Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
7.4
5.2
Journals
Cancers
Special Issues
Advances in Cancer Stem Cell Research
share announcement

Advances in Cancer Stem Cell Research

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 January 2019) | Viewed by 122114

Special Issue Editor

Prof. Dr. Masaharu Seno

E-Mail Website
Guest Editor
Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan
Interests: cancer stem cells; tumor microenvironment; angiogenesis; cancer biology; growth factors and cytokines; drug delivery systems; targeting cancer; liposomes; drug screening; self-organizing map

Special Issue Information

Dear Colleagues,

Although cancer stem cells (CSCs) and their significant importance have frequently been described during the last decade, they have not been sufficiently analyzed, mainly due to the small population in cancer tissues and the difference depending on patients.

To date, CSCs are believed responsible for intratumoral heterogeneity due to plasticity, which should be controlled by epigenetic and genetic changes.

The effects on the changes are described as the tumor microenvironment. The induction of CSCs from normal cells is yet unknown, but suspected to be triggered by chronic condition such as inflammation, which would provide the microenvironment for the development of CSCs. In fact, Wnt/β-Catenin and TGF-β/Smad signaling pathways are thought to crosstalk with the NF-κB signaling pathway. Hedgehog and Notch signaling pathways are also considered to be involved in inflammatory sequences.

On the other hand, these signaling pathways are again considered significant to maintain CSCs in tumor tissues composing the niche. The factors involved in the niche might be traced to hypoxia, Nodal/Cripto-1 and the metabolome specific to CSCs. Investigation of the niche will reveal new CSC markers, which will be the good targets to treat CSCs.

The ecosystem of tumors surrounded by the cancer associated fibroblasts, macrophages, and adipocytes should be closely linked with the epithelial–mesenchymal transition, angiogenesis and so on.

This Special Issue will highlight the recent advances of the biology of cancer stem cells and their niche related significant events.

Prof. Dr. Masaharu Seno
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 heterogeneity
  • self-renewal
  • microenvironment
  • plasticity, epigenetics
  • epithelial–mesenchymal transition

Published Papers (19 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review

24 pages, 12539 KiB  
Article
Serial Xenotransplantation in NSG Mice Promotes a Hybrid Epithelial/Mesenchymal Gene Expression Signature and Stemness in Rhabdomyosarcoma Cells
by Jan Skoda, Jakub Neradil, Iva Staniczkova Zambo, Alena Nunukova, Peter Macsek, Karolina Borankova, Viera Dobrotkova, Pavel Nemec, Jaroslav Sterba and Renata Veselska
Cancers 2020, 12(1), 196; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010196 - 13 Jan 2020
Cited by 5 | Viewed by 4392
Abstract
Serial xenotransplantation of sorted cancer cells in immunodeficient mice remains the most complex test of cancer stem cell (CSC) phenotype. However, we have demonstrated in various sarcomas that putative CSC surface markers fail to identify CSCs, thereby impeding the isolation of CSCs for [...] Read more.
Serial xenotransplantation of sorted cancer cells in immunodeficient mice remains the most complex test of cancer stem cell (CSC) phenotype. However, we have demonstrated in various sarcomas that putative CSC surface markers fail to identify CSCs, thereby impeding the isolation of CSCs for subsequent analyses. Here, we utilized serial xenotransplantation of unsorted rhabdomyosarcoma cells in NOD/SCID gamma (NSG) mice as a proof-of-principle platform to investigate the molecular signature of CSCs. Indeed, serial xenotransplantation steadily enriched for rhabdomyosarcoma stem-like cells characterized by enhanced aldehyde dehydrogenase activity and increased colony and sphere formation capacity in vitro. Although the expression of core pluripotency factors (SOX2, OCT4, NANOG) and common CSC markers (CD133, ABCG2, nestin) was maintained over the passages in mice, gene expression profiling revealed gradual changes in several stemness regulators and genes linked with undifferentiated myogenic precursors, e.g., SOX4, PAX3, MIR145, and CDH15. Moreover, we identified the induction of a hybrid epithelial/mesenchymal gene expression signature that was associated with the increase in CSC number. In total, 60 genes related to epithelial or mesenchymal traits were significantly altered upon serial xenotransplantation. In silico survival analysis based on the identified potential stemness-associated genes demonstrated that serial xenotransplantation of unsorted rhabdomyosarcoma cells in NSG mice might be a useful tool for the unbiased enrichment of CSCs and the identification of novel CSC-specific targets. Using this approach, we provide evidence for a recently proposed link between the hybrid epithelial/mesenchymal phenotype and cancer stemness. Full article
(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)
►▼ Show Figures

