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Yang Y, Fang Y, Du X, Ying Z, Lu X, Zhou J. Application of nanoparticles with activating STING pathway function in tumor synergistic therapy. Int Immunopharmacol 2025; 148:114013. [PMID: 39823790 DOI: 10.1016/j.intimp.2025.114013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/21/2024] [Accepted: 01/01/2025] [Indexed: 01/20/2025]
Abstract
Although immunotherapy is currently one of the most promising methods for cancer treatment, its clinical application is limited due to issues such as excessive autoimmune responses and lack of specificity. Therefore, there is a need to improve immunotherapy by integrating emerging medical technologies with traditional treatments. The activation of the cGAS-STING pathway plays a crucial role in innate immunity and antiviral defense, making it highly promising for immunotherapy and attracting significant attention. In recent years, research on nanomaterials and immunotherapy has achieved groundbreaking progress in the medical field. Due to their unique size, shape, stiffness, surface effects, and quantum size effects, nanomaterials can either carry STING activators or directly activate the STING pathway, offering new opportunities for tumor-specific immunotherapy. These unique advantages of nanomaterials have opened up broader prospects for nanoparticle-based therapies targeting the STING pathway. This paper summarizes the current research on utilizing nanomaterials to activate the STING pathway, detailing the characteristics, classifications, and different approaches for targeting tumor cells. Additionally, it focuses on the latest advancements in combined nanotherapies based on cGAS-STING pathway activation, including the integration of nanomaterial-mediated STING pathway activation with immunotherapy, radiotherapy, chemotherapy, targeted therapy, and photodynamic therapy. This provides new ideas for nanoparticle-based combination therapies involving the STING pathway.
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Affiliation(s)
- Yi Yang
- School of Medical Imaging, Hangzhou Medical College, Hangzhou 310053, Zhejiang, China
| | - Yaning Fang
- School of Medical Imaging, Hangzhou Medical College, Hangzhou 310053, Zhejiang, China
| | - Xinyu Du
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou 310053, Zhejiang, China
| | - Zheye Ying
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou 310053, Zhejiang, China
| | - Xiwen Lu
- Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, Zhejiang 315201, China.
| | - Jing Zhou
- Department of Chemoradiotherapy, Ningbo NO.2 Hospital, Ningbo, Zhejiang, 315000, China.
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El-Tanani M, Rabbani SA, Satyam SM, Rangraze IR, Wali AF, El-Tanani Y, Aljabali AAA. Deciphering the Role of Cancer Stem Cells: Drivers of Tumor Evolution, Therapeutic Resistance, and Precision Medicine Strategies. Cancers (Basel) 2025; 17:382. [PMID: 39941751 PMCID: PMC11815874 DOI: 10.3390/cancers17030382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/17/2025] [Accepted: 01/23/2025] [Indexed: 02/16/2025] Open
Abstract
Cancer stem cells (CSCs) play a central role in tumor progression, recurrence, and resistance to conventional therapies, making them a critical focus in oncology research. This review provides a comprehensive analysis of CSC biology, emphasizing their self-renewal, differentiation, and dynamic interactions with the tumor microenvironment (TME). Key signaling pathways, including Wnt, Notch, and Hedgehog, are discussed in detail to highlight their potential as therapeutic targets. Current methodologies for isolating CSCs are critically examined, addressing their advantages and limitations in advancing precision medicine. Emerging technologies, such as CRISPR/Cas9 and single-cell sequencing, are explored for their transformative potential in unraveling CSC heterogeneity and informing therapeutic strategies. The review also underscores the pivotal role of the TME in supporting CSC survival, promoting metastasis, and contributing to therapeutic resistance. Challenges arising from CSC-driven tumor heterogeneity and dormancy are analyzed, along with strategies to mitigate these barriers, including novel therapeutics and targeted approaches. Ethical considerations and the integration of artificial intelligence in designing CSC-specific therapies are discussed as essential elements of future research. The manuscript advocates for a multi-disciplinary approach that combines innovative technologies, advanced therapeutics, and collaborative research to address the complexities of CSCs. By bridging existing gaps in knowledge and fostering advancements in personalized medicine, this review aims to guide the development of more effective cancer treatment strategies, ultimately improving patient outcomes.
