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Cells
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Targeting Cancer Stem Cell
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Targeting Cancer Stem Cell

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Stem Cells".

Viewed by 44279

Editor

Dr. Ming Luo

E-Mail Website
Collection Editor
Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA
Interests: breast cancer stem cells (BCSCs); CSC metabolism; epithelial–mesenchymal plasticity; redox signaling

Topical Collection Information

Dear Colleagues,

There is substantial evidence that many cancers are hierarchically organized and driven by a population of cells displaying stem cell properties. These cells are termed “cancer stem cells (CSCs)” or “tumor initiating cells (ITCs)”, which maintain or acquire the capacity to renew themselves as well as to differentiate into various progenies that form the bulk of a tumor. As CSCs are inherited with intrinsic abilities to confer therapeutic resistance and also play critical roles in tumor initiation, disease progression, and metastasis, these cells may be part of the reason that conventional treatment approaches including radio- and chemotherapy fail to cure cancer, especially those at advanced stages. Thus, the development of novel treatment strategies to effectively target this biologically and clinically important tumor cell population has the potential to significantly improve the outcomes for patients with cancer. This Topical Collection will summarize the latest molecular and cellular mechanisms involved in the regulation of CSCs, including the characterization of intrinsic and extrinsic signaling mechanisms that regulate their self-renewal and maintenance and the micro-environmental niches or stromal–tumor interactions that maintain or enhance CSC properties and epithelial–mesenchymal plasticity. The identification of potential metabolic vulnerabilities and molecular targets as potential therapies to specifically target CSCs will also be addressed.

We look forward to your contributions.

Dr. Ming Luo
Collection Editor

Manuscript Submission Information

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Keywords

  • cancer stem cells (CSCs)
  • CSC metabolism
  • epithelial–mesenchymal plasticity
  • CSC niches
  • self-renewal and maintenance
  • redox signaling
  • metabolic vulnerabilities

Published Papers (10 papers)

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2022

Jump to: 2021

18 pages, 1393 KiB  
Review
Targeting Gastric Cancer Stem Cells to Enhance Treatment Response
by Xionghui Rao, Chaojun Zhang, Huixing Luo, Jianbao Zhang, Zhehong Zhuang, Zhihao Liang and Xiaobin Wu
Cells 2022, 11(18), 2828; https://doi.org/10.3390/cells11182828 - 10 Sep 2022
Cited by 44 | Viewed by 5552
Abstract
Gastric cancer (GC) was the fourth deadliest cancer in the world in 2020, and about 770,000 people died from GC that year. The death of patients with GC is mainly caused by the metastasis, recurrence, and chemotherapy resistance of GC cells. The cancer [...] Read more.
Gastric cancer (GC) was the fourth deadliest cancer in the world in 2020, and about 770,000 people died from GC that year. The death of patients with GC is mainly caused by the metastasis, recurrence, and chemotherapy resistance of GC cells. The cancer stem cell theory defines cancer stem cells (CSCs) as a key factor in the metastasis, recurrence, and chemotherapy resistance of cancer. It considers targeting gastric cancer stem cells (GCSCs) to be an effective method for the treatment of GC. For GCSCs, genes or noncoding RNAs are important regulatory factors. Many experimental studies have found that some drugs can target the stemness of gastric cancer by regulating these genes or noncoding RNAs, which may bring new directions for the clinical treatment of gastric cancer. Therefore, this review mainly discusses related genes or noncoding RNAs in GCSCs and drugs that target its stemness, thereby providing some information for the treatment of GC. Full article
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2021

