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Cancers
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Cancer Stem Cells and Therapy Resistance
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Cancer Stem Cells and Therapy Resistance

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

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 30915

Special Issue Editor

Dr. Saroj K. Basak

E-Mail Website
Guest Editor
Division of Pulmonary & Critical Care, Department of Medicine, UCLA School of Medicine, Los Angeles, CA 90095‐1690, USA
Interests: cancer stem cells; stem cells; drug resistance; tumor microenvironment; cancer stem cell markers; origin; therapeutic strategies; tumor resistance; tumor heterogenicity

Special Issue Information

Dear Colleagues,

Cancer stem cells (CSCs) are an integral part of cancer origin and progression resulting in tumor heterogenicity. Tumor heterogenicity is characterized by different types of cancer cells in tumor that are, in turn, characterized by differential cell-surface marker expression, genetic and epigenetic changes, and their different cellular function. Tumor heterogenicity arises from the interaction of tumor cells with a tumor microenvironment that includes intrinsic and external factors. The CSCs are also notorious for drug/therapy resistance and are prone to changes due to therapeutic pressure, leading to tumor progression, metastasis, and tumor recurrence.

To better target cancer therapies, we must understand the biology of CSCs and develop novel therapeutic strategies that can target CSCs more efficiently. This Special Issue examines molecular and cellular factors in the tumor microenvironment that cause CSC survival and therapy resistance, and discusses new strategies to improve CSC-targeted therapies.

Dr. Saroj K. Basak
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 communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer stem cells
  • cancer heterogenicity
  • cancer therapy
  • cancer drug resistance

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Published Papers (7 papers)