Graphical abstract

17 pages, 11401 KiB  
Article
F-Box/WD Repeat Domain-Containing 7 Induces Chemotherapy Resistance in Colorectal Cancer Stem Cells
by Shusaku Honma, Shigeo Hisamori, Aya Nishiuchi, Yoshiro Itatani, Kazutaka Obama, Yohei Shimono and Yoshiharu Sakai
Cancers 2019, 11(5), 635; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11050635 - 07 May 2019
Cited by 6 | Viewed by 3190
Abstract
Although the cancer stem cell (CSC) concept has provided a reasonable explanation for cancer recurrence following chemotherapy, the relationship between CSCs and chemotherapy resistance has not been thoroughly investigated, especially in solid tumors. We aimed to identify the mechanism underlying colorectal cancer (CRC) [...] Read more.
Although the cancer stem cell (CSC) concept has provided a reasonable explanation for cancer recurrence following chemotherapy, the relationship between CSCs and chemotherapy resistance has not been thoroughly investigated, especially in solid tumors. We aimed to identify the mechanism underlying colorectal cancer (CRC) chemoresistance focusing on the cell cycle mediator F-Box/WD repeat domain-containing 7 (FBXW7). From 55 consecutive CRC cases who underwent neoadjuvant chemotherapy (NAC) or neoadjuvant chemoradiotherapy (NACRT) at Kyoto University Hospital, pre-treatment endoscopic biopsy specimens were collected and divided into two groups upon immunohistochemical (IHC) analysis: 21 cases of FBXW7 high expression (FBXW7-high group) and 34 cases of low expression (FBXW7-low group). High FBXW7 expression in pre-treatment biopsy specimen was significantly associated with poor pathological therapeutic effect (p = 0.019). The proportion of FBXW7-positive cells in surgically resected CRC specimens from patients who underwent NAC or NACRT was significantly higher than that in the pre-treatment biopsy specimens (p < 0.001). The expression of FBXW7 was inversely correlated with that of Ki67 in both pre-treatment biopsy specimens and surgically resected specimens. FBXW7 expression in the EpCAMhigh/CD44high subpopulation isolated by flow cytometry from CRC samples was significantly higher than that in the EpCAMhigh/CD44low subpopulation. Cell-cycle analysis in CRC cell lines revealed that, upon FBXW7 silencing, the proportion of G0/G1 cells was significantly lower than that in control cells. Moreover, knockdown of FBXW7 in CRC cell lines increased the sensitivity to anti-cancer drugs in vitro and in vivo. A subset of CRC stem cells possesses chemoresistance through FBXW7 expression. Cell cycle arrest induced by FBXW7 expression should be considered as a potential therapeutic target to overcome chemoresistance in CRC stem cell subsets. Full article
(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)
►▼ Show Figures

Figure 1

17 pages, 2798 KiB  
Article
Orthotopic Patient-Derived Xenografts of Gastric Cancer to Decipher Drugs Effects on Cancer Stem Cells and Metastatic Dissemination
by Julie Giraud, Damien Bouriez, Lornella Seeneevassen, Benoit Rousseau, Elodie Sifré, Alban Giese, Francis Mégraud, Philippe Lehours, Pierre Dubus, Caroline Gronnier and Christine Varon
Cancers 2019, 11(4), 560; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11040560 - 19 Apr 2019
Cited by 11 | Viewed by 5295
Abstract
Gastric cancer is the third leading cause of cancer mortality worldwide. Cancer stem cells (CSC) are at the origin of tumor initiation, chemoresistance, and the formation of metastases. However, there is a lack of mouse models enabling the study of the metastatic process [...] Read more.
Gastric cancer is the third leading cause of cancer mortality worldwide. Cancer stem cells (CSC) are at the origin of tumor initiation, chemoresistance, and the formation of metastases. However, there is a lack of mouse models enabling the study of the metastatic process in gastric adenocarcinoma (GC). The aims of this study were to develop original mouse models of patient-derived primary GC orthotopic xenografts (PDOX) allowing the development of distant metastases as preclinical models to study the anti-metastatic efficiency of drugs such as the phosphatidylinositol 3-kinase (PI3K) inhibitor Buparlisib (BKM120). Luciferase-encoding cells generated from primary GC were injected into the stomach wall of immunocompromised mice; gastric tumor and metastases development were followed by bioluminescence imaging. The anti-CSC properties of BKM120 were evaluated on the GC cells’ phenotype (CD44 expression) and tumorigenic properties in vitro and in vivo on BKM120-treated mice. After eight weeks, PDOX mice formed tumors in the stomach as well as distant metastases, that were enriched in CSC, in the liver, the lung, and the peritoneal cavity. BKM120 treatment significantly inhibited the CSC properties in vitro and reduced the number of distant metastases in mice. These new preclinical models offer the opportunity to study the anti-metastatic efficiency of new CSC-based therapeutic strategies. Full article
(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)
►▼ Show Figures

