Special Issue "Stem Cells and Cancer Therapeutics"

A special issue of Biomedicines (ISSN 2227-9059).

Deadline for manuscript submissions: closed (30 September 2018)

Special Issue Editors

Guest Editor
Dr. Anna Vert

Stem Cells and Cancer Research Laboratory, CIBERONC. Institut Hospital del Mar Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain
Website | E-Mail
Interests: patient-derived tumoroids; therapy resistance; intestinal cancer; drug discovery
Guest Editor
Dr. Lluis Espinosa

Stem Cells and Cancer Research Laboratory, CIBERONC. Institut Hospital del Mar Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain
Website | E-Mail
Interests: signaling pathways; NF-kappaB; Notch; intestinal stem cells; colorectal cancer

Special Issue Information

Dear Colleagues,

Stems cells are defined as cells with the ability to self-renew and to differentiate into multiple lineages. This definition applies to both physiologic and pathologic conditions such as cancer, although functional differences in these cell populations crucially impact on their behavior. In the case of cancer, multiple experimental evidences support the existence of specific cell populations that are functionally identified for their capacity to initiate and propagate tumors. These cells have been classically called tumor initiating cells (TICs) or cancer stem cells (CSCs) and are supposed to possess stem cell-like properties, including long-term self-renewal, capacity of multi-lineage differentiation, increased resistance to therapy, and the ability to promote tumor relapse and metastasis. As in normal stem cells, essential developmental related pathways such as Wnt, Notch, Hedgehog, NF-kappaB, or JAK/STAT participate in supporting TIC capacity. This special issue will focus on understanding the molecular mechanisms that control normal and cancer-related stemness and the tools that are currently available for studying them both in vitro and in vivo. In particular, we will pay attention in how TICs contribute to cancer progression and therapy resistance, and the possibility of specifically targeting TIC in anti-cancer therapies.

Dr. Anna Vert
Dr. Lluis Espinosa
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All 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. Biomedicines is an international peer-reviewed open access quarterly 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 550 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

  • Signaling pathways in normal and tumor stem cells
  • Cancer stem cells and their biology
  • Stem cells and metastasis
  • In vivo models for studying normal and cancer stem cells
  • In vitro models for studying normal and cancer stem cells
  • Targeting cancer stem cells

Published Papers (11 papers)

View options order results:
result details:
Displaying articles 1-11
Export citation of selected articles as:

Review

Open AccessReview CRISPR/Cas9 for Cancer Therapy: Hopes and Challenges
Biomedicines 2018, 6(4), 105; https://doi.org/10.3390/biomedicines6040105
Received: 17 October 2018 / Revised: 2 November 2018 / Accepted: 5 November 2018 / Published: 12 November 2018
PDF Full-text (924 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Cancer is the second leading cause of death globally and remains a major economic and social burden. Although our understanding of cancer at the molecular level continues to improve, more effort is needed to develop new therapeutic tools and approaches exploiting these advances.
[...] Read more.
Cancer is the second leading cause of death globally and remains a major economic and social burden. Although our understanding of cancer at the molecular level continues to improve, more effort is needed to develop new therapeutic tools and approaches exploiting these advances. Because of its high efficiency and accuracy, the CRISPR-Cas9 genome editing technique has recently emerged as a potentially powerful tool in the arsenal of cancer therapy. Among its many applications, CRISPR-Cas9 has shown an unprecedented clinical potential to discover novel targets for cancer therapy and to dissect chemical-genetic interactions, providing insight into how tumours respond to drug treatment. Moreover, CRISPR-Cas9 can be employed to rapidly engineer immune cells and oncolytic viruses for cancer immunotherapeutic applications. Perhaps more importantly, the ability of CRISPR-Cas9 to accurately edit genes, not only in cell culture models and model organisms but also in humans, allows its use in therapeutic explorations. In this review, we discuss important considerations for the use of CRISPR/Cas9 in therapeutic settings and major challenges that will need to be addressed prior to its clinical translation for a complex and polygenic disease such as cancer. Full article
(This article belongs to the Special Issue Stem Cells and Cancer Therapeutics)
Figures