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Affiliation(s)
- Mohamed El-Tanani
- RAK College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah P.O. Box 11172, United Arab Emirates
| | - Syed Arman Rabbani
- Department of Clinical Pharmacy, RAK College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah P.O. Box 11172, United Arab Emirates
| | - Shakta Mani Satyam
- Department of Pharmacology, RAK College of Medical Sciences, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah P.O. Box 11172, United Arab Emirates
| | - Imran Rashid Rangraze
- Department of Internal Medicine, RAK College of Medical Sciences, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah P.O. Box 11172, United Arab Emirates
| | - Adil Farooq Wali
- Department of Medicinal Chemistry, RAK College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah P.O. Box 11172, United Arab Emirates
| | | | - Alaa A. A. Aljabali
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Yarmouk University, Irbid 21163, Jordan
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Wu Q, Nandi D, Sharma D. TRIM-endous functional network of tripartite motif 29 (TRIM29) in cancer progression and beyond. Cancer Metastasis Rev 2024; 44:16. [PMID: 39644332 PMCID: PMC11625080 DOI: 10.1007/s10555-024-10226-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 10/16/2024] [Indexed: 12/09/2024]
Abstract
While most Tripartite motif (TRIM) family proteins are E3 ubiquitin ligases, some members have functions beyond the regulation of ubiquitination, impacting normal physiological processes and disease progression. TRIM29, an important member of the TRIM family, exerts a predominant influence on cancer growth, epithelial-to-mesenchymal transition, stemness and metastatic progression by directly potentiating multiple canonical oncogenic pathways. The cancer-promoting effect of TRIM29 is also evident in metabolic interventions and interference with the efficacy of cancer therapeutics. As expected for any key node in cancer, the expression of TRIM29 is tightly regulated by non-coding RNAs, epigenetic modulation, and post-translational regulation. A systematic discussion of how TRIM29 is regulated in cancer, its influences on cancer progression, and its impact on cancer therapeutics is presented in this review. We also explore the context-dependent alterations between TRIM29 function from oncogenic to tumor suppression. As TRIM29 is involved in multiple aspects of cancer progression, a better understanding of its biological impact in cancer may help improve prognosis and develop novel therapeutic combinations, leading to improved personalized cancer care.
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Affiliation(s)
- Qitong Wu
- Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Deeptashree Nandi
- Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Dipali Sharma
- Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB 1, Rm 145, Baltimore, MD, 21231, USA.
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Alcala S, Serralta San Martin G, Muñoz-Fernández de Legaria M, Moreno-Rubio J, Salinas S, López-Gil JC, Rojo López JA, Martínez Alegre J, Cortes Bandy DA, Zambrana F, Jiménez-Gordo AM, Casado E, López-Gómez M, Sainz B. Autofluorescent Cancer Stem Cells: Potential Biomarker to Predict Recurrence in Resected Colorectal Tumors. CANCER RESEARCH COMMUNICATIONS 2024; 4:2575-2588. [PMID: 39225547 PMCID: PMC11445700 DOI: 10.1158/2767-9764.crc-24-0188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 07/27/2024] [Accepted: 08/29/2024] [Indexed: 09/04/2024]
Abstract