Figure 1

15 pages, 11283 KiB  
Article
Low CD8+ T Cell Infiltration and High PD-L1 Expression Are Associated with Level of CD44+/CD133+ Cancer Stem Cells and Predict an Unfavorable Prognosis in Pancreatic Cancer
by Ya-Chin Hou, Ying-Jui Chao, Min-Hua Hsieh, Hui-Ling Tung, Hao-Chen Wang and Yan-Shen Shan
Cancers 2019, 11(4), 541; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11040541 - 15 Apr 2019
Cited by 76 | Viewed by 6355
Abstract
Cancer immunotherapy targeting immune checkpoints has exhibited promising clinical outcomes in many cancers, but it offers only limited benefits for pancreatic cancer (PC). Cancer stem cells (CSCs), a minor subpopulation of cancer cells, play important roles in tumor initiation, progression, and drug resistance. [...] Read more.
Cancer immunotherapy targeting immune checkpoints has exhibited promising clinical outcomes in many cancers, but it offers only limited benefits for pancreatic cancer (PC). Cancer stem cells (CSCs), a minor subpopulation of cancer cells, play important roles in tumor initiation, progression, and drug resistance. Accumulating evidence suggests that CSCs employ immunosuppressive effects to evade immune system recognition. However, the clinical implications of the associations among CD8+ T cells infiltration, programmed death receptor ligand-1 (PD-L1) expression, and CSCs existence are poorly understood in PC. Immunostaining and quantitative analysis were performed to assess CD8+ T cells infiltration, PD-L1 expression, and their relationship with CD44+/CD133+ CSCs and disease progression in PC. CD8+ T cells infiltration was associated with better survival while PD-L1 expression was correlated with PC recurrence. Both the low CD8+ T cells infiltration/high PD-L1 expression group and the high CD8+ T cells infiltration/high PD-L1 expression group show high levels of CD44+/CD133+ CSCs, but patients with low CD8+ T cells infiltration/high PD-L1 expression had worse survival and higher recurrence risk than those with high CD8+ T cells infiltration/high PD-L1 expression. Moreover, high infiltration of CD8+ T cells could reduce unfavorable prognostic effect of high co-expression of PD-L1 and CD44/CD133. Our study highlights an interaction among CD8+ T cells infiltration, PD-L1 expression, and CD44+/CD133+ CSCs existence, which contributes to PC progression and immune evasion. Full article
(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)
►▼ Show Figures

Figure 1

19 pages, 46691 KiB  
Article
Identification of Cancer Stem Cell Molecular Markers and Effects of hsa-miR-21-3p on Stemness in Esophageal Squamous Cell Carcinoma
by Zhikui Gao, Hui Liu, Yajuan Shi, Lihong Yin, Yong Zhu and Ran Liu
Cancers 2019, 11(4), 518; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11040518 - 11 Apr 2019
Cited by 24 | Viewed by 4012
Abstract
Cancer stem cells (CSCs) are closely related to tumor resistance and tumor recurrence in esophageal squamous cell carcinoma (ESCC). The lack of specific biomarkers to identify and isolate CSCs has led to the slow progression of research on CSCs in ESCC. Here, we [...] Read more.
Cancer stem cells (CSCs) are closely related to tumor resistance and tumor recurrence in esophageal squamous cell carcinoma (ESCC). The lack of specific biomarkers to identify and isolate CSCs has led to the slow progression of research on CSCs in ESCC. Here, we established a method to identify and isolate CSCs in ESCC using fluorescence-activated cell sorting with combined surface biomarkers including CD71, CD271, and CD338. CD71−/CD271+/CD338+ subpopulation cells possessed more stem cell properties in proliferation, self-renewal, differentiation, metastasis, drug resistance, and tumorigenesis. We further explored possible roles that microRNAs played in stem cells. Using microarrays, we identified that has-miR-21-3p was highly expressed in positive sorted cells, and further functional and Luciferase reporter assays verified that has-miR-21-3p promoted proliferation and anti-apoptosis by regulating TRAF4. We further analyzed the relationship between hsa-miR-21-3p and ESCC in 137 patients with ESCC. Statistical analysis showed that up-regulation of hsa-miR-21-3p was associated with a high risk of ESCC. Collectively, we identified surface biomarkers of stem cells in esophageal squamous cell carcinoma, and discovered thathsa-miR-21-3p may be involved in stemness maintenance by regulating TRAF4. Full article
(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)
►▼ Show Figures

Figure 1

19 pages, 2957 KiB  
Article
A Novel ALDH1A1 Inhibitor Targets Cells with Stem Cell Characteristics in Ovarian Cancer
by Nkechiyere G. Nwani, Salvatore Condello, Yinu Wang, Wendy M. Swetzig, Emma Barber, Thomas Hurley and Daniela Matei
Cancers 2019, 11(4), 502; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11040502 - 08 Apr 2019
Cited by 46 | Viewed by 6280
Abstract
A small of population of slow cycling and chemo-resistant cells referred to as cancer stem cells (CSC) have been implicated in cancer recurrence. There is emerging interest in developing targeted therapeutics to eradicate CSCs. Aldehyde-dehydrogenase (ALDH) activity was shown to be a functional [...] Read more.
A small of population of slow cycling and chemo-resistant cells referred to as cancer stem cells (CSC) have been implicated in cancer recurrence. There is emerging interest in developing targeted therapeutics to eradicate CSCs. Aldehyde-dehydrogenase (ALDH) activity was shown to be a functional marker of CSCs in ovarian cancer (OC). ALDH activity is increased in cells grown as spheres versus monolayer cultures under differentiating conditions and in OC cells after treatment with platinum. Here, we describe the activity of CM37, a newly identified small molecule with inhibitory activity against ALDH1A1, in OC models enriched in CSCs. Treatment with CM37 reduced OC cells’ proliferation as spheroids under low attachment growth conditions and the expression of stemness-associated markers (OCT4 and SOX2) in ALDH+ cells fluorescence-activated cell sorting (FACS)-sorted from cell lines and malignant OC ascites. Likewise, siRNA-mediated ALDH1A1 knockdown reduced OC cells’ proliferation as spheres, expression of stemness markers, and delayed tumor initiation capacity in vivo. Treatment with CM37 promoted DNA damage in OC cells, as evidenced by induction of γH2AX. This corresponded to increased expression of genes involved in DNA damage response, such as NEIL3, as measured in ALDH+ cells treated with CM37 or in cells where ALDH1A1 was knocked down. By inhibiting ALDH1A1, CM37 augmented intracellular ROS accumulation, which in turn led to increased DNA damage and reduced OC cell viability. Cumulatively, our findings demonstrate that a novel ALDH1A1 small molecule inhibitor is active in OC models enriched in CSCs. Further optimization of this new class of small molecules could provide a novel strategy for targeting treatment-resistant OC. Full article
(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)
►▼ Show Figures

