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Gene Expression and Molecular Profiling of Human Cancer Stem Cells

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Informatics and Big Data".

Deadline for manuscript submissions: closed (15 January 2021) | Viewed by 37236

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Dr. Shihori Tanabe

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Division of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences, Kawasaki 210-9501, Japan
Interests: molecular network in diseases; signaling pathway in cancer; molecular mechanism in cancer therapy; therapeutic response in cancer
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Dear Colleagues,

Gene expression is altered in various conditions of diseases. Cancer stem cells (CSCs) are targets for cancer therapeutics, since CSCs may have the potential to confer drug resistance and the metastatic feature to cancer. CSCs exhibit various gene expressions and molecular alterations which contribute to the cell phenotype transition, such as epithelial–mesenchymal transition (EMT), drug resistance in which the transporters play an important role, and signal transduction, which is important for metastasis. Gene expression and molecular profiling of human CSCs, as well as other types of the feature of CSCs, is mainly focused on in this Special Issue.

Furthermore, molecular networks are also altered in CSCs, which may be linked to the cancer characteristics. The cross-talk and linkage of the molecular networks in CSCs are of importance to understand the overall picture of the cancer and related diseases. The signaling transduction both intra- and intercells may play important roles in the development of CSCs and cancer. The emergence and maintenance, as well as the plasticity and migration, of CSCs are also in the scope of this Special Issue. To reveal the mechanism of CSCs, the investigation in gene expression and molecular profiling, and the regulation of molecular networks is essential.

Dr. Shihori Tanabe
Guest Editor

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Keywords

gene expression
cancer stem cell
molecular profiling

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Published Papers (8 papers)

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Research

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22 pages, 13913 KiB

Open AccessArticle

Nanopore Sequencing Reveals Global Transcriptome Signatures of Mitochondrial and Ribosomal Gene Expressions in Various Human Cancer Stem-like Cell Populations

by Kaya E. Witte, Oliver Hertel, Beatrice A. Windmöller, Laureen P. Helweg, Anna L. Höving, Cornelius Knabbe, Tobias Busche, Johannes F. W. Greiner, Jörn Kalinowski, Thomas Noll, Fritz Mertzlufft, Morris Beshay, Jesco Pfitzenmaier, Barbara Kaltschmidt, Christian Kaltschmidt, Constanze Banz-Jansen and Matthias Simon

Cancers 2021, 13(5), 1136; https://doi.org/10.3390/cancers13051136 - 6 Mar 2021

Cited by 17 | Viewed by 4552

Abstract

Cancer stem cells (CSCs) are crucial mediators of tumor growth, metastasis, therapy resistance, and recurrence in a broad variety of human cancers. Although their biology is increasingly investigated within the distinct types of cancer, direct comparisons of CSCs from different tumor types allowing comprehensive mechanistic insights are rarely assessed. In the present study, we isolated CSCs from endometrioid carcinomas, glioblastoma multiforme as well as adenocarcinomas of lung and prostate and assessed their global transcriptomes using full-length cDNA nanopore sequencing. Despite the expression of common CSC markers, principal component analysis showed a distinct separation of the CSC populations into three clusters independent of the specific type of tumor. However, GO-term and KEGG pathway enrichment analysis revealed upregulated genes related to ribosomal biosynthesis, the mitochondrion, oxidative phosphorylation, and glycolytic pathways, as well as the proteasome, suggesting a great extent of metabolic flexibility in CSCs. Interestingly, the GO term “NF-kB binding” was likewise found to be elevated in all investigated CSC populations. In summary, we here provide evidence for high global transcriptional similarities between CSCs from various tumors, which particularly share upregulated gene expression associated with mitochondrial and ribosomal activity. Our findings may build the basis for identifying novel therapeutic strategies targeting CSCs. Full article

(This article belongs to the Special Issue Gene Expression and Molecular Profiling of Human Cancer Stem Cells)

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18 pages, 3521 KiB

Open AccessArticle

The Claudin-Low Subtype of High-Grade Serous Ovarian Carcinoma Exhibits Stem Cell Features

by Chiara Romani, Davide Capoferri, Elisabetta Grillo, Marco Silvestri, Michela Corsini, Laura Zanotti, Paola Todeschini, Antonella Ravaggi, Eliana Bignotti, Franco Odicino, Enrico Sartori, Stefano Calza and Stefania Mitola