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Research

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20 pages, 2906 KiB  
Article
The MEK1/2 Pathway as a Therapeutic Target in High-Grade Serous Ovarian Carcinoma
by Mikhail S. Chesnokov, Imran Khan, Yeonjung Park, Jessica Ezell, Geeta Mehta, Abdelrahman Yousif, Linda J. Hong, Ronald J. Buckanovich, Akimasa Takahashi and Ilana Chefetz
Cancers 2021, 13(6), 1369; https://doi.org/10.3390/cancers13061369 - 18 Mar 2021
Cited by 17 | Viewed by 4400
Abstract
High-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to its high recurrence rate and acquired chemoresistance. RAS/MEK/ERK pathway activation is linked to cell proliferation and therapeutic resistance, but the role of MEK1/2-ERK1/2 pathway in HGSOC is poorly investigated. We [...] Read more.
High-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to its high recurrence rate and acquired chemoresistance. RAS/MEK/ERK pathway activation is linked to cell proliferation and therapeutic resistance, but the role of MEK1/2-ERK1/2 pathway in HGSOC is poorly investigated. We evaluated MEK1/2 pathway activity in clinical HGSOC samples and ovarian cancer cell lines using immunohistochemistry, immunoblotting, and RT-qPCR. HGSOC cell lines were used to assess immediate and lasting effects of MEK1/2 inhibition with trametinib in vitro. Trametinib effect on tumor growth in vivo was investigated using mouse xenografts. MEK1/2 pathway is hyperactivated in HGSOC and is further stimulated by cisplatin treatment. Trametinib treatment causes cell cycle arrest in G1/0-phase and reduces tumor growth rate in vivo but does not induce cell death or reduce fraction of CD133+ stem-like cells, while increasing expression of stemness-associated genes instead. Transient trametinib treatment causes long-term increase in a subpopulation of cells with high aldehyde dehydrogenase (ALDH)1 activity that can survive and grow in non-adherent conditions. We conclude that MEK1/2 inhibition may be a promising approach to suppress ovarian cancer growth as a maintenance therapy. Promotion of stem-like properties upon MEK1/2 inhibition suggests a possible mechanism of resistance, so a combination with CSC-targeting drugs should be considered. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Therapy Resistance)
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19 pages, 4841 KiB  
Article
Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide
by Andres Vargas-Toscano, Ann-Christin Nickel, Guanzhang Li, Marcel Alexander Kamp, Sajjad Muhammad, Gabriel Leprivier, Ellen Fritsche, Roger A. Barker, Michael Sabel, Hans-Jakob Steiger, Wei Zhang, Daniel Hänggi and Ulf Dietrich Kahlert
Cancers 2020, 12(12), 3859; https://doi.org/10.3390/cancers12123859 - 21 Dec 2020
Cited by 25 | Viewed by 4099
Abstract
Glioblastoma (GBM) is a lethal disease with limited clinical treatment options available. Recently, a new inhibitor targeting the prominent cancer signaling pathway mTOR was discovered (Rapalink-1), but its therapeutic potential on stem cell populations of GBM is unknown. We applied a collection of [...] Read more.
Glioblastoma (GBM) is a lethal disease with limited clinical treatment options available. Recently, a new inhibitor targeting the prominent cancer signaling pathway mTOR was discovered (Rapalink-1), but its therapeutic potential on stem cell populations of GBM is unknown. We applied a collection of physiological relevant organoid-like stem cell models of GBM and studied the effect of RL1 exposure on various cellular features as well as on the expression of mTOR signaling targets and stem cell molecules. We also undertook combination treatments with this agent and clinical GBM treatments tumor treating fields (TTFields) and the standard-of-care drug temozolomide, TMZ. Low nanomolar (nM) RL1 treatment significantly reduced cell growth, proliferation, migration, and clonogenic potential of our stem cell models. It acted synergistically to reduce cell growth when applied in combination with TMZ and TTFields. We performed an in silico analysis from the molecular data of diverse patient samples to probe for a relationship between the expression of mTOR genes, and mesenchymal markers in different GBM cohorts. We supported the in silico results with correlative protein data retrieved from tumor specimens. Our study further validates mTOR signaling as a druggable target in GBM and supports RL1, representing a promising therapeutic target in brain oncology. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Therapy Resistance)
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20 pages, 2812 KiB  
Article
Melanoma Stem Cell-Like Phenotype and Significant Suppression of Immune Response within a Tumor Are Regulated by TRIM28 Protein
by Patrycja Czerwinska, Anna Maria Jaworska, Nikola Agata Wlodarczyk and Andrzej Adam Mackiewicz
Cancers 2020, 12(10), 2998; https://doi.org/10.3390/cancers12102998 - 15 Oct 2020
Cited by 25 | Viewed by 4028
Abstract
TRIM28 emerged as a guard of the intrinsic “state of cell differentiation”, facilitating self-renewal of pluripotent stem cells. Recent reports imply TRIM28 engagement in cancer stem cell (CSC) maintenance, although the exact mechanism remains unresolved. TRIM28 high expression is associated with worse melanoma [...] Read more.
TRIM28 emerged as a guard of the intrinsic “state of cell differentiation”, facilitating self-renewal of pluripotent stem cells. Recent reports imply TRIM28 engagement in cancer stem cell (CSC) maintenance, although the exact mechanism remains unresolved. TRIM28 high expression is associated with worse melanoma patient outcomes. Here, we investigated the association between TRIM28 level and melanoma stemness, and aligned it with the antitumor immune response to find the mechanism of “stemness high/immune low” melanoma phenotype acquisition. Based on the SKCM TCGA data, the TRIM28 expression profile, clinicopathological features, expression of correlated genes, and the level of stemness and immune scores were analyzed in patient samples. The biological function for differentially expressed genes was annotated with GSEA. Results were validated with additional datasets from R2: Genomics Analysis and Visualization Platform and in vitro with a panel of seven melanoma cell lines. All statistical analyses were accomplished using GraphPad Prism 8. TRIM28HIGH-expressing melanoma patients are characterized by worse outcomes and significantly different gene expression profiles than the TRIM28NORM cohort. TRIM28 high level related to higher melanoma stemness as measured with several distinct scores and TRIM28HIGH-expressing melanoma cell lines possess the greater potential of melanosphere formation. Moreover, TRIM28HIGH melanoma tumors were significantly depleted with infiltrating immune cells, especially cytotoxic T cells, helper T cells, and B cells. Furthermore, TRIM28 emerged as a good predictor of “stemness high/immune low” melanoma phenotype. Our data indicate that TRIM28 might facilitate this phenotype by direct repression of interferon signaling. TRIM28 emerged as a direct link between stem cell-like phenotype and attenuated antitumor immune response in melanoma, although further studies are needed to evaluate the direct mechanism of TRIM28-mediated stem-like phenotype acquisition. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Therapy Resistance)