Figure 1

19 pages, 35568 KiB  
Article
SERPINB2 Is a Novel Indicator of Cancer Stem Cell Tumorigenicity in Multiple Cancer Types
by Na-Hee Lee, Se-Ra Park, Jin Woo Lee, Soyi Lim, Seung-Ho Lee, Seungyoon Nam, Dong Young Kim, Seung Yeon Hah, In-Sun Hong and Hwa-Yong Lee
Cancers 2019, 11(4), 499; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11040499 - 08 Apr 2019
Cited by 21 | Viewed by 4312
Abstract
Drug resistance is one of the major characteristics of cancer stem cells (CSCs) and a mechanism of tumor recurrence. Therefore, selectively targeting CSCs may be an effective therapeutic strategy to overcome cancer recurrence. In the present study, we found that exposure to tumorigenic [...] Read more.
Drug resistance is one of the major characteristics of cancer stem cells (CSCs) and a mechanism of tumor recurrence. Therefore, selectively targeting CSCs may be an effective therapeutic strategy to overcome cancer recurrence. In the present study, we found that exposure to tumorigenic compounds significantly increased the growth potential and stem-cell-like properties of various CSCs. Early-response genes involved in tumorigenesis can be used as specific markers to predict potential tumorigenicity. Importantly, for the first time we identified, a labile tumorigenic response gene—SERPINB2—and showed that tumorigenic compound exposure more profoundly affected its expression in CSCs than in non-stem cancer cells, although both cells exhibit basal expression of SERPINB2 in multiple cancer types. Our data also revealed a strong relationship between the significantly enhanced expression of SERPINB2 and metastatic progression in multiple cancer types. To the best of our knowledge, this is the first study to focus on the functions of SERPINB2 in the tumorigenicity of various CSCs and these findings will facilitate the development of promising tumorigenicity test platforms. Full article
(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)
►▼ Show Figures

Figure 1

11 pages, 4092 KiB  
Article
The Stem Cell Phenotype of Aggressive Breast Cancer Cells
by Naira V. Margaryan, Hannah Hazard-Jenkins, Mohamad A. Salkeni, Matthew B. Smolkin, James A. Coad, Sijin Wen, Elisabeth A. Seftor, Richard E. B. Seftor and Mary J. C. Hendrix
Cancers 2019, 11(3), 340; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11030340 - 08 Mar 2019
Cited by 10 | Viewed by 3798
Abstract
Aggressive cancer cells are characterized by their capacity to proliferate indefinitely and to propagate a heterogeneous tumor comprised of subpopulations with varying degrees of metastatic propensity and drug resistance properties. Particularly daunting is the challenge we face in the field of oncology of [...] Read more.
Aggressive cancer cells are characterized by their capacity to proliferate indefinitely and to propagate a heterogeneous tumor comprised of subpopulations with varying degrees of metastatic propensity and drug resistance properties. Particularly daunting is the challenge we face in the field of oncology of effectively targeting heterogeneous tumor cells expressing a variety of markers, especially those associated with a stem cell phenotype. This dilemma is especially relevant in breast cancer, where therapy is based on traditional classification schemes, including histological criteria, differentiation status, and classical receptor markers. However, not all patients respond in a similar manner to standard-of-care therapy, thereby necessitating the need to identify and evaluate novel biomarkers associated with the difficult-to-target stem cell phenotype and drug resistance. Findings related to the convergence of embryonic and tumorigenic signaling pathways have identified the embryonic morphogen Nodal as a promising new oncofetal target that is reactivated only in aggressive cancers, but not in normal tissues. The work presented in this paper confirms previous studies demonstrating the importance of Nodal as a cancer stem cell molecule associated with aggressive breast cancer, and advances the field by providing new findings showing that Nodal is not targeted by standard-of-care therapy in breast cancer patients. Most noteworthy is the linkage found between Nodal expression and the drug resistance marker ATP-binding cassette member 1 (ABCA1), which may provide new insights into developing combinatorial approaches to overcome drug resistance and disease recurrence. Full article
(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)
►▼ Show Figures

