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Cancers
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Cancer Stem Cells (CSCs) in Drug Resistance and Their Therapeutic...
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Cancer Stem Cells (CSCs) in Drug Resistance and Their Therapeutic Implications in Cancer Treatment

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (25 September 2022) | Viewed by 22839

Special Issue Editor

Dr. Peter Van Veldhuizen

E-Mail Website
Guest Editor
Department of Internal Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
Interests: bladder cancer; kidney cancer; prostate cancer; clinical trials; survivorship

Special Issue Information

Dear Colleagues,

Cancer stem cells (CSCs) are a small subpopulation of cells that possess characteristics associated with normal stem cells, allowing for self-renewal and differentiation. These stem cells too frequently have the ability to escape standard therapeutic options. They are integrally responsible for tumor relapses, as well as the development of resistance to chemotherapy and radiation. In the case of prostate cancer, for example, there is a near 90% response to androgen deprivation therapy, but it appears that it is the prostate cancer stem cells which ultimately escape the effect of this therapy, resulting in universal relapse despite encouraging and prolonged initial tumor responses. 

Increasing evidence has demonstrated that several developmental signaling pathways, such as the Wnt, Notch, Hedgehog, and Hippo, are frequently deregulated and play an important role in regulating cancer stem cell activity. CSCs are regulated by cell surface receptors and intracellular factors that are triggered by stimuli from the tumor microenvironment. For example, mesenchymal stem cells play an important role in the intercellular signaling within the tumor microenvironment, exchanging signals with cancer cells and tumor stromal cells.

Despite our increasing knowledge of the biology and role of CSCSs and their interaction with the tumor stroma, therapeutic options which specifically target CSCSs are limited, and there is a clear need for new targeted approaches. This Special Issue will focus on mechanisms of cancer stem cell therapeutic resistance, stem cell interactions with the microenvironment which may contribute to that resistance, and potential treatment strategies which could circumvent this resistance.

Dr. Peter Van Veldhuizen
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

  • therapeutic resistance
  • cancer stem cell
  • exosomes
  • microenvironment
  • mitochondria

Published Papers (8 papers)