Jump to: 2022

17 pages, 4544 KiB  
Article
p66α Suppresses Breast Cancer Cell Growth and Migration by Acting as Co-Activator of p53
by Qun Zhang, Yihong Zhang, Jie Zhang, Dan Zhang, Mengying Li, Han Yan, Hui Zhang, Liwei Song, Jiamin Wang, Zhaoyuan Hou, Yunhai Yang and Xiuqun Zou
Cells 2021, 10(12), 3593; https://doi.org/10.3390/cells10123593 - 20 Dec 2021
Cited by 4 | Viewed by 3450
Abstract
p66α is a GATA zinc finger domain-containing transcription factor that has been shown to be essential for gene silencing by participating in the NuRD complex. Several studies have suggested that p66α is a risk gene for a wide spectrum of diseases such as [...] Read more.
p66α is a GATA zinc finger domain-containing transcription factor that has been shown to be essential for gene silencing by participating in the NuRD complex. Several studies have suggested that p66α is a risk gene for a wide spectrum of diseases such as diabetes, schizophrenia, and breast cancer; however, its biological role has not been defined. Here, we report that p66α functions as a tumor suppressor to inhibit breast cancer cell growth and migration, evidenced by the fact that the depletion of p66α results in accelerated tumor growth and migration of breast cancer cells. Mechanistically, immunoprecipitation assays identify p66α as a p53-interacting protein that binds the DNA-binding domain of p53 molecule predominantly via its CR2 domain. Depletion of p66α in multiple breast cells results in decreased expression of p53 target genes, while over-expression of p66α results in increased expression of these target genes. Moreover, p66α promotes the transactivity of p53 by enhancing p53 binding at target promoters. Together, these findings demonstrate that p66α is a tumor suppressor by functioning as a co-activator of p53. Full article
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15 pages, 5476 KiB  
Article
Death-Associated Protein Kinase 1 Inhibits Progression of Thyroid Cancer by Regulating Stem Cell Markers
by Mi-Hyeon You, Woo Kyung Lee, Meihua Jin, Dong Eun Song, Sheue-yann Cheng, Tae Yong Kim, Won Bae Kim, Min Ji Jeon and Won Gu Kim
Cells 2021, 10(11), 2994; https://doi.org/10.3390/cells10112994 - 3 Nov 2021
Cited by 8 | Viewed by 3110
Abstract
The activation of metastatic reprogramming is vital for cancer metastasis, but little is known about its mechanism. This study investigated the potential role of death-associated protein kinase 1 (DAPK1) in thyroid cancer progression. We generated knockdown (KD) DAPK1 using siRNA or shRNA in [...] Read more.
The activation of metastatic reprogramming is vital for cancer metastasis, but little is known about its mechanism. This study investigated the potential role of death-associated protein kinase 1 (DAPK1) in thyroid cancer progression. We generated knockdown (KD) DAPK1 using siRNA or shRNA in 8505C and KTC-1 cell lines, which we transiently or stably overexpressed in MDA-T32 and BCPAP cell lines. DAPK1 KD in 8505C and KTC-1 cells significantly increased cell proliferation and colony formation compared with controls. We observed significant inhibition of cancer cell invasion in cells overexpressing DAPK1, but the opposite effect in KD cells. Tumorsphere formation significantly increased after inhibition of DAPK1 expression in 8505C cells and was significantly suppressed in DAPK1-overexpressing MDA-T32 and BCPAP cells. DAPK1 overexpression inhibited mRNA and protein levels of stem markers (OCT4, Sox2, KLF4, and Nanog). Furthermore, the expression of these markers increased after KD of DAPK1 in 8505C cells. Mechanistic studies suggest that DAPK1 may modulate the expression of stem cell markers through the inhibition of β-catenin pathways. These findings were consistent with the public data and our thyroid tissue analysis, which showed higher DAPK1 expression was associated with advanced-stage papillary thyroid cancer with a higher stemness index and lower disease-free survival. Full article
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13 pages, 3825 KiB  
Article
Single-Cell Proteomic Profiling Identifies Nanoparticle Enhanced Therapy for Triple Negative Breast Cancer Stem Cells
by Wenzheng Wang, Bo Lei, Lin Li, Jianyu Liu, Zhihui Li, Yuheng Pang, Tong Liu and Zhigao Li
Cells 2021, 10(11), 2842; https://doi.org/10.3390/cells10112842 - 22 Oct 2021
Cited by 5 | Viewed by 2760
Abstract
Breast cancer remains a major cause of cancer-related deaths in women worldwide. Chemotherapy-promoted stemness and enhanced stem cell plasticity in breast cancer is a cause for great concern. The discovery of drugs targeting BCSCs was suggested to be an important advancement in the [...] Read more.