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16 pages, 6264 KiB  
Article
Reciprocal Regulation Between Indoleamine 2,3-Dioxigenase 1 and Notch1 Involved in Radiation Response of Cervical Cancer Stem Cells
by Hui-Ying Low, Yueh-Chun Lee, Yi-Ju Lee, Hui-Lin Wang, Yu-I Chen, Peng-Ju Chien, Shao-Ti Li and Wen-Wei Chang
Cancers 2020, 12(6), 1547; https://doi.org/10.3390/cancers12061547 - 12 Jun 2020
Cited by 15 | Viewed by 3261
Abstract
Cervical cancer is the fourth most common cancer in women around the world. Cancer stem cells (CSCs) are responsible for cancer initiation, as well as resistance to radiation therapy, and are considered as the effective target of cancer therapy. Indoleamine 2,3-dioxygenase 1 (IDO1) [...] Read more.
Cervical cancer is the fourth most common cancer in women around the world. Cancer stem cells (CSCs) are responsible for cancer initiation, as well as resistance to radiation therapy, and are considered as the effective target of cancer therapy. Indoleamine 2,3-dioxygenase 1 (IDO1) mediates tryptophan metabolism and T cell suppression, but the immune-independent function of IDO1 in cancer behavior is not fully understood. Using tumorsphere cultivation for enriched CSCs, we firstly found that IDO1 was increased in HeLa and SiHa cervical cancer cells and in these two cell lines after radiation treatment. The radiosensitivity of HeLa and SiHa tumorsphere cells was increased after the inhibition of IDO1 through RNA interference or by the treatment of INCB-024360, an IDO1 inhibitor. With the treatment of kynurenine, the first breakdown product of the IDO1-mediated tryptophan metabolism, the radiosensitivity of HeLa and SiHa cells decreased. The inhibition of Notch1 by shRNA downregulated IDO1 expression in cervical CSCs and the binding of the intracellular domain of Notch (NICD) on the IDO1 promoter was reduced by Ro-4929097, a γ-secretase inhibitor. Moreover, the knockdown of IDO1 also decreased NICD expression in cervical CSCs, which was correlated with the reduced binding of aryl hydrocarbon receptor nuclear translocator to Notch1 promoter. In vivo treatment of INCB-0234360 sensitized SiHa xenograft tumors to radiation treatment in nude mice through increased DNA damage. Furthermore, kynurenine increased the tumorsphere formation capability and the expression of cancer stemness genes including Oct4 and Sox2. Our data provide a reciprocal regulation mechanism between IDO1 and Notch1 expression in cervical cancer cells and suggest that the IDO1 inhibitors may potentially be used as radiosensitizers. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Therapy Resistance)
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19 pages, 1802 KiB  
Article
Chromenopyrimidinone Controls Stemness and Malignancy by suppressing CD133 Expression in Hepatocellular Carcinoma
by Yeonhwa Song, Sanghwa Kim, Hyeryon Lee, Joo Hwan No, Hyung Chul Ryu, Jason Kim, Jee Woong Lim, Moonhee Kim, Inhee Choi and Haeng Ran Seo
Cancers 2020, 12(5), 1193; https://doi.org/10.3390/cancers12051193 - 8 May 2020
Cited by 9 | Viewed by 3273
Abstract
Hepatocellular carcinoma (HCC) is a highly malignant human cancer that has increasing mortality rates worldwide. Because CD133+ cells control tumor maintenance and progression, compounds that target CD133+ cancer cells could be effective in combating HCC. We found that the administration of [...] Read more.
Hepatocellular carcinoma (HCC) is a highly malignant human cancer that has increasing mortality rates worldwide. Because CD133+ cells control tumor maintenance and progression, compounds that target CD133+ cancer cells could be effective in combating HCC. We found that the administration of chromenopyrimidinone (CPO) significantly decreased spheroid formation and the number of CD133+ cells in mixed HCC cell populations. CPO not only significantly inhibited cell proliferation in HCC cells exhibiting different CD133 expression levels, but also effectively induced apoptosis and increased the expression of LC3-II in HCC cells. CPO also exhibits in vivo therapeutic efficiency in HCC. Specifically, CPO suppressed the expression of CD133 by altering the subcellular localization of CD133 from the membrane to lysosomes in CD133+ HCC cells. Moreover, CPO treatment induced point mutations in the ADRB1, APOB, EGR2, and UBE2C genes and inhibited the expression of these proteins in HCC and the expression of UBE2C is particularly controlled by CD133 expression among those four proteins in HCC. Our results suggested that CPO may suppress stemness and malignancies in vivo and in vitro by decreasing CD133 and UBE2C expression in CD133+ HCC. Our study provides evidence that CPO could act as a novel therapeutic agent for the effective treatment of CD133+ HCC. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Therapy Resistance)
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17 pages, 7854 KiB  
Article
SOX2 Expression and Transcriptional Activity Identifies a Subpopulation of Cancer Stem Cells in Sarcoma with Prognostic Implications
by Sofia T. Menendez, Veronica Rey, Lucia Martinez-Cruzado, M. Victoria Gonzalez, Alvaro Morales-Molina, Laura Santos, Verónica Blanco, Carlos Alvarez, Oscar Estupiñan, Eva Allonca, Juan Pablo Rodrigo, Javier García-Castro, Juana Maria Garcia-Pedrero and Rene Rodriguez
Cancers 2020, 12(4), 964; https://doi.org/10.3390/cancers12040964 - 13 Apr 2020
Cited by 21 | Viewed by 5207
Abstract
Stemness in sarcomas is coordinated by the expression of pluripotency factors, like SOX2, in cancer stem cells (CSC). The role of SOX2 in tumor initiation and progression has been well characterized in osteosarcoma. However, the pro-tumorigenic features of SOX2 have been scarcely investigated [...] Read more.
Stemness in sarcomas is coordinated by the expression of pluripotency factors, like SOX2, in cancer stem cells (CSC). The role of SOX2 in tumor initiation and progression has been well characterized in osteosarcoma. However, the pro-tumorigenic features of SOX2 have been scarcely investigated in other sarcoma subtypes. Here, we show that SOX2 depletion dramatically reduced the ability of undifferentiated pleomorphic sarcoma (UPS) cells to form tumorspheres and to initiate tumor growth. Conversely, SOX2 overexpression resulted in increased in vivo tumorigenicity. Moreover, using a reporter system (SORE6) which allows to monitor viable cells expressing SOX2 and/or OCT4, we found that SORE6+ cells were significantly more tumorigenic than the SORE6- subpopulation. In agreement with this findings, SOX2 expression in sarcoma patients was associated to tumor grade, differentiation, invasive potential and lower patient survival. Finally, we studied the effect of a panel of anti-tumor drugs on the SORE6+ cells of the UPS model and patient-derived chondrosarcoma lines. We found that the mithramycin analogue EC-8042 was the most efficient in reducing SORE6+ cells in vitro and in vivo. Overall, this study demonstrates that SOX2 is a pro-tumorigenic factor with prognostic potential in sarcoma. Moreover, SORE6 transcriptional activity is a bona fide CSC marker in sarcoma and constitutes an excellent biomarker for evaluating the efficacy of anti-tumor treatments on CSC subpopulations. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Therapy Resistance)
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Review

