Editorial

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Open AccessEditorial

Editorial: Special Issue “Stem Cell Biology and Cancer”

by Carolina Vicente-Dueñas, Isidro Sánchez-García and Geoffrey Brown

Int. J. Mol. Sci. 2023, 24(14), 11533; https://doi.org/10.3390/ijms241411533 - 16 Jul 2023

Cited by 1 | Viewed by 1054

Cancer stem cells (CSCs) are now well-established as key players in tumor initiation, progression, and therapy resistance [...] Full article

(This article belongs to the Special Issue Stem Cell Biology and Cancer)

Research

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21 pages, 6000 KiB

Open AccessArticle

Pevonedistat Inhibits SOX2 Expression and Sphere Formation but Also Drives the Induction of Terminal Differentiation Markers and Apoptosis within Arsenite-Transformed Urothelial Cells

by Aaron A. Mehus, Madison Jones, Mason Trahan, Kaija Kinnunen, Kaitlyn Berwald, Becker Lindner, Sarmad Al-Marsoummi, Xu Dong Zhou, Scott H. Garrett, Donald A. Sens, Mary Ann Sens and Seema Somji

Int. J. Mol. Sci. 2023, 24(11), 9149; https://doi.org/10.3390/ijms24119149 - 23 May 2023

Cited by 3 | Viewed by 1499

Abstract

Urothelial cancer (UC) is a common malignancy and its development is associated with arsenic exposure. Around 25% of diagnosed UC cases are muscle invasive (MIUC) and are frequently associated with squamous differentiation. These patients commonly develop cisplatin (CIS) resistance and have poor prognosis. [...] Read more.

Urothelial cancer (UC) is a common malignancy and its development is associated with arsenic exposure. Around 25% of diagnosed UC cases are muscle invasive (MIUC) and are frequently associated with squamous differentiation. These patients commonly develop cisplatin (CIS) resistance and have poor prognosis. SOX2 expression is correlated to reduced overall and disease-free survival in UC. SOX2 drives malignant stemness and proliferation in UC cells and is associated with development of CIS resistance. Using quantitative proteomics, we identified that SOX2 was overexpressed in three arsenite (As³⁺)-transformed UROtsa cell lines. We hypothesized that inhibition of SOX2 would reduce stemness and increase sensitivity to CIS in the As³⁺-transformed cells. Pevonedistat (PVD) is a neddylation inhibitor and is a potent inhibitor of SOX2. We treated non-transformed parent and As³⁺-transformed cells with PVD, CIS, or in combination and monitored cell growth, sphere forming abilities, apoptosis, and gene/protein expression. PVD treatment alone caused morphological changes, reduced cell growth, attenuated sphere formation, induced apoptosis, and elevated the expression of terminal differentiation markers. However, the combined treatment of PVD with CIS significantly elevated the expression of terminal differentiation markers and eventually led to more cell death than either solo treatment. Aside from a reduced proliferation rate, these effects were not seen in the parent. Further research is needed to explore the potential use of PVD with CIS as a differentiation therapy or alternative treatment for MIUC tumors that may have become resistant to CIS. Full article

(This article belongs to the Special Issue Stem Cell Biology and Cancer)

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Review

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19 pages, 2250 KiB

Open AccessReview

Targeting the Retinoic Acid Pathway to Eradicate Cancer Stem Cells

by Geoffrey Brown

Int. J. Mol. Sci. 2023, 24(3), 2373; https://doi.org/10.3390/ijms24032373 - 25 Jan 2023

Cited by 5 | Viewed by 3290

Abstract

All-trans retinoic acid is a morphogen during embryogenesis and a teratogen. Cancer is an error of development, and the retinoic acid receptors (RAR) for all-trans retinoic acid play a role in cancer. Expression of the cytosolic aldehyde dehydrogenases, which mediate the [...] Read more.