Figure 1

16 pages, 2969 KiB  
Article
The Cancer Stem Cell Inhibitor Napabucasin (BBI608) Shows General Cytotoxicity in Biliary Tract Cancer Cells and Reduces Cancer Stem Cell Characteristics
by Marlena Beyreis, Martin Gaisberger, Martin Jakab, Daniel Neureiter, Katharina Helm, Markus Ritter, Tobias Kiesslich and Christian Mayr
Cancers 2019, 11(3), 276; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11030276 - 26 Feb 2019
Cited by 19 | Viewed by 4424
Abstract
Biliary tract cancer is a devastating disease with limited therapeutic options. The involvement of cancer stem cells in biliary tract cancer is likely. Napabucasin is a previously described cancer stem cell inhibitor that is currently being used in clinical trials. However, data regarding [...] Read more.
Biliary tract cancer is a devastating disease with limited therapeutic options. The involvement of cancer stem cells in biliary tract cancer is likely. Napabucasin is a previously described cancer stem cell inhibitor that is currently being used in clinical trials. However, data regarding napabucasin and biliary tract cancer are not available yet. We tested the general cytotoxic effect of napabucasin on a comprehensive biliary tract cancer in vitro model, using resazurin assay and Annexin V/7-AAD staining. The effect of napabucasin on functional cancer stem cell characteristics was analyzed via soft agar assay, aldehyde-dehydrogenase-1 assay, measurement of surface CD326 expression, and measurement of clonogenic growth. The evaluation of the effect of napabucasin on cancer stem cell protein and gene expression was performed using Western blot and reverse transcription-PCR-based human cancer stem cell array. Napabucasin showed a concentration- and cell line-dependent cytotoxic effect, and increased the apoptotic and necrotic cell fractions. Treatment with napabucasin significantly reduced the formation of tumor spheres and clonogenic growth, as well as CD326 surface expression. Expression of cancer stem cell markers were reduced following napabucasin treatment on the protein and mRNA levels. Our study provides first data regarding napabucasin as a promising substance for the treatment of biliary tract cancer. Full article
(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)
►▼ Show Figures

Figure 1

16 pages, 4132 KiB  
Article
A Novel Combination Cancer Therapy with Iron Chelator Targeting Cancer Stem Cells via Suppressing Stemness
by Yuki Katsura, Toshiaki Ohara, Kazuhiro Noma, Takayuki Ninomiya, Hajime Kashima, Takuya Kato, Hiroaki Sato, Satoshi Komoto, Toru Narusaka, Yasuko Tomono, Boyi Xing, Yuehua Chen, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Tomonari Kasai, Masaharu Seno, Akihiro Matsukawa and Toshiyoshi Fujiwara
Cancers 2019, 11(2), 177; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11020177 - 03 Feb 2019
Cited by 17 | Viewed by 5147
Abstract
Excess iron causes cancer and is thought to be related to carcinogenesis and cancer progression including stemness, but the details remain unclear. Here, we hypothesized that stemness in cancer is related to iron metabolism and that regulating iron metabolism in cancer stem cells [...] Read more.
Excess iron causes cancer and is thought to be related to carcinogenesis and cancer progression including stemness, but the details remain unclear. Here, we hypothesized that stemness in cancer is related to iron metabolism and that regulating iron metabolism in cancer stem cells (CSCs) may be a novel therapy. In this study, we used murine induced pluripotent stem cells that expressed specific stem cell genes such as Nanog, Oct3/4, Sox2, Klf4, and c-Myc, and two human cancer cell lines with similar stem cell gene expression. Deferasirox, an orally available iron chelator, suppressed expression of stemness markers and spherogenesis of cells with high stemness status in vitro. Combination therapy had a marked antitumor effect compared with deferasirox or cisplatin alone. Iron metabolism appears important for maintenance of stemness in CSCs. An iron chelator combined with chemotherapy may be a novel approach via suppressing stemness for CSC targeted therapy. Full article
(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)
►▼ Show Figures

Figure 1

10 pages, 4701 KiB  
Article
The Dilemma of Cure and Damage in Oligodendroglioma: Ways to Tip the Balance Away from the Damage
by Ruurd Torensma
Cancers 2018, 10(11), 431; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers10110431 - 12 Nov 2018
Cited by 6 | Viewed by 5258
Abstract
Current treatments for oligodendrogliomas are powerful but have a negative impact on the rest of the body. The bone marrow is damaged by the chemotherapeutics, but other parts of the body are also affected. In this paper, the current treatment method and its [...] Read more.
Current treatments for oligodendrogliomas are powerful but have a negative impact on the rest of the body. The bone marrow is damaged by the chemotherapeutics, but other parts of the body are also affected. In this paper, the current treatment method and its collateral damage is described. Therefore, therapies are needed that are more effective against the tumor while having less negative effects on the patient’s quality of life. Some potential therapies include optimal removal of the tumor by fluorescent-guided surgery (FGS), intraoperative desorption electrospray ionization-mass spectrometry (DESI-MS), better monitoring of the effects of therapy by pseudo-coloring shades of gray of MRI pictures, and using recent data from RNA sequencing of single cells and immunotherapy. These are all open new ways of treating this tumor. The RNA sequencing of single tumor cells unravels specific tumor antigens present in the differentiation status of the cancer cell. Stem cell antigens were expressed in dividing cells, while hypoxia inducible factor-α (HIF-1α) is expressed in all tumor cells. Cancer stem cell antigens can be loaded on dendritic cells to induce cytotoxic T-cells directed to cancer stem cells. These recent discoveries suggest a better quality of life with the same overall survival. Full article
(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)
►▼ Show Figures