Cancer stem cells (CSC) in colorectal cancer drive intratumoral heterogeneity and distant metastases. Previous research from our group showed that CSCs can be easily detected by autofluorescence (AF). The aim of the present study was to evaluate the potential role of AF CSCs as a prognostic biomarker for colorectal cancer relapse. Seventy-five freshly resected tumors were analyzed by flow cytometry. AF was categorized as high (H-AF) or low, and the results were correlated with histologic features [grade of differentiation, presence of metastases in lymph nodes (LN), perivascular and lymphovascular invasion] and clinical variables (time to relapse and overall survival). Nineteen of the 75 (25.3%) patients experienced relapse (local or distant); of these 19 patients, 13 showed positive LNs and 6 had H-AF. Of note, four of them died before 5 years. Although patients with H-AF CSC percentages in the global population experienced 1.5 times increased relapse [HR, 1.47; 95% confidence interval (0.60-3.63)], patients with H-AF CSC percentages and LN metastases had the highest risk of relapse [HR, 7.92; P < 0.004; 95% confidence interval (1.97-31.82)]. These data support AF as an accurate and feasible marker to identify CSCs in resected colorectal cancer. A strong statistical association between H-AF CSCs and the risk of relapse was observed, particularly in patients with positive LNs, suggesting that H-AF patients might benefit from adjuvant chemotherapy regimens and intensive surveillance due to their high propensity to experience disease recurrence. Significance: AF has been proven to be an accurate biomarker for CSC identification; however, to date, their role as a prognostic factor after resection of colorectal cancer tumors has not been investigated. Our results show that determining the presence of AF CSCs after tumor resection has prognostic value and represents a potentially important tool for the management of patients with colorectal cancer.
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Affiliation(s)
- Sonia Alcala
- Department of Biochemistry, School of Medicine, Autónoma University of Madrid and Department of Cancer, Instituto de Investigaciones Biomédicas (IIBm) Sols-Morreale (CSIC-UAM), Madrid, Spain.
- Biomarkers and Personalized Approach to Cancer (BIOPAC) Group, Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
| | - Gonzalo Serralta San Martin
- Department of Internal Medicine, Infanta Sofía University Hospital, FIIB HUIS HHEN, Madrid, Spain.
- Universidad Europea de Madrid, Madrid, Spain.
| | | | - Juan Moreno-Rubio
- Department of Medical Oncology, Infanta Sofía University Hospital, FIIB HUIS HHEN, Madrid, Spain.
- Precision Nutrition and Cancer Program, Clinical Oncology Group, IMDEA Food Institute, CEI UAM-CSIC, Madrid, Spain.
| | - Silvia Salinas
- Department of Pathology, Infanta Sofía University Hospital, FIIB HUIS HHEN, Madrid, Spain.
| | - Juan Carlos López-Gil
- Department of Biochemistry, School of Medicine, Autónoma University of Madrid and Department of Cancer, Instituto de Investigaciones Biomédicas (IIBm) Sols-Morreale (CSIC-UAM), Madrid, Spain.
- Biomarkers and Personalized Approach to Cancer (BIOPAC) Group, Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
| | - José Alberto Rojo López
- Department of General Surgery, Infanta Sofía University Hospital, FIIB HUIS HHEN, Madrid, Spain.
| | - Javier Martínez Alegre
- Universidad Europea de Madrid, Madrid, Spain.
- Department of General Surgery, Infanta Sofía University Hospital, FIIB HUIS HHEN, Madrid, Spain.
| | | | - Francisco Zambrana
- Universidad Europea de Madrid, Madrid, Spain.
- Department of Medical Oncology, Infanta Sofía University Hospital, FIIB HUIS HHEN, Madrid, Spain.
- Precision Nutrition and Cancer Program, Clinical Oncology Group, IMDEA Food Institute, CEI UAM-CSIC, Madrid, Spain.
| | - Ana-María Jiménez-Gordo
- Universidad Europea de Madrid, Madrid, Spain.
- Department of Medical Oncology, Infanta Sofía University Hospital, FIIB HUIS HHEN, Madrid, Spain.
- Precision Nutrition and Cancer Program, Clinical Oncology Group, IMDEA Food Institute, CEI UAM-CSIC, Madrid, Spain.
| | - Enrique Casado
- Universidad Europea de Madrid, Madrid, Spain.
- Department of Medical Oncology, Infanta Sofía University Hospital, FIIB HUIS HHEN, Madrid, Spain.