Figure 1

Open AccessReview Cellular Plasticity of Mammary Epithelial Cells Underlies Heterogeneity of Breast Cancer
Biomedicines 2018, 6(4), 103; https://doi.org/10.3390/biomedicines6040103
Received: 1 October 2018 / Revised: 25 October 2018 / Accepted: 30 October 2018 / Published: 1 November 2018
PDF Full-text (1013 KB) | HTML Full-text | XML Full-text
Abstract
The hierarchical relationships between stem cells, lineage-committed progenitors, and differentiated cells remain unclear in several tissues, due to a high degree of cell plasticity, allowing cells to switch between different cell states. The mouse mammary gland, similarly to other tissues such as the
[...] Read more.
The hierarchical relationships between stem cells, lineage-committed progenitors, and differentiated cells remain unclear in several tissues, due to a high degree of cell plasticity, allowing cells to switch between different cell states. The mouse mammary gland, similarly to other tissues such as the prostate, the sweat gland, and the respiratory tract airways, consists of an epithelium exclusively maintained by unipotent progenitors throughout adulthood. Such unipotent progenitors, however, retain a remarkable cellular plasticity, as they can revert to multipotency during epithelial regeneration as well as upon oncogene activation. Here, we revise the current knowledge on mammary cell hierarchies in light of the most recent lineage tracing studies performed in the mammary gland and highlight how stem cell differentiation or reversion to multipotency are at the base of tumor development and progression. In addition, we will discuss the current knowledge about the interplay between tumor cells of origin and defined genetic mutations, leading to different tumor types, and its implications in choosing specific therapeutic protocols for breast cancer patients. Full article
(This article belongs to the Special Issue Stem Cells and Cancer Therapeutics)
Figures

Graphical abstract

Open AccessReview Notch and Wnt Dysregulation and Its Relevance for Breast Cancer and Tumor Initiation
Biomedicines 2018, 6(4), 101; https://doi.org/10.3390/biomedicines6040101
Received: 10 October 2018 / Revised: 24 October 2018 / Accepted: 26 October 2018 / Published: 1 November 2018
PDF Full-text (803 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Breast cancer is the second leading cause of cancer deaths among women in the world. Treatment has been improved and, in combination with early detection, this has resulted in reduced mortality rates. Further improvement in therapy development is however warranted. This will be
[...] Read more.
Breast cancer is the second leading cause of cancer deaths among women in the world. Treatment has been improved and, in combination with early detection, this has resulted in reduced mortality rates. Further improvement in therapy development is however warranted. This will be particularly important for certain sub-classes of breast cancer, such as triple-negative breast cancer, where currently no specific therapies are available. An important therapy development focus emerges from the notion that dysregulation of two major signaling pathways, Notch and Wnt signaling, are major drivers for breast cancer development. In this review, we discuss recent insights into the Notch and Wnt signaling pathways and into how they act synergistically both in normal development and cancer. We also discuss how dysregulation of the two pathways contributes to breast cancer and strategies to develop novel breast cancer therapies starting from a Notch and Wnt dysregulation perspective. Full article
(This article belongs to the Special Issue Stem Cells and Cancer Therapeutics)
Figures

Figure 1

Open AccessReview Gastric Stem Cell and Cellular Origin of Cancer
Biomedicines 2018, 6(4), 100; https://doi.org/10.3390/biomedicines6040100
Received: 30 September 2018 / Revised: 28 October 2018 / Accepted: 28 October 2018 / Published: 31 October 2018
PDF Full-text (791 KB) | HTML Full-text | XML Full-text
Abstract
Several stem cell markers within the gastrointestinal epithelium have been identified in mice. One of the best characterized is Lgr5 (leucine-rich repeat-containing G-protein coupled receptor 5) and evidence suggests that Lgr5+ cells in the gut are the origin of gastrointestinal cancers. Reserve
[...] Read more.
Several stem cell markers within the gastrointestinal epithelium have been identified in mice. One of the best characterized is Lgr5 (leucine-rich repeat-containing G-protein coupled receptor 5) and evidence suggests that Lgr5+ cells in the gut are the origin of gastrointestinal cancers. Reserve or facultative stem or progenitor cells with the ability to convert to Lgr5+ cells following injury have also been identified. Unlike the intestine, where Lgr5+ cells at the crypt base act as active stem cells, the stomach may contain unique stem cell populations, since gastric Lgr5+ cells seem to behave as a reserve rather than active stem cells, both in the corpus and in the antral glands. Gastrointestinal stem cells are supported by a specific microenvironment, the stem cell niche, which also promotes tumorigenesis. This review focuses on stem cell markers in the gut and their supporting niche factors. It also discusses the molecular mechanisms that regulate stem cell function and tumorigenesis. Full article
(This article belongs to the Special Issue Stem Cells and Cancer Therapeutics)
Figures