Breast cancer remains a major cause of cancer-related deaths in women worldwide. Chemotherapy-promoted stemness and enhanced stem cell plasticity in breast cancer is a cause for great concern. The discovery of drugs targeting BCSCs was suggested to be an important advancement in the establishment of therapy that improves the efficacy of chemotherapy. In this work, by using single-cell mass cytometry, we observed that stemness in spheroid-forming cells derived from MDA-MB-231 cells was significantly increased after doxorubicin administration and up-regulated integrin αvβ3 expression was also observed. An RGD-included nanoparticle (CS-V) was designed, and it was found that it could promote doxorubicin’s efficacy against MDA-MB-231 spheroid cells. The above observations suggested that the combination of RGD-included nanoparticles (CS-V) with the chemo-drug doxorubicin could be developed as a potential therapy for breast cancer. Full article
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25 pages, 1330 KiB  
Review
Modulation of Immune Components on Stem Cell and Dormancy in Cancer
by Xiaofan Jiang, Lu Liang, Guanglei Chen and Caigang Liu
Cells 2021, 10(11), 2826; https://doi.org/10.3390/cells10112826 - 21 Oct 2021
Cited by 14 | Viewed by 3725
Abstract
Cancer stem cells (CSCs) refer to a certain subpopulation within the tumor entity that is characterized by restricted cellular proliferation and multipotent differentiation potency. The existence of CSCs has been proven to contribute to the heterogeneity of malignancies, accounting for intensified tumorigenesis, treatment [...] Read more.
Cancer stem cells (CSCs) refer to a certain subpopulation within the tumor entity that is characterized by restricted cellular proliferation and multipotent differentiation potency. The existence of CSCs has been proven to contribute to the heterogeneity of malignancies, accounting for intensified tumorigenesis, treatment resistance, and metastatic spread. Dormancy was proposed as a reversible state of cancer cells that are temporarily arrested in the cell cycle, possessing several hallmarks that facilitate their survival within a devastating niche. This transient period is evoked to enter an actively proliferating state by multiple regulatory alterations, and one of the most significant and complex factors comes from local and systemic inflammatory reactions and immune components. Although CSCs and dormant cancer cells share several similarities, the clear relationship between these two concepts remains unclear. Thus, the detailed mechanism of immune cells interacting with CSCs and dormant cancer cells also warrants elucidation for prevention of cancer relapse and metastasis. In this review, we summarize recent findings and prospective studies on CSCs and cancer dormancy to conclude the relationship between these two concepts. Furthermore, we aim to outline the mechanism of immune components in interfering with CSCs and dormant cancer cells to provide a theoretical basis for the prevention of relapse and metastasis. Full article
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18 pages, 13182 KiB  
Review
Redox Control of the Dormant Cancer Cell Life Cycle
by Bowen Li, Yichun Huang, Hui Ming, Edouard C. Nice, Rongrong Xuan and Canhua Huang
Cells 2021, 10(10), 2707; https://doi.org/10.3390/cells10102707 - 9 Oct 2021
Cited by 21 | Viewed by 4295
Abstract
Following efficient tumor therapy, some cancer cells may survive through a dormancy process, contributing to tumor recurrence and worse outcomes. Dormancy is considered a process where most cancer cells in a tumor cell population are quiescent with no, or only slow, proliferation. Recent [...] Read more.
Following efficient tumor therapy, some cancer cells may survive through a dormancy process, contributing to tumor recurrence and worse outcomes. Dormancy is considered a process where most cancer cells in a tumor cell population are quiescent with no, or only slow, proliferation. Recent advances indicate that redox mechanisms control the dormant cancer cell life cycle, including dormancy entrance, long-term dormancy, and metastatic relapse. This regulatory network is orchestrated mainly through redox modification on key regulators or global change of reactive oxygen species (ROS) levels in dormant cancer cells. Encouragingly, several strategies targeting redox signaling, including sleeping, awaking, or killing dormant cancer cells are currently under early clinical evaluation. However, the molecular mechanisms underlying redox control of the dormant cancer cell cycle are poorly understood and need further exploration. In this review, we discuss the underlying molecular basis of redox signaling in the cell life cycle of dormant cancer and the potential redox-based targeting strategies for eliminating dormant cancer cells. Full article