Graphical abstract

Review

Jump to: Research

18 pages, 921 KiB  
Review
Targeting Cancer Stem Cells: A Strategy for Effective Eradication of Cancer
by Masahiro Shibata and Mohammad Obaidul Hoque
Cancers 2019, 11(5), 732; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11050732 - 27 May 2019
Cited by 119 | Viewed by 9258
Abstract
Cancer stem cells (CSCs) are subpopulations of tumor cells with the ability to self-renew, differentiate, and initiate and maintain tumor growth, and they are considered to be the main drivers of intra- and inter-tumoral heterogeneity. While conventional chemotherapy can eradicate the majority of [...] Read more.
Cancer stem cells (CSCs) are subpopulations of tumor cells with the ability to self-renew, differentiate, and initiate and maintain tumor growth, and they are considered to be the main drivers of intra- and inter-tumoral heterogeneity. While conventional chemotherapy can eradicate the majority of non-CSC tumor cells, CSCs are often drug-resistant, leading to tumor recurrence and metastasis. The heterogeneity of CSCs is the main challenge in developing CSC-targeting therapy; therefore, we and other investigators have focused on developing novel therapeutic strategies that combine conventional chemotherapy with inhibitors of CSC-regulating pathways. Encouraging preclinical findings have suggested that CSC pathway blockade can indeed enhance cellular sensitivity to non-targeted conventional therapy, and this work has led to several ongoing clinical trials of CSC pathway inhibitors. Our studies in bladder cancer and lung adenocarcinoma have demonstrated a crucial role of YAP1, a transcriptional regulator of genes that promote cell survival and proliferation, in regulating CSC phenotypes. Moreover, using cell lines and patient-derived xenograft models, we showed that inhibition of YAP1 enhances the efficacy of conventional therapies by attenuating CSC stemness features. In this review, we summarize the therapeutic strategies for targeting CSCs in several cancers and discuss the potential and challenges of the approach. Full article
(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)
►▼ Show Figures

Figure 1

20 pages, 1185 KiB  
Review
Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy
by Elisabeth Peer, Suzana Tesanovic and Fritz Aberger
Cancers 2019, 11(4), 538; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11040538 - 15 Apr 2019
Cited by 67 | Viewed by 7539
Abstract
The Hedgehog/Glioma-associated oncogene homolog (HH/GLI) signaling pathway regulates self-renewal of rare and highly malignant cancer stem cells (CSC), which have been shown to account for the initiation and maintenance of tumor growth as well as for drug resistance, metastatic spread and relapse. Efficacious [...] Read more.
The Hedgehog/Glioma-associated oncogene homolog (HH/GLI) signaling pathway regulates self-renewal of rare and highly malignant cancer stem cells (CSC), which have been shown to account for the initiation and maintenance of tumor growth as well as for drug resistance, metastatic spread and relapse. Efficacious therapeutic approaches targeting CSC pathways, such as HH/GLI signaling in combination with chemo, radiation or immunotherapy are, therefore, of high medical need. Pharmacological inhibition of HH/GLI pathway activity represents a promising approach to eliminate malignant CSC. Clinically approved HH/GLI pathway inhibitors target the essential pathway effector Smoothened (SMO) with striking therapeutic efficacy in skin and brain cancer patients. However, multiple genetic and molecular mechanisms resulting in de novo and acquired resistance to SMO inhibitors pose major limitations to anti-HH/GLI therapies and, thus, the eradication of CSC. In this review, we summarize reasons for clinical failure of SMO inhibitors, including mechanisms caused by genetic alterations in HH pathway effectors or triggered by additional oncogenic signals activating GLI transcription factors in a noncanonical manner. We then discuss emerging novel and rationale-based approaches to overcome SMO-inhibitor resistance, focusing on pharmacological perturbations of enzymatic modifiers of GLI activity and on compounds either directly targeting oncogenic GLI factors or interfering with synergistic crosstalk signals known to boost the oncogenicity of HH/GLI signaling. Full article
(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)
►▼ Show Figures