Figure 1

Open AccessReview Stem-Like Signature Predicting Disease Progression in Early Stage Bladder Cancer. The Role of E2F3 and SOX4
Biomedicines 2018, 6(3), 85; https://doi.org/10.3390/biomedicines6030085
Received: 6 June 2018 / Revised: 25 July 2018 / Accepted: 26 July 2018 / Published: 2 August 2018
PDF Full-text (259 KB) | HTML Full-text | XML Full-text
Abstract
The rapid development of the cancer stem cells (CSC) field, together with powerful genome-wide screening techniques, have provided the basis for the development of future alternative and reliable therapies aimed at targeting tumor-initiating cell populations. Urothelial bladder cancer stem cells (BCSCs) that were
[...] Read more.
The rapid development of the cancer stem cells (CSC) field, together with powerful genome-wide screening techniques, have provided the basis for the development of future alternative and reliable therapies aimed at targeting tumor-initiating cell populations. Urothelial bladder cancer stem cells (BCSCs) that were identified for the first time in 2009 are heterogenous and originate from multiple cell types; including urothelial stem cells and differentiated cell types—basal, intermediate stratum and umbrella cells Some studies hypothesize that BCSCs do not necessarily arise from normal stem cells but might derive from differentiated progenies following mutational insults and acquisition of tumorigenic properties. Conversely, there is data that normal bladder tissues can generate CSCs through mutations. Prognostic risk stratification by identification of predictive markers is of major importance in the management of urothelial cell carcinoma (UCC) patients. Several stem cell markers have been linked to recurrence or progression. The CD44v8-10 to standard CD44-ratio (total ratio of all CD44 alternative splicing isoforms) in urothelial cancer has been shown to be closely associated with tumor progression and aggressiveness. ALDH1, has also been reported to be associated with BCSCs and a worse prognosis in a large number of studies. UCC include low-grade and high-grade non-muscle invasive bladder cancer (NMIBC) and high-grade muscle invasive bladder cancer (MIBC). Important genetic defects characterize the distinct pathways in each one of the stages and probably grades. As an example, amplification of chromosome 6p22 is one of the most frequent changes seen in MIBC and might act as an early event in tumor progression. Interestingly, among NMIBC there is a much higher rate of amplification in high-grade NMIBC compared to low grade NMIBC. CDKAL1, E2F3 and SOX4 are highly expressed in patients with the chromosomal 6p22 amplification aside from other six well known genes (ID4, MBOAT1, LINC00340, PRL, and HDGFL1). Based on that, SOX4, E2F3 or 6q22.3 amplifications might represent potential targets in this tumor type. Focusing more in SOX4, it seems to exert its critical regulatory functions upstream of the Snail, Zeb, and Twist family of transcriptional inducers of EMT (epithelial–mesenchymal transition), but without directly affecting their expression as seen in several cell lines of the Cancer Cell Line Encyclopedia (CCLE) project. SOX4 gene expression correlates with advanced cancer stages and poor survival rate in bladder cancer, supporting a potential role as a regulator of the bladder CSC properties. SOX4 might serve as a biomarker of the aggressive phenotype, also underlying progression from NMIBC to MIBC. The amplicon in chromosome 6 contains SOX4 and E2F3 and is frequently found amplified in bladder cancer. These genes/amplicons might be a potential target for therapy. As an existing hypothesis is that chromatin deregulation through enhancers or super-enhancers might be the underlying mechanism responsible of this deregulation, a potential way to target these transcription factors could be through epigenetic modifiers. Full article
(This article belongs to the Special Issue Stem Cells and Cancer Therapeutics)
Open AccessReview Breast Cancer Stem Cells
Biomedicines 2018, 6(3), 77; https://doi.org/10.3390/biomedicines6030077
Received: 26 June 2018 / Revised: 13 July 2018 / Accepted: 14 July 2018 / Published: 17 July 2018
PDF Full-text (263 KB) | HTML Full-text | XML Full-text
Abstract
Breast cancer stem cells (BCSC) have been implicated in tumor initiation, progression, metastasis, recurrence, and resistance to therapy. The origins of BCSCs remain controversial due to tumor heterogeneity and the presence of such small side populations for study, but nonetheless, cell surface markers
[...] Read more.
Breast cancer stem cells (BCSC) have been implicated in tumor initiation, progression, metastasis, recurrence, and resistance to therapy. The origins of BCSCs remain controversial due to tumor heterogeneity and the presence of such small side populations for study, but nonetheless, cell surface markers and their correlation with BCSC functionality continue to be identified. BCSCs are driven by persistent activation of developmental pathways, such as Notch, Wnt, Hippo, and Hedgehog and new treatment strategies that are aimed at these pathways are in preclinical and clinical development. Full article
(This article belongs to the Special Issue Stem Cells and Cancer Therapeutics)
Figures

