Special Issue "Advances in Cancer Stem Cell Research"

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

Deadline for manuscript submissions: closed (31 January 2019)

Special Issue Editor

Guest Editor
Prof. Dr. Masaharu Seno

Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan
Website | E-Mail
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 papers will be 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 monthly 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 1800 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 (15 papers)

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Research

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Open AccessArticle 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
Cancers 2019, 11(4), 541; https://doi.org/10.3390/cancers11040541
Received: 1 March 2019 / Revised: 8 April 2019 / Accepted: 12 April 2019 / Published: 15 April 2019
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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)
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Open AccessArticle Identification of Cancer Stem Cell Molecular Markers and Effects of hsa-miR-21-3p on Stemness in Esophageal Squamous Cell Carcinoma
Cancers 2019, 11(4), 518; https://doi.org/10.3390/cancers11040518
Received: 11 March 2019 / Revised: 1 April 2019 / Accepted: 8 April 2019 / Published: 11 April 2019
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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)
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Open AccessArticle A Novel ALDH1A1 Inhibitor Targets Cells with Stem Cell Characteristics in Ovarian Cancer
Cancers 2019, 11(4), 502; https://doi.org/10.3390/cancers11040502
Received: 8 February 2019 / Revised: 30 March 2019 / Accepted: 3 April 2019 / Published: 8 April 2019
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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)
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Open AccessArticle SERPINB2 Is a Novel Indicator of Cancer Stem Cell Tumorigenicity in Multiple Cancer Types
Cancers 2019, 11(4), 499; https://doi.org/10.3390/cancers11040499
Received: 19 February 2019 / Revised: 2 April 2019 / Accepted: 3 April 2019 / Published: 8 April 2019
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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 [...] 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)
Open AccessArticle The Stem Cell Phenotype of Aggressive Breast Cancer Cells
Cancers 2019, 11(3), 340; https://doi.org/10.3390/cancers11030340
Received: 23 January 2019 / Revised: 25 February 2019 / Accepted: 4 March 2019 / Published: 8 March 2019
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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)
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Open AccessArticle The Cancer Stem Cell Inhibitor Napabucasin (BBI608) Shows General Cytotoxicity in Biliary Tract Cancer Cells and Reduces Cancer Stem Cell Characteristics
Cancers 2019, 11(3), 276; https://doi.org/10.3390/cancers11030276
Received: 25 January 2019 / Revised: 14 February 2019 / Accepted: 18 February 2019 / Published: 26 February 2019
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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)
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Open AccessArticle A Novel Combination Cancer Therapy with Iron Chelator Targeting Cancer Stem Cells via Suppressing Stemness
Cancers 2019, 11(2), 177; https://doi.org/10.3390/cancers11020177
Received: 24 December 2018 / Revised: 28 January 2019 / Accepted: 31 January 2019 / Published: 3 February 2019
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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)
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Open AccessArticle The Dilemma of Cure and Damage in Oligodendroglioma: Ways to Tip the Balance Away from the Damage
Cancers 2018, 10(11), 431; https://doi.org/10.3390/cancers10110431
Received: 9 October 2018 / Revised: 2 November 2018 / Accepted: 9 November 2018 / Published: 12 November 2018
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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)
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Review

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Open AccessFeature PaperReview Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy
Cancers 2019, 11(4), 538; https://doi.org/10.3390/cancers11040538
Received: 19 March 2019 / Revised: 4 April 2019 / Accepted: 9 April 2019 / Published: 15 April 2019
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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)
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Open AccessReview The Evolving Landscape of Cancer Stem Cells and Ways to Overcome Cancer Heterogeneity
Cancers 2019, 11(4), 532; https://doi.org/10.3390/cancers11040532
Received: 19 January 2019 / Revised: 2 April 2019 / Accepted: 4 April 2019 / Published: 14 April 2019
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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)
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Open AccessReview Heterogeneity in Circulating Tumor Cells: The Relevance of the Stem-Cell Subset
Cancers 2019, 11(4), 483; https://doi.org/10.3390/cancers11040483
Received: 1 February 2019 / Revised: 16 March 2019 / Accepted: 30 March 2019 / Published: 5 April 2019
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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)
Open AccessReview Pathological and Molecular Features of Glioblastoma and Its Peritumoral Tissue
Cancers 2019, 11(4), 469; https://doi.org/10.3390/cancers11040469
Received: 5 February 2019 / Revised: 19 March 2019 / Accepted: 26 March 2019 / Published: 3 April 2019
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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)
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Open AccessReview The Contributions of Prostate Cancer Stem Cells in Prostate Cancer Initiation and Metastasis
Cancers 2019, 11(4), 434; https://doi.org/10.3390/cancers11040434
Received: 29 January 2019 / Revised: 15 March 2019 / Accepted: 21 March 2019 / Published: 27 March 2019
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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)
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Open AccessFeature PaperReview Conversion of Stem Cells to Cancer Stem Cells: Undercurrent of Cancer Initiation
Cancers 2019, 11(3), 345; https://doi.org/10.3390/cancers11030345
Received: 31 January 2019 / Revised: 2 March 2019 / Accepted: 6 March 2019 / Published: 11 March 2019
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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)
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Open AccessReview Recent Advances in Cancer Stem Cell-Targeted Immunotherapy
Cancers 2019, 11(3), 310; https://doi.org/10.3390/cancers11030310
Received: 28 January 2019 / Revised: 22 February 2019 / Accepted: 1 March 2019 / Published: 5 March 2019
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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)
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