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Research

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19 pages, 2901 KiB  
Article
Magmas Inhibition in Prostate Cancer: A Novel Target for Treatment-Resistant Disease
by Jianhui Yang, Bhaskar C. Das, Omar Aljitawi, Avinash Kumar, Sasmita Das and Peter Van Veldhuizen
Cancers 2022, 14(11), 2732; https://doi.org/10.3390/cancers14112732 - 31 May 2022
Cited by 4 | Viewed by 1675
Abstract
The purpose of our study was to evaluate Magmas as a potential target in prostate cancer. In addition, we evaluated our synthetic Magmas inhibitor (BT#9) effects on prostate cancer and examined the molecular mechanism of BT#9. A cell viability assay showed that treatment [...] Read more.
The purpose of our study was to evaluate Magmas as a potential target in prostate cancer. In addition, we evaluated our synthetic Magmas inhibitor (BT#9) effects on prostate cancer and examined the molecular mechanism of BT#9. A cell viability assay showed that treatment with BT#9 caused a significant decrease in the viability of DU145 and PC3 prostate cancer cells with little effect on the viability of WPMY-1 normal prostate cells. Western blot proved that BT#9 downregulated the Magmas protein and caspase-3 activation. Flow cytometry studies demonstrated increased apoptosis and disturbed mitochondrial membrane potential. However, the main mode of cell death was caspase-independent necrosis, which was correlated with the accumulation of mitochondrial and intra-cellular Reactive Oxygen Species (ROS). Taken together, our data suggest Magmas is a potential molecular target for the treatment of prostate cancer and that Magmas inhibition results in ROS-dependent and caspase-independent necrotic cell death. Full article
(This article belongs to the Special Issue Cancer Stem Cells (CSCs) in Drug Resistance and Their Therapeutic Implications in Cancer Treatment)
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18 pages, 3691 KiB  
Article
Celastrol and Resveratrol Modulate SIRT Genes Expression and Exert Anticancer Activity in Colon Cancer Cells and Cancer Stem-like Cells
by Helena Moreira, Anna Szyjka, Justyna Grzesik, Katarzyna Pelc, Magdalena Żuk, Anna Kulma, Fathi Emhemmed, Christian D. Muller, Kazimierz Gąsiorowski and Ewa Barg
Cancers 2022, 14(6), 1372; https://doi.org/10.3390/cancers14061372 - 08 Mar 2022
Cited by 19 | Viewed by 2452
Abstract
Metastatic colorectal cancer (CRC) remains a hard-to-cure neoplasm worldwide. Its curability declines with successive lines of treatment due to the development of various cancer resistance mechanisms and the presence of colorectal cancer stem cells (CSCs). Celastrol and resveratrol are very promising phytochemicals for [...] Read more.
Metastatic colorectal cancer (CRC) remains a hard-to-cure neoplasm worldwide. Its curability declines with successive lines of treatment due to the development of various cancer resistance mechanisms and the presence of colorectal cancer stem cells (CSCs). Celastrol and resveratrol are very promising phytochemicals for colon cancer therapy, owing to their pleiotropic activity that enables them to interact with various biological targets. In the present study, the anticancer activities of both compounds were investigated in metastatic colon cancer cells (LoVo cells) and cancer stem-like cells (LoVo/DX). We showed that celastrol is a very potent anti-tumor compound against metastatic colon cancer, capable of attenuating CSC-like cells at the molecular and cellular levels. In contrast, resveratrol has a much greater effect on colon cancer cells that are expressing standard sensitivity to anticancer drugs, than on CSC-like cells. In addition, both polyphenols have different influences on the expression of SIRT genes, which seems to be at least partly related to their anti-tumor activity. Full article
(This article belongs to the Special Issue Cancer Stem Cells (CSCs) in Drug Resistance and Their Therapeutic Implications in Cancer Treatment)
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19 pages, 2625 KiB  
Article
Low Levels of TRIM28-Interacting KRAB-ZNF Genes Associate with Cancer Stemness and Predict Poor Prognosis of Kidney Renal Clear Cell Carcinoma Patients
by Patrycja Czerwinska and Andrzej Adam Mackiewicz
Cancers 2021, 13(19), 4835; https://doi.org/10.3390/cancers13194835 - 28 Sep 2021
Cited by 6 | Viewed by 2490
Abstract
Krüppel-associated box zinc finger (KRAB-ZNF) proteins are known to regulate diverse biological processes, such as embryonic development, tissue-specific gene expression, and cancer progression. However, their involvement in the regulation of cancer stemness-like phenotype acquisition and maintenance is scarcely explored across solid tumor types, [...] Read more.
Krüppel-associated box zinc finger (KRAB-ZNF) proteins are known to regulate diverse biological processes, such as embryonic development, tissue-specific gene expression, and cancer progression. However, their involvement in the regulation of cancer stemness-like phenotype acquisition and maintenance is scarcely explored across solid tumor types, and to date, there are no data for kidney renal clear cell cancer (KIRC). We have harnessed The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database transcriptomic data and used several bioinformatic tools (i.e., GEPIA2, GSCALite, TISIDB, GSEA, CIBERSORT) to verify the relation between the expression and genomic alterations in KRAB-ZNFs and kidney cancer, focusing primarily on tumor dedifferentiation status and antitumor immune response. Our results demonstrate a significant negative correlation between KRAB-ZNFs and kidney cancer dedifferentiation status followed by an attenuated immune-suppressive response. The transcriptomic profiles of high KRAB-ZNF-expressing kidney tumors are significantly enriched with stem cell markers and show a depletion of several inflammatory pathways known for favoring cancer stemness. Moreover, we show for the first time the prognostic role for several KRAB-ZNFs in kidney cancer. Our results provide new insight into the role of selected KRAB-ZNF proteins in kidney cancer development. We believe that our findings may help better understand the molecular basis of KIRC. Full article
(This article belongs to the Special Issue Cancer Stem Cells (CSCs) in Drug Resistance and Their Therapeutic Implications in Cancer Treatment)
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Review

