Saraswathi

Cancers 2023, 15(9), 2593; https://doi.org/10.3390/cancers15092593 - 03 May 2023

Cited by 1 | Viewed by 2445

Abstract

Due to the severe toxicity posed by chemotherapeutic drugs, adjuvant nutritional intervention has gained increased attention in the treatment of pancreatic cancer (PC). Amino acid (AA) metabolism is aberrantly regulated in PC and circulating histidine (His) levels are low in PC patients. We hypothesized that His uptake and/or metabolism is dysregulated in PC and that combining His with gemcitabine (Gem), a drug used in the treatment of PC, will enhance the anti-cancer effects of Gem. We performed in vitro and in vivo studies to determine the anticancer effect of the combination of His and Gem against lethal PC. We demonstrate that circulating His levels are low in both human subjects and genetically engineered mice exhibiting pancreatic tumors. Interestingly, the expression of histidine ammonia lyase, an enzyme involved in His catabolism, is higher in PC compared to normal subjects. His + Gem exerts a more potent cytotoxic effect in PC cells compared to individual treatments. His treatment results in a profound increase in His accumulation, accompanied by a depletion of a number of AAs, promoting cancer cell survival and/or glutathione (GSH) synthesis. His but not Gem increases hydrogen peroxide and depletes cellular GSH. Supplementation with GSH protects cells against His + Gem-induced cytotoxicity. Further, our in vivo studies demonstrate that His + Gem potently reduced tumor mass and improved mouse survival. Taken together, our data suggest that PC cells exhibit an aberrant His uptake/accumulation which, in turn, leads to oxidative stress and depletion of AA pool, thereby enhancing the anticancer effect of Gem. Full article

(This article belongs to the Special Issue Signalling Pathways of Cancer Stem Cells)

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0 pages, 2433 KiB

Open AccessArticle

A Signaling Crosstalk Links SNAIL to the 37/67 kDa Laminin-1 Receptor Ribosomal Protein SA and Regulates the Acquisition of a Cancer Stem Cell Molecular Signature in U87 Glioblastoma Neurospheres

by Loraine Gresseau, Marie-Eve Roy, Stéphanie Duhamel and Borhane Annabi

Cancers 2022, 14(23), 5944; https://doi.org/10.3390/cancers14235944 - 30 Nov 2022

Cited by 5 | Viewed by 1502 | Correction

Abstract

Background: Three-dimensional in vitro neurospheres cultures recapitulate stemness features associated with poor clinical outcome in glioblastoma patients. They are commonly used to address brain cancer stem cell (CSC) signal transducing biology that regulates spheroids formation and stemness phenotype, and to assess the in vitro pharmacological impact of chemotherapeutic drugs. Objective: Here, we addressed the role of a new signaling axis involved in the regulation of in vitro spheroids formation and assessed the chemopreventive ability of diet-derived epigallocatechin gallate (EGCG) to impact the processes that govern the acquisition of spheroids CSC stemness traits. Methods: Neurospheres were generated from adherent human U87 glioblastoma cancer cell cultures under conditions that recapitulate stemness features. Total RNA and protein lysates were isolated for gene expression by RT-qPCR and protein expression by immunoblot. Transcriptomic analysis was performed through RNA-Seq. Results: Compared to their parental adherent cells, tumorspheres expressed increased levels of the CSC markers NANOG, SOX2, PROM1 (CD133), as well as of the epithelial-to-mesenchymal transition (EMT) markers Fibronectin, SNAI1, and 37/67 kDa laminin-1 receptor ribosomal protein SA (RPSA). Increased PROM1, SOX2, Fibronectin, and RPSA transcripts level were also observed in clinical grade IV glioblastoma tissues compared to normal tissue. EGCG treatment reduced dose-dependently tumorspheres size and inhibited the transcriptional regulation of those genes. An apoptotic signature was also found in spheroids with increased signal transducing events involving GSK3α/β, RSK, and CREB. These were repressed upon RPSA gene silencing and partially by SNAI1 silencing. Conclusion: This work highlights a signaling axis linking RPSA upstream of SNAIL in neurospheres genesis and supports the chemopreventive impact that diet-derived EGCG may exert on the acquisition of CSC traits. Full article