All-trans retinoic acid is a morphogen during embryogenesis and a teratogen. Cancer is an error of development, and the retinoic acid receptors (RAR) for all-trans retinoic acid play a role in cancer. Expression of the cytosolic aldehyde dehydrogenases, which mediate the last step to the synthesis of all-trans retinoic acid, is deregulated in various human cancers. Inhibiting these enzymes using a variety of agents reduced the proliferation of lung cancer cells, reduced the proliferation and induced apoptosis of ovarian, prostate, squamous, and uterine cancer cells, and sensitised breast, colorectal and ovarian cancer cells to chemotherapeutic agents. RARγ is an oncogene within some cases of AML, cholangiocarcinoma, colorectal cancer, clear cell renal cell carcinoma, hepatocellular carcinoma, pancreatic ductal adenocarcinoma, prostate cancer, and ovarian cancer. Pan-RAR and RARγ antagonist inhibition of the action of RARγ led to necroptosis of human prostate and pediatric brain tumour cancer stem cells. Treatment of hepatocellular carcinoma cells with the flavenoid acacetin, which interferes with the action of RARγ, decreased cell growth and induced apoptosis. Targeting the retinoic acid pathway is promising regarding the development of new drugs to eradicate cancer stem cells. Full article

(This article belongs to the Special Issue Stem Cell Biology and Cancer)

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13 pages, 1159 KiB

Open AccessReview

Hematopoietic and Chronic Myeloid Leukemia Stem Cells: Multi-Stability versus Lineage Restriction

by Geoffrey Brown

Int. J. Mol. Sci. 2022, 23(21), 13570; https://doi.org/10.3390/ijms232113570 - 05 Nov 2022

Cited by 9 | Viewed by 1676

Abstract

There is compelling evidence to support the view that the cell-of-origin for chronic myeloid leukemia is a hematopoietic stem cell. Unlike normal hematopoietic stem cells, the progeny of the leukemia stem cells are predominantly neutrophils during the disease chronic phase and there is [...] Read more.

There is compelling evidence to support the view that the cell-of-origin for chronic myeloid leukemia is a hematopoietic stem cell. Unlike normal hematopoietic stem cells, the progeny of the leukemia stem cells are predominantly neutrophils during the disease chronic phase and there is a mild anemia. The hallmark oncogene for chronic myeloid leukemia is the BCR-ABLp210 fusion gene. Various studies have excluded a role for BCR-ABLp210 expression in maintaining the population of leukemia stem cells. Studies of BCR-ABLp210 expression in embryonal stem cells that were differentiated into hematopoietic stem cells and of the expression in transgenic mice have revealed that BCR-ABLp210 is able to veer hematopoietic stem and progenitor cells towards a myeloid fate. For the transgenic mice, global changes to the epigenetic landscape were observed. In chronic myeloid leukemia, the ability of the leukemia stem cells to choose from the many fates that are available to normal hematopoietic stem cells appears to be deregulated by BCR-ABLp210 and changes to the epigenome are also important. Even so, we still do not have a precise picture as to why neutrophils are abundantly produced in chronic myeloid leukemia. Full article

(This article belongs to the Special Issue Stem Cell Biology and Cancer)

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15 pages, 742 KiB

Open AccessReview

NSD2 as a Promising Target in Hematological Disorders

by Alba Azagra and César Cobaleda

Int. J. Mol. Sci. 2022, 23(19), 11075; https://doi.org/10.3390/ijms231911075 - 21 Sep 2022

Cited by 5 | Viewed by 2126

Abstract

Alterations of the epigenetic machinery are critically involved in cancer development and maintenance; therefore, the proteins in charge of the generation of epigenetic modifications are being actively studied as potential targets for anticancer therapies. A very important and widespread epigenetic mark is the [...] Read more.