Cancers 2021, 13(4), 906; https://doi.org/10.3390/cancers13040906 - 22 Feb 2021

Cited by 7 | Viewed by 3453

Abstract

Claudin-low cancer (CL) represents a rare and biologically aggressive variant of epithelial tumor. Here, we identified a claudin-low molecular profile of ovarian high-grade serous carcinoma (HGSOC), which exhibits the main characteristics of the homonym breast cancer subtype, including low epithelial differentiation and high mesenchymal signature. Hierarchical clustering and a centroid based algorithm applied to cell line collection expression dataset labeled 6 HGSOC cell lines as CL. These have a high energy metabolism and are enriched in CD44⁺/CD24⁻ mesenchymal stem-like cells expressing low levels of cell-cell adhesion molecules (claudins and E-Cadherin) and high levels of epithelial-to-mesenchymal transition (EMT) induction transcription factors (Zeb1, Snai2, Twist1 and Twist2). Accordingly, the centroid base algorithm applied to large retrospective collections of primary HGSOC samples reveals a tumor subgroup with transcriptional features consistent with the CL profile, and reaffirms EMT as the dominant biological pathway functioning in CL-HGSOC. HGSOC patients carrying CL profiles have a worse overall survival when compared to others, likely to be attributed to its undifferentiated/stem component. These observations highlight the lack of a molecular diagnostic in the management of HGSOC and suggest a potential prognostic utility of this molecular subtyping. Full article

(This article belongs to the Special Issue Gene Expression and Molecular Profiling of Human Cancer Stem Cells)

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21 pages, 7341 KiB

Open AccessArticle

Molecular Network Profiling in Intestinal- and Diffuse-Type Gastric Cancer

by Shihori Tanabe, Sabina Quader, Ryuichi Ono, Horacio Cabral, Kazuhiko Aoyagi, Akihiko Hirose, Hiroshi Yokozaki and Hiroki Sasaki

Cancers 2020, 12(12), 3833; https://doi.org/10.3390/cancers12123833 - 18 Dec 2020

Cited by 22 | Viewed by 4742

Abstract

Epithelial-mesenchymal transition (EMT) plays an important role in the acquisition of cancer stem cell (CSC) feature and drug resistance, which are the main hallmarks of cancer malignancy. Although previous findings have shown that several signaling pathways are activated in cancer progression, the precise mechanism of signaling pathways in EMT and CSCs are not fully understood. In this study, we focused on the intestinal and diffuse-type gastric cancer (GC) and analyzed the gene expression of public RNAseq data to understand the molecular pathway regulation in different subtypes of gastric cancer. Network pathway analysis was performed by Ingenuity Pathway Analysis (IPA). A total of 2815 probe set IDs were significantly different between intestinal- and diffuse-type GC data in cBioPortal Cancer Genomics. Our analysis uncovered 10 genes including male-specific lethal 3 homolog (Drosophila) pseudogene 1 (MSL3P1), CDC28 protein kinase regulatory subunit 1B (CKS1B), DEAD-box helicase 27 (DDX27), golgi to ER traffic protein 4 (GET4), chromosome segregation 1 like (CSE1L), translocase of outer mitochondrial membrane 34 (TOMM34), YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), ribonucleic acid export 1 (RAE1), par-6 family cell polarity regulator beta (PARD6B), and MRG domain binding protein (MRGBP), which have differences in gene expression between intestinal- and diffuse-type GC. A total of 463 direct relationships with three molecules (MYC, NTRK1, UBE2M) were found in the biomarker-filtered network generated by network pathway analysis. The networks and features in intestinal- and diffuse-type GC have been investigated and profiled in bioinformatics. Our results revealed the signaling pathway networks in intestinal- and diffuse-type GC, bringing new light for the elucidation of drug resistance mechanisms in CSCs. Full article

(This article belongs to the Special Issue Gene Expression and Molecular Profiling of Human Cancer Stem Cells)