(This article belongs to the Special Issue Signalling Pathways of Cancer Stem Cells)

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17 pages, 1713 KiB

Open AccessArticle

Inhibiting ALK2/ALK3 Signaling to Differentiate and Chemo-Sensitize Medulloblastoma

by Doria Filipponi, Marina Pagnuzzi-Boncompagni and Gilles Pagès

Cancers 2022, 14(9), 2095; https://doi.org/10.3390/cancers14092095 - 22 Apr 2022

Cited by 2 | Viewed by 2212

Abstract

Background: Medulloblastoma (MB) is a malignant pediatric brain tumor, and it represents the leading cause of death related to cancer in childhood. New perspectives for therapeutic development have emerged with the identification of cancer stem cells (CSCs) displaying tumor initiating capability and chemoresistance. However, the mechanisms responsible for CSCs maintenance are poorly understood. The lack of a universal marker signature represents the main constraints to identify and isolate CSCs within the tumor. Methods: To identify signaling pathways promoting CSC maintenance in MB, we combined tumorsphere assays with targeted neurogenesis PCR pathway arrays. Results: We showed a consistent induction of signaling pathways regulating pluripotency of CSCs in all the screened MB cells. BMP4 signaling was consistently enriched in all tumorsphere(s) independently of their specific stem-cell marker profile. The octamer-binding transcription factor 4 (OCT4), an important regulator of embryonic pluripotency, enhanced CSC maintenance in MBs by inducing the BMP4 signaling pathway. Consistently, inhibition of BMP4 signaling with LDN-193189 reduced stem-cell traits and promoted cell differentiation. Conclusions: Our work suggests that interfering with the BMP4 signaling pathway impaired the maintenance of the CSC pool by promoting cell differentiation. Hence, differentiation therapy might represent an innovative therapeutic to improve the current standard of care in MB patients. Full article

(This article belongs to the Special Issue Signalling Pathways of Cancer Stem Cells)

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16 pages, 14033 KiB

Open AccessEditor’s ChoiceArticle

Biglycan Promotes Cancer Stem Cell Properties, NFκB Signaling and Metastatic Potential in Breast Cancer Cells

by Kanakaraju Manupati, Ritama Paul, Mingang Hao, Michael Haas, Zhaoqun Christine Bian, Tammy M. Holm, Jun-Lin Guan and Syn Kok Yeo

Cancers 2022, 14(2), 455; https://doi.org/10.3390/cancers14020455 - 17 Jan 2022

Cited by 8 | Viewed by 2959

Abstract

It is a major challenge to treat metastasis due to the presence of heterogenous BCSCs. Therefore, it is important to identify new molecular targets and their underlying molecular mechanisms in various BCSCs to improve treatment of breast cancer metastasis. Here, we performed RNA sequencing on two distinct co-existing BCSC populations, ALDH⁺ and CD29^hi CD61⁺ from PyMT mammary tumor cells and detected upregulation of biglycan (BGN) in these BCSCs. Genetic depletion of BGN reduced BCSC proportions and tumorsphere formation. Furthermore, BCSC associated aggressive traits such as migration and invasion were significantly reduced by depletion of BGN. Glycolytic and mitochondrial metabolic assays also revealed that BCSCs exhibited decreased metabolism upon loss of BGN. BCSCs showed decreased activation of the NFκB transcription factor, p65, and phospho-IκB levels upon BGN ablation, indicating regulation of NFκB pathway by BGN. To further support our data, we also characterized CD24⁻/CD44⁺ BCSCs from human luminal MCF-7 breast cancer cells. These CD24⁻/CD44⁺ BCSCs similarly exhibited reduced tumorigenic phenotypes, metabolism and attenuation of NFκB pathway after knockdown of BGN. Finally, loss of BGN in ALDH⁺ and CD29^hi CD61⁺ BCSCs showed decreased metastatic potential, suggesting BGN serves as an important therapeutic target in BCSCs for treating metastasis of breast cancer. Full article