Alterations of the epigenetic machinery are critically involved in cancer development and maintenance; therefore, the proteins in charge of the generation of epigenetic modifications are being actively studied as potential targets for anticancer therapies. A very important and widespread epigenetic mark is the dimethylation of Histone 3 in Lysine 36 (H3K36me2). Until recently, it was considered as merely an intermediate towards the generation of the trimethylated form, but recent data support a more specific role in many aspects of genome regulation. H3K36 dimethylation is mainly carried out by proteins of the Nuclear SET Domain (NSD) family, among which NSD2 is one of the most relevant members with a key role in normal hematopoietic development. Consequently, NSD2 is frequently altered in several types of tumors—especially in hematological malignancies. Herein, we discuss the role of NSD2 in these pathological processes, and we review the most recent findings in the development of new compounds aimed against the oncogenic forms of this novel anticancer candidate. Full article

(This article belongs to the Special Issue Stem Cell Biology and Cancer)

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14 pages, 691 KiB

Open AccessReview

Childhood B-Cell Preleukemia Mouse Modeling

by Marta Isidro-Hernández, Silvia Alemán-Arteaga, Ana Casado-García, Belén Ruiz-Corzo, Susana Riesco, Pablo Prieto-Matos, Jorge Martínez-Cano, Lucía Sánchez, César Cobaleda, Isidro Sánchez-García and Carolina Vicente-Dueñas

Int. J. Mol. Sci. 2022, 23(14), 7562; https://doi.org/10.3390/ijms23147562 - 08 Jul 2022

Cited by 2 | Viewed by 1995

Abstract

Leukemia is the most usual childhood cancer, and B-cell acute lymphoblastic leukemia (B-ALL) is its most common presentation. It has been proposed that pediatric leukemogenesis occurs through a “multi-step” or “multi-hit” mechanism that includes both in utero and postnatal steps. Many childhood leukemia-initiating [...] Read more.

Leukemia is the most usual childhood cancer, and B-cell acute lymphoblastic leukemia (B-ALL) is its most common presentation. It has been proposed that pediatric leukemogenesis occurs through a “multi-step” or “multi-hit” mechanism that includes both in utero and postnatal steps. Many childhood leukemia-initiating events, such as chromosomal translocations, originate in utero, and studies so far suggest that these “first-hits” occur at a far higher frequency than the incidence of childhood leukemia itself. The reason why only a small percentage of the children born with such preleukemic “hits” will develop full-blown leukemia is still a mystery. In order to better understand childhood leukemia, mouse modeling is essential, but only if the multistage process of leukemia can be recapitulated in the model. Therefore, mouse models naturally reproducing the “multi-step” process of childhood B-ALL will be essential to identify environmental or other factors that are directly linked to increased risk of disease. Full article

(This article belongs to the Special Issue Stem Cell Biology and Cancer)

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17 pages, 1932 KiB

Open AccessReview

Stem Cell Models for Cancer Therapy

by Nitin Telang

Int. J. Mol. Sci. 2022, 23(13), 7055; https://doi.org/10.3390/ijms23137055 - 24 Jun 2022

Cited by 8 | Viewed by 2209

Abstract

Metastatic progression of female breast and colon cancer represents a major cause of mortality in women. Spontaneous/acquired resistance to conventional and targeted chemo-endocrine therapy is associated with the emergence of drug-resistant tumor-initiating cancer stem cell populations. The cancer-initiating premalignant stem cells exhibit activation [...] Read more.

Metastatic progression of female breast and colon cancer represents a major cause of mortality in women. Spontaneous/acquired resistance to conventional and targeted chemo-endocrine therapy is associated with the emergence of drug-resistant tumor-initiating cancer stem cell populations. The cancer-initiating premalignant stem cells exhibit activation of select cancer cell signaling pathways and undergo epithelial–mesenchymal transition, leading to the evolution of a metastatic phenotype. The development of reliable cancer stem cell models provides valuable experimental approaches to identify novel testable therapeutic alternatives for therapy-resistant cancer. Drug-resistant stem cell models for molecular subtypes of clinical breast cancer and for genetically predisposed colon cancer are developed by selecting epithelial cells that survive in the presence of cytostatic concentrations of relevant therapeutic agents. These putative stem cells are characterized by the expression status of select cellular and molecular stem cell markers. The stem cell models are utilized as experimental approaches to examine the stem-cell-targeted growth inhibitory efficacy of naturally occurring dietary phytochemicals. The present review provides a systematic discussion on (i) conceptual and experimental aspects relevant to the chemo-endocrine therapy of breast and colon cancer, (ii) molecular/cellular aspects of cancer stem cells and (iii) potential stem-cell-targeting lead compounds as testable alternatives against the progression of therapy-resistant breast and colon cancer. Full article