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27 pages, 3967 KiB

Open AccessArticle

Metabolic Plasticity in Ovarian Cancer Stem Cells

by Alia Ghoneum, Daniela Gonzalez, Ammar Yasser Abdulfattah and Neveen Said

Cancers 2020, 12(5), 1267; https://doi.org/10.3390/cancers12051267 - 17 May 2020

Cited by 25 | Viewed by 4677

Abstract

Ovarian Cancer is the fifth most common cancer in females and remains the most lethal gynecological malignancy as most patients are diagnosed at late stages of the disease. Despite initial responses to therapy, recurrence of chemo-resistant disease is common. The presence of residual cancer stem cells (CSCs) with the unique ability to adapt to several metabolic and signaling pathways represents a major challenge in developing novel targeted therapies. The objective of this study is to investigate the transcripts of putative ovarian cancer stem cell (OCSC) markers in correlation with transcripts of receptors, transporters, and enzymes of the energy generating metabolic pathways involved in high grade serous ovarian cancer (HGSOC). We conducted correlative analysis in data downloaded from The Cancer Genome Atlas (TCGA), studies of experimental OCSCs and their parental lines from Gene Expression Omnibus (GEO), and Cancer Cell Line Encyclopedia (CCLE). We found positive correlations between the transcripts of OCSC markers, specifically CD44, and glycolytic markers. TCGA datasets revealed that NOTCH1, CD133, CD44, CD24, and ALDH1A1, positively and significantly correlated with tricarboxylic acid cycle (TCA) enzymes. OVCAR3-OCSCs (cancer stem cells derived from a well-established epithelial ovarian cancer cell line) exhibited enrichment of the electron transport chain (ETC) mainly in complexes I, III, IV, and V, further supporting reliance on the oxidative phosphorylation (OXPHOS) phenotype. OVCAR3-OCSCs also exhibited significant increase in CD36, ACACA, SCD, and CPT1A, with CD44, CD133, and ALDH1A1 exhibiting positive correlations with lipid metabolic enzymes. TCGA data show positive correlations between OCSC markers and glutamine metabolism enzymes, whereas in OCSC experimental models of GSE64999, GSE28799, and CCLE, the number of positive and negative correlations observed was significantly lower and was different between model systems. Appropriate integration and validation of data model systems with those in patients’ specimens is needed not only to bridge our knowledge gap of metabolic programing of OCSCs, but also in designing novel strategies to target the metabolic plasticity of dormant, resistant, and CSCs. Full article

(This article belongs to the Special Issue Gene Expression and Molecular Profiling of Human Cancer Stem Cells)

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9 pages, 1065 KiB

Open AccessArticle

The Prognostic and Predictive Value of SOX2⁺ Cell Densities in Patients Treated for Colorectal Cancer

by Tim J. Miller, Melanie J. McCoy, Tracey F. Lee-Pullen, Chidozie C. Anyaegbu, Christine Hemmings, Max K. Bulsara and Cameron F. Platell

Cancers 2020, 12(5), 1110; https://doi.org/10.3390/cancers12051110 - 29 Apr 2020

Cited by 7 | Viewed by 3031

Abstract

SOX2 (sex-determining region-Y homeobox-2) is a transcription factor essential for the maintenance of pluripotency and is also associated with stem-cell-like properties in preclinical cancer models. Our previous study on a cohort of stage III colon cancer patients demonstrated high SOX2⁺ cell densities were associated with poor prognosis. However, most patients were treated with adjuvant chemotherapy so the prognostic value of SOX2 could not be assessed independently from its value as a predictive marker for non-response to chemotherapy. This study aimed to assess whether SOX2 was a true prognostic marker or a marker for chemotherapy response in a historical cohort of patients, a high proportion of whom were chemotherapy-naïve. SOX2 immunostaining was performed on tissue micro-arrays containing tumor cores from 797 patients with stage II and III colorectal cancer. SOX2⁺ cell densities were then quantified with StrataQuest digital image analysis software. Overall survival was assessed using Kaplan–Meier estimates and Cox regression. It was found that high SOX2⁺ cell densities were not associated with poor overall survival. Furthermore, all patients had a significant improvement in survival after 5-fluorouracil (5-FU) treatment, irrespective of their SOX2⁺ cell density. Therefore, SOX2⁺ cell densities were not associated with prognosis or chemotherapy benefit in this study. This is in contrast to our previous study, in which most patients received oxaliplatin as part of their treatment, in addition to 5-FU. This suggests SOX2 may predict response to oxaliplatin treatment, but not 5-FU. Full article

(This article belongs to the Special Issue Gene Expression and Molecular Profiling of Human Cancer Stem Cells)

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22 pages, 9521 KiB

Open AccessArticle

Knockdown of UTX/KDM6A Enriches Precursor Cell Populations in Urothelial Cell Cultures and Cell Lines

by Alexander Lang, Patcharawalai Whongsiri, Merve Yilmaz, Tobias Lautwein, Patrick Petzsch, Annemarie Greife, Cagatay Günes, Karl Köhrer, Günter Niegisch, Michèle Hoffmann and Wolfgang A. Schulz