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15 pages, 1168 KiB  
Review
Prostate Cancer Stem Cells: The Role of CD133
by Jianhui Yang, Omar Aljitawi and Peter Van Veldhuizen
Cancers 2022, 14(21), 5448; https://doi.org/10.3390/cancers14215448 - 05 Nov 2022
Cited by 9 | Viewed by 2000
Abstract
Prostate cancer stem cells (PCSCs), possessing self-renewal properties and resistance to anticancer treatment, are possibly the leading cause of distant metastasis and treatment failure in prostate cancer (PC). CD133 is one of the most well-known and valuable cell surface markers of cancer stem [...] Read more.
Prostate cancer stem cells (PCSCs), possessing self-renewal properties and resistance to anticancer treatment, are possibly the leading cause of distant metastasis and treatment failure in prostate cancer (PC). CD133 is one of the most well-known and valuable cell surface markers of cancer stem cells (CSCs) in many cancers, including PC. In this article, we focus on reviewing the role of CD133 in PCSC. Any other main stem cell biomarkers in PCSC reported from key publications, as well as about vital research progress of CD133 in CSCs of different cancers, will be selectively reviewed to help us inform the main topic. Full article
(This article belongs to the Special Issue Cancer Stem Cells (CSCs) in Drug Resistance and Their Therapeutic Implications in Cancer Treatment)
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10 pages, 507 KiB  
Review
The Potential Role of 3D In Vitro Acute Myeloid Leukemia Culture Models in Understanding Drug Resistance in Leukemia Stem Cells
by Basil Al-Kaabneh, Benjamin Frisch and Omar S. Aljitawi
Cancers 2022, 14(21), 5252; https://doi.org/10.3390/cancers14215252 - 26 Oct 2022
Cited by 3 | Viewed by 2530
Abstract
The complexity of the bone marrow (BM) microenvironment makes studying hematological malignancies in vitro a challenging task. Three-dimensional cell cultures are being actively studied, particularly due to their ability to serve as a bridge of the gap between 2D cultures and animal models. [...] Read more.
The complexity of the bone marrow (BM) microenvironment makes studying hematological malignancies in vitro a challenging task. Three-dimensional cell cultures are being actively studied, particularly due to their ability to serve as a bridge of the gap between 2D cultures and animal models. The role of 3D in vitro models in studying the mechanisms of chemotherapeutic resistance and leukemia stem cells (LSCs) in acute myeloid leukemia (AML) is not well-reviewed. We present an overview of 3D cell models used for studying AML, emphasizing the recent advancements in microenvironment modeling, chemotherapy testing, and resistance. Full article
(This article belongs to the Special Issue Cancer Stem Cells (CSCs) in Drug Resistance and Their Therapeutic Implications in Cancer Treatment)
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19 pages, 1199 KiB  
Review
Impact of Cancer Stem Cells on Therapy Resistance in Gastric Cancer
by Maddalen Otaegi-Ugartemendia, Ander Matheu and Estefania Carrasco-Garcia
Cancers 2022, 14(6), 1457; https://doi.org/10.3390/cancers14061457 - 11 Mar 2022
Cited by 12 | Viewed by 3558
Abstract
Gastric cancer (GC) is the fourth leading cause of cancer death worldwide, with an average 5-year survival rate of 32%, being of 6% for patients presenting distant metastasis. Despite the advances made in the treatment of GC, chemoresistance phenomena arise and promote recurrence, [...] Read more.
Gastric cancer (GC) is the fourth leading cause of cancer death worldwide, with an average 5-year survival rate of 32%, being of 6% for patients presenting distant metastasis. Despite the advances made in the treatment of GC, chemoresistance phenomena arise and promote recurrence, dissemination and dismal prognosis. In this context, gastric cancer stem cells (gCSCs), a small subset of cancer cells that exhibit unique characteristics, are decisive in therapy failure. gCSCs develop different protective mechanisms, such as the maintenance in a quiescent state as well as enhanced detoxification procedures and drug efflux activity, that make them insusceptible to current treatments. This, together with their self-renewal capacity and differentiation ability, represents major obstacles for the eradication of this disease. Different gCSC regulators have been described and used to isolate and characterize these cell populations. However, at the moment, no therapeutic strategy has achieved the effective targeting of gCSCs. This review will focus on the properties of cancer stem cells in the context of therapy resistance and will summarize current knowledge regarding the impact of the gCSC regulators that have been associated with GC chemoradioresistance. Full article
(This article belongs to the Special Issue Cancer Stem Cells (CSCs) in Drug Resistance and Their Therapeutic Implications in Cancer Treatment)
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17 pages, 867 KiB  
Review
Intrinsic and Extrinsic Factors Impacting Cancer Stemness and Tumor Progression
by Alexey Ponomarev, Zarema Gilazieva, Valeriya Solovyeva, Cinzia Allegrucci and Albert Rizvanov
Cancers 2022, 14(4), 970; https://doi.org/10.3390/cancers14040970 - 15 Feb 2022
Cited by 16 | Viewed by 5066
Abstract
Tumor heterogeneity represents an important limitation to the development of effective cancer therapies. The presence of cancer stem cells (CSCs) and their differentiation hierarchies contribute to cancer complexity and confer tumors the ability to grow, resist treatment, survive unfavorable conditions, and invade neighboring [...] Read more.
Tumor heterogeneity represents an important limitation to the development of effective cancer therapies. The presence of cancer stem cells (CSCs) and their differentiation hierarchies contribute to cancer complexity and confer tumors the ability to grow, resist treatment, survive unfavorable conditions, and invade neighboring and distant tissues. A large body of research is currently focusing on understanding the properties of CSCs, including their cellular and molecular origin, as well as their biological behavior in different tumor types. In turn, this knowledge informs strategies for targeting these tumor initiating cells and related cancer stemness. Cancer stemness is modulated by the tumor microenvironment, which influences CSC function and survival. Several advanced in vitro models are currently being developed to study cancer stemness in order to advance new knowledge of the key molecular pathways involved in CSC self-renewal and dormancy, as well as to mimic the complexity of patients’ tumors in pre-clinical drug testing. In this review, we discuss CSCs and the modulation of cancer stemness by the tumor microenvironment, stemness factors and signaling pathways. In addition, we introduce current models that allow the study of CSCs for the development of new targeted therapies. Full article
(This article belongs to the Special Issue Cancer Stem Cells (CSCs) in Drug Resistance and Their Therapeutic Implications in Cancer Treatment)
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Other