Figure 1

16 pages, 895 KiB  
Review
The Evolving Landscape of Cancer Stem Cells and Ways to Overcome Cancer Heterogeneity
by Hiroaki Taniguchi, Yasunori Suzuki and Yukikazu Natori
Cancers 2019, 11(4), 532; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11040532 - 14 Apr 2019
Cited by 14 | Viewed by 3708
Abstract
Cancer stem cells (CSCs) with therapeutic resistance and plasticity can be found in various types of tumors and are recognized as attractive targets for treatments. As CSCs are derived from tissue stem or progenitor cells, and/or dedifferentiated mature cells, their signal transduction pathways [...] Read more.
Cancer stem cells (CSCs) with therapeutic resistance and plasticity can be found in various types of tumors and are recognized as attractive targets for treatments. As CSCs are derived from tissue stem or progenitor cells, and/or dedifferentiated mature cells, their signal transduction pathways are critical in the regulation of CSCs; chronic inflammation causes the accumulation of genetic mutations and aberrant epigenetic changes in these cells, potentially leading to the production of CSCs. However, the nature of CSCs appears to be stronger than the treatments of the past. To improve the treatments targeting CSCs, it is important to inhibit several molecules on the signaling cascades in CSCs simultaneously, and to overcome cancer heterogeneity caused by the plasticity. To select suitable target molecules for CSCs, we have to explore the landscape of CSCs from the perspective of cancer stemness and signaling systems, based on the curated databases of cancer-related genes. We have been studying the integration of a broad range of knowledge and experiences from cancer biology, and also from other interdisciplinary basic sciences. In this review, we have introduced the concept of developing novel strategies targeting CSCs. Full article
(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)
►▼ Show Figures

Figure 1

36 pages, 392 KiB  
Review
Heterogeneity in Circulating Tumor Cells: The Relevance of the Stem-Cell Subset
by Chiara Agnoletto, Fabio Corrà, Linda Minotti, Federica Baldassari, Francesca Crudele, William Joseph James Cook, Gianpiero Di Leva, Adamo Pio d’Adamo, Paolo Gasparini and Stefano Volinia
Cancers 2019, 11(4), 483; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11040483 - 05 Apr 2019
Cited by 107 | Viewed by 6191
Abstract
The release of circulating tumor cells (CTCs) into vasculature is an early event in the metastatic process. The analysis of CTCs in patients has recently received widespread attention because of its clinical implications, particularly for precision medicine. Accumulated evidence documents a large heterogeneity [...] Read more.
The release of circulating tumor cells (CTCs) into vasculature is an early event in the metastatic process. The analysis of CTCs in patients has recently received widespread attention because of its clinical implications, particularly for precision medicine. Accumulated evidence documents a large heterogeneity in CTCs across patients. Currently, the most accepted view is that tumor cells with an intermediate phenotype between epithelial and mesenchymal have the highest plasticity. Indeed, the existence of a meta-stable or partial epithelial–mesenchymal transition (EMT) cell state, with both epithelial and mesenchymal features, can be easily reconciled with the concept of a highly plastic stem-like state. A close connection between EMT and cancer stem cells (CSC) traits, with enhanced metastatic competence and drug resistance, has also been described. Accordingly, a subset of CTCs consisting of CSC, present a stemness profile, are able to survive chemotherapy, and generate metastases after xenotransplantation in immunodeficient mice. In the present review, we discuss the current evidence connecting CTCs, EMT, and stemness. An improved understanding of the CTC/EMT/CSC connections may uncover novel therapeutic targets, irrespective of the tumor type, since most cancers seem to harbor a pool of CSCs, and disclose important mechanisms underlying tumorigenicity. Full article
(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)
19 pages, 676 KiB  
Review
Pathological and Molecular Features of Glioblastoma and Its Peritumoral Tissue
by Alessio D’Alessio, Gabriella Proietti, Gigliola Sica and Bianca Maria Scicchitano
Cancers 2019, 11(4), 469; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11040469 - 03 Apr 2019
Cited by 157 | Viewed by 11710
Abstract
Glioblastoma (GBM) is one of the most aggressive and lethal human brain tumors. At present, GBMs are divided in primary and secondary on the basis of the mutational status of the isocitrate dehydrogenase (IDH) genes. In addition, IDH1 and IDH2 mutations [...] Read more.
Glioblastoma (GBM) is one of the most aggressive and lethal human brain tumors. At present, GBMs are divided in primary and secondary on the basis of the mutational status of the isocitrate dehydrogenase (IDH) genes. In addition, IDH1 and IDH2 mutations are considered crucial to better define the prognosis. Although primary and secondary GBMs are histologically indistinguishable, they retain distinct genetic alterations that account for different evolution of the tumor. The high invasiveness, the propensity to disperse throughout the brain parenchyma, and the elevated vascularity make these tumors extremely recidivist, resulting in a short patient median survival even after surgical resection and chemoradiotherapy. Furthermore, GBM is considered an immunologically cold tumor. Several studies highlight a highly immunosuppressive tumor microenvironment that promotes recurrence and poor prognosis. Deeper insight into the tumor immune microenvironment, together with the recent discovery of a conventional lymphatic system in the central nervous system (CNS), led to new immunotherapeutic strategies. In the last two decades, experimental evidence from different groups proved the existence of cancer stem cells (CSCs), also known as tumor-initiating cells, that may play an active role in tumor development and progression. Recent findings also indicated the presence of highly infiltrative CSCs in the peritumoral region of GBM. This region appears to play a key role in tumor growing and recurrence. However, until recently, few studies investigated the biomolecular characteristics of the peritumoral tissue. The aim of this review is to recapitulate the pathological features of GBM and of the peritumoral region associated with progression and recurrence. Full article
(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)
►▼ Show Figures