Cancers 2020, 12(4), 1023; https://doi.org/10.3390/cancers12041023 - 21 Apr 2020

Cited by 7 | Viewed by 4324

Abstract

The histone demethylase UTX (gene: KDM6A) directs cell and tissue differentiation during development. Deleterious mutations in KDM6A occur in many human cancers, most frequently in urothelial carcinoma. The consequences of these mutations are poorly understood; plausibly, they may disturb urothelial differentiation. We therefore investigated the effects of UTX siRNA-mediated knockdown in two in vitro models of urothelial differentiation; namely, primary cultures of urothelial epithelial cells treated with troglitazone and PD153035 and the immortalized urothelial cell line HBLAK treated with high calcium and serum. In both models, efficient UTX knockdown did not block morphological and biochemical differentiation. An apparent delay was due to a cytotoxic effect on the cell cultures before the initiation of differentiation, which induced apoptosis partly in a p53-dependent manner. As a consequence, slowly cycling, smaller, KRT14^high precursor cells in the HBLAK cell line were enriched at the expense of more differentiated, larger, proliferating KRT14^low cells. UTX knockdown induced apoptosis and enriched KRT14^high cells in the BFTC-905 papillary urothelial carcinoma cell line as well. Our findings suggest an explanation for the frequent occurrence of KDM6A mutations across all stages and molecular subtypes of urothelial carcinoma, whereby loss of UTX function does not primarily impede later stages of urothelial differentiation, but favors the expansion of precursor populations to provide a reservoir of potential tumor-initiating cells. Full article

(This article belongs to the Special Issue Gene Expression and Molecular Profiling of Human Cancer Stem Cells)

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18 pages, 2939 KiB

Open AccessArticle

Ex Vivo Organoid Cultures Reveal the Importance of the Tumor Microenvironment for Maintenance of Colorectal Cancer Stem Cells

by Xingru Li, Pär Larsson, Ingrid Ljuslinder, Daniel Öhlund, Robin Myte, Anna Löfgren-Burström, Carl Zingmark, Agnes Ling, Sofia Edin and Richard Palmqvist

Cancers 2020, 12(4), 923; https://doi.org/10.3390/cancers12040923 - 10 Apr 2020

Cited by 46 | Viewed by 6481

Abstract

Colorectal cancer (CRC) is a heterogeneous disease, with varying clinical presentations and patient prognosis. Different molecular subgroups of CRC should be treated differently and therefore, must be better characterized. Organoid culture has recently been suggested as a good model to reflect the heterogeneous nature of CRC. However, organoid cultures cannot be established from all CRC tumors. The study examines which CRC tumors are more likely to generate organoids and thus benefit from ex vivo organoid drug testing. Long-term organoid cultures from 22 out of 40 CRC tumor specimens were established. It was found that organoid cultures were more difficult to establish from tumors characterized as microsatellite instable (MSI), BRAF-mutated, poorly differentiated and/or of a mucinous type. This suggests that patients with such tumors are less likely to benefit from ex vivo organoid drug testing, but it may also suggest biological difference in tumor growth. RNA sequencing analysis of tumor sections revealed that the in vivo maintenance of these non-organoid-forming tumors depends on factors related to inflammation and pathogen exposure. Furthermore, using TCGA data we could show a trend towards a worse prognosis for patients with organoid-forming tumors, suggesting also clinical differences. Results suggest that organoids are more difficult to establish from tumors characterized as MSI, BRAF-mutated, poorly differentiated and/or of a mucinous type. We further suggest that the maintenance of cell growth of these tumors in vivo may be promoted by immune-related factors and other stromal components within the tumor microenvironment. Full article

(This article belongs to the Special Issue Gene Expression and Molecular Profiling of Human Cancer Stem Cells)

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Review

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28 pages, 1437 KiB

Open AccessReview

Cancer Stem Cells Are Possible Key Players in Regulating Anti-Tumor Immune Responses: The Role of Immunomodulating Molecules and MicroRNAs

by Sara Tomei, Ola Ibnaof, Shilpa Ravindran, Soldano Ferrone and Cristina Maccalli

Cancers 2021, 13(7), 1674; https://doi.org/10.3390/cancers13071674 - 2 Apr 2021

Cited by 9 | Viewed by 4523

Abstract

Cancer cells endowed with stemness properties and representing a rare population of cells within malignant lesions have been isolated from tumors with different histological origins. These cells, denominated as cancer stem cells (CSCs) or cancer initiating cells (CICs), are responsible for tumor initiation, progression and resistance to therapies, including immunotherapy. The dynamic crosstalk of CSCs/CICs with the tumor microenvironment orchestrates their fate and plasticity as well as their immunogenicity. CSCs/CICs, as observed in multiple studies, display either the aberrant expression of immunomodulatory molecules or suboptimal levels of molecules involved in antigen processing and presentation, leading to immune evasion. MicroRNAs (miRNAs) that can regulate either stemness properties or their immunological profile, with in some cases dual functions, can provide insights into these mechanisms and possible interventions to develop novel therapeutic strategies targeting CSCs/CICs and reverting their immunogenicity. In this review, we provide an overview of the immunoregulatory features of CSCs/CICs including miRNA profiles involved in the regulation of the interplay between stemness and immunological properties. Full article

(This article belongs to the Special Issue Gene Expression and Molecular Profiling of Human Cancer Stem Cells)

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