(This article belongs to the Special Issue Stem Cell Biology and Cancer)

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14 pages, 1286 KiB

Open AccessReview

The Social Norm of Hematopoietic Stem Cells and Dysregulation in Leukemia

by Geoffrey Brown

Int. J. Mol. Sci. 2022, 23(9), 5063; https://doi.org/10.3390/ijms23095063 - 03 May 2022

Cited by 3 | Viewed by 1893

Abstract

The hematopoietic cell system is a complex ecosystem that meets the steady-state and emergency needs of the production of the mature blood cell types. Steady-state hematopoiesis replaces worn out cells, and the hematopoietic system is highly adaptive to needs during, for example, an [...] Read more.

The hematopoietic cell system is a complex ecosystem that meets the steady-state and emergency needs of the production of the mature blood cell types. Steady-state hematopoiesis replaces worn out cells, and the hematopoietic system is highly adaptive to needs during, for example, an infection or bleeding. Hematopoiesis is highly integrated and the cell hierarchy behaves in a highly social manner. The social tailoring of hematopoietic stem cells to needs includes the generation of cells that are biased towards a cell lineage; these cells remain versatile and can still adopt a different pathway having made a lineage “choice”, and some cytokines instruct the lineage fate of hematopoietic stem and progenitor cells. Leukemia stem cells, which may well often arise from the transformation of a hematopoietic stem cell, sustain the hierarchy of cells for leukemia. Unlike hematopoietic stem cells, the offspring of leukemia stem cells belongs to just one cell lineage. The human leukemias are classified by virtue of their differentiating or partially differentiating cells belonging to just one cell lineage. Some oncogenes set the fate of leukemia stem cells to a single lineage. Therefore, lineage restriction may be largely an attribute whereby leukemia stem cells escape from the normal cellular society. Additional antisocial behaviors are that leukemia cells destroy and alter bone marrow stromal niches, and they can create their own niches. Full article

(This article belongs to the Special Issue Stem Cell Biology and Cancer)

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19 pages, 775 KiB

Open AccessReview

Glioblastoma Stem Cells—Useful Tools in the Battle against Cancer

by Silvia Mara Baez Rodriguez, Georgiana-Adeline Staicu, Ani-Simona Sevastre, Carina Baloi, Vasile Ciubotaru, Anica Dricu and Ligia Gabriela Tataranu

Int. J. Mol. Sci. 2022, 23(9), 4602; https://doi.org/10.3390/ijms23094602 - 21 Apr 2022

Cited by 14 | Viewed by 2913

Abstract

Glioblastoma stem cells (GSCs) are cells with a self-renewal ability and capacity to initiate tumors upon serial transplantation that have been linked to tumor cell heterogeneity. Most standard treatments fail to completely eradicate GSCs, causing the recurrence of the disease. GSCs could represent [...] Read more.

Glioblastoma stem cells (GSCs) are cells with a self-renewal ability and capacity to initiate tumors upon serial transplantation that have been linked to tumor cell heterogeneity. Most standard treatments fail to completely eradicate GSCs, causing the recurrence of the disease. GSCs could represent one reason for the low efficacy of cancer therapy and for the short relapse time. Nonetheless, experimental data suggest that the presence of therapy-resistant GSCs could explain tumor recurrence. Therefore, to effectively target GSCs, a comprehensive understanding of their biology and the survival and developing mechanisms during treatment is mandatory. This review provides an overview of the molecular features, microenvironment, detection, and targeting strategies of GSCs, an essential information required for an efficient therapy. Despite the outstanding results in oncology, researchers are still developing novel strategies, of which one could be targeting the GSCs present in the hypoxic regions and invasive edge of the glioblastoma. Full article

(This article belongs to the Special Issue Stem Cell Biology and Cancer)

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