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22 pages, 1919 KiB  
Review
The Possible Role of Cancer Stem Cells in the Resistance to Kinase Inhibitors of Advanced Thyroid Cancer
by Fiorenza Gianì, Veronica Vella, Dario Tumino, Pasqualino Malandrino and Francesco Frasca
Cancers 2020, 12(8), 2249; https://doi.org/10.3390/cancers12082249 - 11 Aug 2020
Cited by 15 | Viewed by 5794
Abstract
Target therapy with various kinase inhibitors (KIs) has been extended to patients with advanced thyroid cancer, but only a subset of these compounds has displayed efficacy in clinical use. However, after an initial response to KIs, dramatic disease progression occurs in most cases. [...] Read more.
Target therapy with various kinase inhibitors (KIs) has been extended to patients with advanced thyroid cancer, but only a subset of these compounds has displayed efficacy in clinical use. However, after an initial response to KIs, dramatic disease progression occurs in most cases. With the discovery of cancer stem cells (CSCs), it is possible to postulate that thyroid cancer resistance to KI therapies, both intrinsic and acquired, may be sustained by this cell subtype. Indeed, CSCs have been considered as the main drivers of metastatic activity and therapeutic resistance, because of their ability to generate heterogeneous secondary cell populations and survive treatment by remaining in a quiescent state. Hence, despite the impressive progress in understanding of the molecular basis of thyroid tumorigenesis, drug resistance is still the major challenge in advanced thyroid cancer management. In this view, definition of the role of CSCs in thyroid cancer resistance may be crucial to identifying new therapeutic targets and preventing resistance to anti-cancer treatments and tumor relapse. The aim of this review is to elucidate the possible role of CSCs in the development of resistance of advanced thyroid cancer to current anti-cancer therapies and their potential implications in the management of these patients. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Therapy Resistance)
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