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11 pages, 676 KiB  
Perspective
Stem Cell Theory of Cancer: Implications for Drug Resistance and Chemosensitivity in Cancer Care
by Shi-Ming Tu, Charles C. Guo, Diana S. -L. Chow and Niki M. Zacharias
Cancers 2022, 14(6), 1548; https://doi.org/10.3390/cancers14061548 - 18 Mar 2022
Cited by 8 | Viewed by 2030
Abstract
When it concerns cancer care and cancer therapy, drug resistance is more than an obstacle to successful treatment; it is a major cause of frustration in our attempts to optimize drug development versus therapy development. Importantly, overcoming the challenges of drug resistance may [...] Read more.
When it concerns cancer care and cancer therapy, drug resistance is more than an obstacle to successful treatment; it is a major cause of frustration in our attempts to optimize drug development versus therapy development. Importantly, overcoming the challenges of drug resistance may provide invaluable clues about the origin and nature of cancer. From this perspective, we discuss how chemoresistance and chemosensitivity in cancer therapy could be directly linked to the stem cell origin of cancer. A stem cell theory of cancer stipulates that both normal stem cells and cancer stem cells are similarly endowed with robust efflux pumps, potent antiapoptotic mechanisms, redundant DNA repair systems, and abundant antioxidation reserves. Cancer stem cells, like their normal stem cell counterparts, are equipped with the same drug resistance phenotypes (e.g., ABC transporters, anti-apoptotic pathways, and DNA repair mechanisms). Drug resistance, like other cancer hallmarks (e.g., tumor heterogeneity and cancer dormancy), could be intrinsically ingrained and innately embedded within malignancy. We elaborate that cellular context and the microenvironment may attenuate the effects of cancer treatments. We examine the role of circadian rhythms and the value of chronotherapy to maximize efficacy and minimize toxicity. We propose that a stem cell theory of drug resistance and drug sensitivity will ultimately empower us to enhance drug development and enable us to improve therapy development in patient care. Full article
(This article belongs to the Special Issue Cancer Stem Cells (CSCs) in Drug Resistance and Their Therapeutic Implications in Cancer Treatment)
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