Graphical abstract

Open AccessReview Mammary Stem Cells and Breast Cancer Stem Cells: Molecular Connections and Clinical Implications
Biomedicines 2018, 6(2), 50; https://doi.org/10.3390/biomedicines6020050
Received: 5 March 2018 / Revised: 29 March 2018 / Accepted: 31 March 2018 / Published: 4 May 2018
Cited by 1 | PDF Full-text (794 KB) | HTML Full-text | XML Full-text
Abstract
Cancer arises from subpopulations of transformed cells with high tumor initiation and repopulation ability, known as cancer stem cells (CSCs), which share many similarities with their normal counterparts. In the mammary gland, several studies have shown common molecular regulators between adult mammary stem
[...] Read more.
Cancer arises from subpopulations of transformed cells with high tumor initiation and repopulation ability, known as cancer stem cells (CSCs), which share many similarities with their normal counterparts. In the mammary gland, several studies have shown common molecular regulators between adult mammary stem cells (MaSCs) and breast cancer stem cells (bCSCs). Cell plasticity and self-renewal are essential abilities for MaSCs to maintain tissue homeostasis and regenerate the gland after pregnancy. Intriguingly, these properties are similarly executed in breast cancer stem cells to drive tumor initiation, tumor heterogeneity and recurrence after chemotherapy. In addition, both stem cell phenotypes are strongly influenced by external signals from the microenvironment, immune cells and supportive specific niches. This review focuses on the intrinsic and extrinsic connections of MaSC and bCSCs with clinical implications for breast cancer progression and their possible therapeutic applications. Full article
(This article belongs to the Special Issue Stem Cells and Cancer Therapeutics)
Figures

Graphical abstract

Open AccessReview Semaphorin 3C and Its Receptors in Cancer and Cancer Stem-Like Cells
Biomedicines 2018, 6(2), 42; https://doi.org/10.3390/biomedicines6020042
Received: 3 March 2018 / Revised: 27 March 2018 / Accepted: 3 April 2018 / Published: 8 April 2018
PDF Full-text (6408 KB) | HTML Full-text | XML Full-text
Abstract
Neurodevelopmental programs are frequently dysregulated in cancer. Semaphorins are a large family of guidance cues that direct neuronal network formation and are also implicated in cancer. Semaphorins have two kinds of receptors, neuropilins and plexins. Besides their role in development, semaphorin signaling may
[...] Read more.
Neurodevelopmental programs are frequently dysregulated in cancer. Semaphorins are a large family of guidance cues that direct neuronal network formation and are also implicated in cancer. Semaphorins have two kinds of receptors, neuropilins and plexins. Besides their role in development, semaphorin signaling may promote or suppress tumors depending on their context. Sema3C is a secreted semaphorin that plays an important role in the maintenance of cancer stem-like cells, promotes migration and invasion, and may facilitate angiogenesis. Therapeutic strategies that inhibit Sema3C signaling may improve cancer control. This review will summarize the current research on the Sema3C pathway and its potential as a therapeutic target. Full article
(This article belongs to the Special Issue Stem Cells and Cancer Therapeutics)
Figures

Graphical abstract

Open AccessReview CD117/c-kit in Cancer Stem Cell-Mediated Progression and Therapeutic Resistance
Biomedicines 2018, 6(1), 31; https://doi.org/10.3390/biomedicines6010031
Received: 2 February 2018 / Revised: 28 February 2018 / Accepted: 5 March 2018 / Published: 8 March 2018
Cited by 1 | PDF Full-text (1413 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Metastasis is the primary cause of cancer patient morbidity and mortality, but due to persisting gaps in our knowledge, it remains untreatable. Metastases often occur as patient tumors progress or recur after initial therapy. Tumor recurrence at the primary site may be driven
[...] Read more.
Metastasis is the primary cause of cancer patient morbidity and mortality, but due to persisting gaps in our knowledge, it remains untreatable. Metastases often occur as patient tumors progress or recur after initial therapy. Tumor recurrence at the primary site may be driven by a cancer stem-like cell or tumor progenitor cell, while recurrence at a secondary site is driven by metastatic cancer stem cells or metastasis-initiating cells. Ongoing efforts are aimed at identifying and characterizing these stem-like cells driving recurrence and metastasis. One potential marker for the cancer stem-like cell subpopulation is CD117/c-kit, a tyrosine kinase receptor associated with cancer progression and normal stem cell maintenance. Further, activation of CD117 by its ligand stem cell factor (SCF; kit ligand) in the progenitor cell niche stimulates several signaling pathways driving proliferation, survival, and migration. This review examines evidence that the SCF/CD117 signaling axis may contribute to the control of cancer progression through the regulation of stemness and resistance to tyrosine kinase inhibitors. Full article
(This article belongs to the Special Issue Stem Cells and Cancer Therapeutics)
Figures