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16 pages, 5186 KiB  
Article
Co-Expression of CD34, CD90, OV-6 and Cell-Surface Vimentin Defines Cancer Stem Cells of Hepatoblastoma, Which Are Affected by Hsp90 Inhibitor 17-AAG
by Mieun Lee-Theilen, Julia R. Hadhoud, Giulietta Volante, Delaine D. Fadini, Julia Eichhorn, Udo Rolle and Henning C. Fiegel
Cells 2021, 10(10), 2598; https://doi.org/10.3390/cells10102598 - 29 Sep 2021
Cited by 6 | Viewed by 2728
Abstract
Cancer stem cells (CSCs) are nowadays one of the major focuses in tumor research since this subpopulation was revealed to be a great obstacle for successful treatment. The identification of CSCs in pediatric solid tumors harbors major challenges because of the immature character [...] Read more.
Cancer stem cells (CSCs) are nowadays one of the major focuses in tumor research since this subpopulation was revealed to be a great obstacle for successful treatment. The identification of CSCs in pediatric solid tumors harbors major challenges because of the immature character of these tumors. Here, we present CD34, CD90, OV-6 and cell-surface vimentin (csVimentin) as reliable markers to identify CSCs in hepatoblastoma cell lines. We were able to identify CSC characteristics for the subset of CD34+CD90+OV-6+csVimentin+-co-expressing cells, such as pluripotency, self-renewal, increased expression of EMT markers and migration. Treatment with Cisplatin as the standard chemotherapeutic drug in hepatoblastoma therapy further revealed the chemo-resistance of this subset, which is a main characteristic of CSCs. When we treated the cells with the Hsp90 inhibitor 17-AAG, we observed a significant reduction in the CSC subset. With our study, we identified CSCs of hepatoblastoma using CD34, CD90, OV-6 and csVimentin. This set of markers could be helpful to estimate the success of novel therapeutic approaches, as resistant CSCs are responsible for tumor relapses. Full article
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21 pages, 3465 KiB  
Review
The Roles of the Let-7 Family of MicroRNAs in the Regulation of Cancer Stemness
by Yuxi Ma, Na Shen, Max S. Wicha and Ming Luo
Cells 2021, 10(9), 2415; https://doi.org/10.3390/cells10092415 - 14 Sep 2021
Cited by 76 | Viewed by 8863
Abstract
Cancer has long been viewed as a disease of normal development gone awry. Cancer stem-like cells (CSCs), also termed as tumor-initiating cells (TICs), are increasingly recognized as a critical tumor cell population that drives not only tumorigenesis but also cancer progression, treatment resistance [...] Read more.
Cancer has long been viewed as a disease of normal development gone awry. Cancer stem-like cells (CSCs), also termed as tumor-initiating cells (TICs), are increasingly recognized as a critical tumor cell population that drives not only tumorigenesis but also cancer progression, treatment resistance and metastatic relapse. The let-7 family of microRNAs (miRNAs), first identified in C. elegans but functionally conserved from worms to human, constitutes an important class of regulators for diverse cellular functions ranging from cell proliferation, differentiation and pluripotency to cancer development and progression. Here, we review the current state of knowledge regarding the roles of let-7 miRNAs in regulating cancer stemness. We outline several key RNA-binding proteins, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) involved in the regulation of let-7 biogenesis, maturation and function. We then highlight key gene targets and signaling pathways that are regulated or mutually regulated by the let-7 family of miRNAs to modulate CSC characteristics in various types of cancer. We also summarize the existing evidence indicating distinct metabolic pathways regulated by the let-7 miRNAs to impact CSC self-renewal, differentiation and treatment resistance. Lastly, we review current preclinical studies and discuss the clinical implications for developing let-7-based replacement strategies as potential cancer therapeutics that can be delivered through different platforms to target CSCs and reduce/overcome treatment resistance when applied alone or in combination with current chemo/radiation or molecularly targeted therapies. By specifically targeting CSCs, these strategies have the potential to significantly improve the efficacy of cancer therapies. Full article