Figure 1

22 pages, 1286 KiB  
Review
The Contributions of Prostate Cancer Stem Cells in Prostate Cancer Initiation and Metastasis
by Wenjuan Mei, Xiaozeng Lin, Anil Kapoor, Yan Gu, Kuncheng Zhao and Damu Tang
Cancers 2019, 11(4), 434; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11040434 - 27 Mar 2019
Cited by 68 | Viewed by 6331
Abstract
Research in the last decade has clearly revealed a critical role of prostate cancer stem cells (PCSCs) in prostate cancer (PC). Prostate stem cells (PSCs) reside in both basal and luminal layers, and are the target cells of oncogenic transformation, suggesting a role [...] Read more.
Research in the last decade has clearly revealed a critical role of prostate cancer stem cells (PCSCs) in prostate cancer (PC). Prostate stem cells (PSCs) reside in both basal and luminal layers, and are the target cells of oncogenic transformation, suggesting a role of PCSCs in PC initiation. Mutations in PTEN, TP53, and RB1 commonly occur in PC, particularly in metastasis and castration-resistant PC. The loss of PTEN together with Ras activation induces partial epithelial–mesenchymal transition (EMT), which is a major mechanism that confers plasticity to cancer stem cells (CSCs) and PCSCs, which contributes to metastasis. While PTEN inactivation leads to PC, it is not sufficient for metastasis, the loss of PTEN concurrently with the inactivation of both TP53 and RB1 empower lineage plasticity in PC cells, which substantially promotes PC metastasis and the conversion to PC adenocarcinoma to neuroendocrine PC (NEPC), demonstrating the essential function of TP53 and RB1 in the suppression of PCSCs. TP53 and RB1 suppress lineage plasticity through the inhibition of SOX2 expression. In this review, we will discuss the current evidence supporting a major role of PCSCs in PC initiation and metastasis, as well as the underlying mechanisms regulating PCSCs. These discussions will be developed along with the cancer stem cell (CSC) knowledge in other cancer types. Full article
(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)
►▼ Show Figures

Figure 1

19 pages, 5894 KiB  
Review
Conversion of Stem Cells to Cancer Stem Cells: Undercurrent of Cancer Initiation
by Said M. Afify and Masaharu Seno
Cancers 2019, 11(3), 345; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11030345 - 11 Mar 2019
Cited by 124 | Viewed by 16445
Abstract
Cancer stem cells (CSCs) also known as cancer-initiating cells (CIC), are responsible for the sustained and uncontrolled growth of malignant tumors and are proposed to play significant roles in metastasis and recurrence. Several hypotheses have proposed that the events in either stem and/or [...] Read more.
Cancer stem cells (CSCs) also known as cancer-initiating cells (CIC), are responsible for the sustained and uncontrolled growth of malignant tumors and are proposed to play significant roles in metastasis and recurrence. Several hypotheses have proposed that the events in either stem and/or differentiated cells, such as genomic instability, inflammatory microenvironment, cell fusion, and lateral gene transfer, should be considered as the possible origin of CSCs. However, until now, the exact origin of CSC has been obscure. The development of induced pluripotent stem cells (iPSCs) in 2007, by Yamanaka’s group, has been met with much fervency and hailed as a breakthrough discovery by the scientific and research communities, especially in regeneration therapy. The studies on the development of CSC from iPSCs should also open a new page of cancer research, which will help in designing new therapies applicable to CSCs. Currently most reviews have focused on CSCs and CSC niches. However, the insight into the niche before the CSC niche should also be of keen interest. This review introduces the novel concept of cancer initiation introducing the conversion of iPSCs to CSCs and proposes a relationship between the inflammatory microenvironment and cancer initiation as the key concept of the cancer-inducing niche responsible for the development of CSC. Full article
(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)
►▼ Show Figures

Figure 1

14 pages, 1201 KiB  
Review
Recent Advances in Cancer Stem Cell-Targeted Immunotherapy
by Narayanasamy Badrinath and So Young Yoo
Cancers 2019, 11(3), 310; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11030310 - 05 Mar 2019
Cited by 54 | Viewed by 7169
Abstract
Cancer stem cells (CSCs) are one of the reasons for the relapse of cancer cells and metastasis. They have drug resistance against most chemotherapeutic agents. CSCs are also responsible for tumor cell heterogeneity and cause minimal residual disease. In order to achieve complete [...] Read more.
Cancer stem cells (CSCs) are one of the reasons for the relapse of cancer cells and metastasis. They have drug resistance against most chemotherapeutic agents. CSCs are also responsible for tumor cell heterogeneity and cause minimal residual disease. In order to achieve complete regression of tumors, CSCs have to be targeted. Recent advances in immunotherapies have shown promising outcomes in curing cancer, which are also applicable to target CSCs. CSCs express immune markers and exhibit specific immune characteristics in various cancers, which can be used in immunotherapies to target CSCs in the tumor microenvironment. Recently, various strategies have been used to target CSCs. Adaptive T-cells, dendritic cell (DC)-based vaccines, oncolytic viruses, immune checkpoint inhibitors, and combination therapies are now being used to target CSCs. Here, we discuss the feasibility of these immunological approaches and the recent trends in immunotherapies to target CSCs. Full article
(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-19
Back to TopTop