Graphical abstract

Open AccessReview Role of Akt Isoforms Controlling Cancer Stem Cell Survival, Phenotype and Self-Renewal
Biomedicines 2018, 6(1), 29; https://doi.org/10.3390/biomedicines6010029
Received: 31 January 2018 / Revised: 23 February 2018 / Accepted: 6 March 2018 / Published: 7 March 2018
Cited by 3 | PDF Full-text (514 KB) | HTML Full-text | XML Full-text
Abstract
The cancer stem cell (CSC) hypothesis suggests that tumours are maintained by a subpopulation of cells with stem cell properties. Although the existence of CSCs was initially described in human leukaemia, less evidence exists for CSCs in solid tumours. Recently, a CD133+ cell
[...] Read more.
The cancer stem cell (CSC) hypothesis suggests that tumours are maintained by a subpopulation of cells with stem cell properties. Although the existence of CSCs was initially described in human leukaemia, less evidence exists for CSCs in solid tumours. Recently, a CD133+ cell subpopulation was isolated from human brain tumours exhibiting stem cell properties in vitro as well as the capacity to initiate tumours in vivo. In the present work, we try to summarize the data showing that some elements of the Phosphoinositide 3-kinase Class I (PI3K)/ Thymoma viral oncogene protein kinase (Akt) pathway, such the activity of PI3K Class I or Akt2, are necessary to maintain the CSC-like phenotype as well as survival of CSCs (also denoted as tumour-initiating cells (TICs)). Our data and other laboratory data permit a working hypothesis in which each Akt isoform plays an important and specific role in CSC/TIC growth, self-renewal, maintaining survival, and epithelial-mesenchymal transition (EMT) phenotype, not only in breast cancer, but also in glioma. We suggest that a more complete understanding is needed of the possible roles of isoforms in human tumours (iso-signalling determination). Thus, a comprehensive analysis of how hierarchical signalling is assembled during oncogenesis, how cancer landmarks are interconnected to favour CSC and tumour growth, and how some protein isoforms play a specific role in CSCs to ensure that survival and proliferation must be done in order to propose/generate new therapeutic approaches (alone or in combination with existing ones) to use against cancer. Full article
(This article belongs to the Special Issue Stem Cells and Cancer Therapeutics)
Figures

Graphical abstract

Open AccessReview Targeting Leukemia Stem Cells in the Bone Marrow Niche
Biomedicines 2018, 6(1), 22; https://doi.org/10.3390/biomedicines6010022
Received: 8 January 2018 / Revised: 6 February 2018 / Accepted: 17 February 2018 / Published: 21 February 2018
PDF Full-text (698 KB) | HTML Full-text | XML Full-text
Abstract
The bone marrow (BM) niche encompasses multiple cells of mesenchymal and hematopoietic origin and represents a unique microenvironment that is poised to maintain hematopoietic stem cells. In addition to its role as a primary lymphoid organ through the support of lymphoid development, the
[...] Read more.
The bone marrow (BM) niche encompasses multiple cells of mesenchymal and hematopoietic origin and represents a unique microenvironment that is poised to maintain hematopoietic stem cells. In addition to its role as a primary lymphoid organ through the support of lymphoid development, the BM hosts various mature lymphoid cell types, including naïve T cells, memory T cells and plasma cells, as well as mature myeloid elements such as monocyte/macrophages and neutrophils, all of which are crucially important to control leukemia initiation and progression. The BM niche provides an attractive milieu for tumor cell colonization given its ability to provide signals which accelerate tumor cell proliferation and facilitate tumor cell survival. Cancer stem cells (CSCs) share phenotypic and functional features with normal counterparts from the tissue of origin of the tumor and can self-renew, differentiate and initiate tumor formation. CSCs possess a distinct immunological profile compared with the bulk population of tumor cells and have evolved complex strategies to suppress immune responses through multiple mechanisms, including the release of soluble factors and the over-expression of molecules implicated in cancer immune evasion. This chapter discusses the latest advancements in understanding of the immunological BM niche and highlights current and future immunotherapeutic strategies to target leukemia CSCs and overcome therapeutic resistance in the clinic. Full article
(This article belongs to the Special Issue Stem Cells and Cancer Therapeutics)
Figures

Graphical abstract

Back to Top