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21 pages, 7778 KiB  
Article
Comprehensive Omics Analysis of a Novel Small-Molecule Inhibitor of Chemoresistant Oncogenic Signatures in Colorectal Cancer Cell with Antitumor Effects
by Tse-Hung Huang, Ntlotlang Mokgautsi, Yan-Jiun Huang, Alexander T. H. Wu and Hsu-Shan Huang
Cells 2021, 10(8), 1970; https://doi.org/10.3390/cells10081970 - 3 Aug 2021
Cited by 11 | Viewed by 4452
Abstract
Tumor recurrence from cancer stem cells (CSCs) and metastasis often occur post-treatment in colorectal cancer (CRC), leading to chemoresistance and resistance to targeted therapy. MYC is a transcription factor in the nuclei that modulates cell growth and development, and regulates immune response in [...] Read more.
Tumor recurrence from cancer stem cells (CSCs) and metastasis often occur post-treatment in colorectal cancer (CRC), leading to chemoresistance and resistance to targeted therapy. MYC is a transcription factor in the nuclei that modulates cell growth and development, and regulates immune response in an antitumor direction by mediating programmed death ligand 1 (PD-L1) and promoting CRC tumor recurrence after adjuvant chemotherapy. However, the molecular mechanism through which c-MYC maintains stemness and confers treatment resistance still remains elusive in CRC. In addition, recent reports demonstrated that CRC solid colon tumors expresses C-X-C motif chemokine ligand 8 (CXCL8). Expression of CXCL8 in CRC was reported to activate the expression of PD-L1 immune checkpoint through c-MYC, this ultimately induces chemoresistance in CRC. Accumulating studies have also demonstrated increased expression of CXCL8, matrix metalloproteinase 7 (MMP7), tissue inhibitor of metalloproteinase 1 (TIMP1), and epithelial-to-mesenchymal transition (EMT) components, in CRC tumors suggesting their potential collaboration to promote EMT and CSCs. TIMP1 is MMP-independent and regulates cell development and apoptosis in various cancer cell types, including CRC. Recent studies showed that TIMP1 cleaves CXCL8 on its chemoattractant, thereby influencing its mechanistic response to therapy. This therefore suggests crosstalk among the c-MYC/CXCL8/TIMP1 oncogenic signatures. In this study, we explored computer simulations through bioinformatics to identify and validate that the MYC/CXCL8/TIMP1 oncogenic signatures are overexpressed in CRC, Moreover, our docking results exhibited putative binding affinities of the above-mentioned oncogenes, with our novel small molecule, RV59, Finally, we demonstrated the anticancer activities of RV59 against NCI human CRC cancer cell lines both as single-dose and dose-dependent treatments, and also demonstrated the MYC/CXCL8/TIMP1 signaling pathway as a potential RV59 drug target. Full article
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11 pages, 972 KiB  
Review
Cancer Stem Cells and Neovascularization
by Fengkai Li, Jiahui Xu and Suling Liu
Cells 2021, 10(5), 1070; https://doi.org/10.3390/cells10051070 - 30 Apr 2021
Cited by 38 | Viewed by 3976
Abstract
Cancer stem cells (CSCs) refer to a subpopulation of cancer cells responsible for tumorigenesis, metastasis, and drug resistance. Increasing evidence suggests that CSC-associated tumor neovascularization partially contributes to the failure of cancer treatment. In this review, we discuss the roles of CSCs on [...] Read more.
Cancer stem cells (CSCs) refer to a subpopulation of cancer cells responsible for tumorigenesis, metastasis, and drug resistance. Increasing evidence suggests that CSC-associated tumor neovascularization partially contributes to the failure of cancer treatment. In this review, we discuss the roles of CSCs on tumor-associated angiogenesis via trans-differentiation or forming the capillary-like vasculogenic mimicry, as well as the roles of CSCs on facilitating endothelial cell-involved angiogenesis to support tumor progression and metastasis. Furthermore, we discuss the underlying regulation mechanisms, including the intrinsic signals of CSCs and the extrinsic signals such as cytokines from the tumor microenvironment. Further research is required to identify and verify some novel targets to develop efficient therapeutic approaches for more efficient cancer treatment through interfering CSC-mediated neovascularization. Full article
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