(This article belongs to the Special Issue Signalling Pathways of Cancer Stem Cells)

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Review

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19 pages, 1507 KiB

Open AccessReview

The Expanding Role of Cancer Stem Cell Marker ALDH1A3 in Cancer and Beyond

by Meghan E. McLean, Maya R. MacLean, Hannah F. Cahill, Raj Pranap Arun, Olivia L. Walker, Marie-Claire D. Wasson, Wasundara Fernando, Jaganathan Venkatesh and Paola Marcato

Cancers 2023, 15(2), 492; https://doi.org/10.3390/cancers15020492 - 13 Jan 2023

Cited by 7 | Viewed by 3219

Abstract

Aldehyde dehydrogenase 1A3 (ALDH1A3) is one of 19 ALDH enzymes expressed in humans, and it is critical in the production of hormone receptor ligand retinoic acid (RA). We review the role of ALDH1A3 in normal physiology, its identification as a cancer stem cell marker, and its modes of action in cancer and other diseases. ALDH1A3 is often over-expressed in cancer and promotes tumor growth, metastasis, and chemoresistance by altering gene expression, cell signaling pathways, and glycometabolism. The increased levels of ALDH1A3 in cancer occur due to genetic amplification, epigenetic modifications, post-transcriptional regulation, and post-translational modification. Finally, we review the potential of targeting ALDH1A3, with both general ALDH inhibitors and small molecules specifically designed to inhibit ALDH1A3 activity. Full article

(This article belongs to the Special Issue Signalling Pathways of Cancer Stem Cells)

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27 pages, 1155 KiB

Open AccessReview

At the Intersection of Cardiology and Oncology: TGFβ as a Clinically Translatable Therapy for TNBC Treatment and as a Major Regulator of Post-Chemotherapy Cardiomyopathy

by Andrew Sulaiman, Jason Chambers, Sai Charan Chilumula, Vishak Vinod, Rohith Kandunuri, Sarah McGarry and Sung Kim

Cancers 2022, 14(6), 1577; https://doi.org/10.3390/cancers14061577 - 19 Mar 2022

Cited by 1 | Viewed by 2762

Abstract

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that accounts for the majority of breast cancer-related deaths due to the lack of specific targets for effective treatments. While there is immense focus on the development of novel therapies for TNBC treatment, a persistent and critical issue is the rate of heart failure and cardiomyopathy, which is a leading cause of mortality and morbidity amongst cancer survivors. In this review, we highlight mechanisms of post-chemotherapeutic cardiotoxicity exposure, evaluate how this is assessed clinically and highlight the transforming growth factor-beta family (TGF-β) pathway and its significance as a mediator of cardiomyopathy. We also highlight recent findings demonstrating TGF-β inhibition as a potent method to prevent cardiac remodeling, fibrosis and cardiomyopathy. We describe how dysregulation of the TGF-β pathway is associated with negative patient outcomes across 32 types of cancer, including TNBC. We then highlight how TGF-β modulation may be a potent method to target mesenchymal (CD44⁺/CD24⁻) and epithelial (ALDH^high) cancer stem cell (CSC) populations in TNBC models. CSCs are associated with tumorigenesis, metastasis, relapse, resistance and diminished patient prognosis; however, due to plasticity and differential regulation, these populations remain difficult to target and continue to present a major barrier to successful therapy. TGF-β inhibition represents an intersection of two fields: cardiology and oncology. Through the inhibition of cardiomyopathy, cardiac damage and heart failure may be prevented, and through CSC targeting, patient prognoses may be improved. Together, both approaches, if successfully implemented, would target the two greatest causes of cancer-related morbidity in patients and potentially lead to a breakthrough therapy. Full article

(This article belongs to the Special Issue Signalling Pathways of Cancer Stem Cells)

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