- Precision Nutrition and Cancer Program, Clinical Oncology Group, IMDEA Food Institute, CEI UAM-CSIC, Madrid, Spain.
| | - Miriam López-Gómez
- Universidad Europea de Madrid, Madrid, Spain.
- Department of Medical Oncology, Infanta Sofía University Hospital, FIIB HUIS HHEN, Madrid, Spain.
| | - Bruno Sainz
- Department of Biochemistry, School of Medicine, Autónoma University of Madrid and Department of Cancer, Instituto de Investigaciones Biomédicas (IIBm) Sols-Morreale (CSIC-UAM), Madrid, Spain.
- Biomarkers and Personalized Approach to Cancer (BIOPAC) Group, Area 3 Cancer, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
- Centro de Investigación Biomédica en Red, Área Cáncer, CIBERONC, ISCIII, Madrid, Spain.
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Heidarnejad K, Nooreddin Faraji S, Mahfoozi S, Ghasemi Z, Sadat Dashti F, Asadi M, Ramezani A. Breast cancer immunotherapy using scFv antibody-based approaches, a systematic review. Hum Immunol 2024; 85:111090. [PMID: 39214066 DOI: 10.1016/j.humimm.2024.111090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 08/07/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024]
Abstract
Breast cancer is considered as the most common malignancy in women and the second leading cause of death related to cancer. Recombinant DNA technologies accelerated the development of antibody-based cancer therapy, which is effective in a broad range of cancers. The objective of the present study was to perform a systematic review on breast cancer immunotherapy using single-chain fragment variable (scFv) antibody formats. Searches were performed up to March 2023 using PubMed, Scopus, and Web of Science (ISI) databases. Three reviewers independently assessed study eligibility, data extraction, and evaluated the methodological quality of included primary studies. Different immunotherapy approaches have been identified and the most common approaches were scFv-conjugates, followed by simple scFvs and chimeric antigen receptor (CAR) therapy, respectively. Among breast cancer antigens, HER superfamily, CD family, and EpCAM were applied as the most important breast cancer immunotherapy targets. The present study shed more lights on scFv-based breast cancer immunotherapy approaches.
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Affiliation(s)
- Kamran Heidarnejad
- Department of Immunology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Nooreddin Faraji
- Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Shirin Mahfoozi
- Department of Immunology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Ghasemi
- Department of Immunology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fateme Sadat Dashti
- Reproductive Immunology Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Maryam Asadi
- School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amin Ramezani
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
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Wang Z, Thakare RP, Chitale S, Mishra AK, Goldstein SI, Fan AC, Li R, Zhu LJ, Brown LE, Cencic R, Huang S, Green MR, Pelletier J, Malonia SK, Porco JA. Identification of Rocaglate Acyl Sulfamides as Selective Inhibitors of Glioblastoma Stem Cells. ACS CENTRAL SCIENCE 2024; 10:1640-1656. [PMID: 39220711 PMCID: PMC11363328 DOI: 10.1021/acscentsci.4c01073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 07/22/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024]
Abstract
Glioblastoma (GBM) is the most aggressive and frequently occurring type of malignant brain tumor in adults. The initiation, progression, and recurrence of malignant tumors are known to be driven by a small subpopulation of cells known as tumor-initiating cells or cancer stem cells (CSCs). GBM CSCs play a pivotal role in orchestrating drug resistance and tumor relapse. As a prospective avenue for GBM intervention, the targeted suppression of GBM CSCs holds considerable promise. In this study, we found that rocaglates, compounds which are known to inhibit translation via targeting of the DEAD-box helicase eIF4A, exert a robust, dose-dependent cytotoxic impact on GBM CSCs with minimal killing of nonstem GBM cells. Subsequent optimization identified novel rocaglate derivatives (rocaglate acyl sulfamides or Roc ASFs) that selectively inhibit GBM CSCs with nanomolar EC50 values. Furthermore, comparative evaluation of a lead CSC-optimized Roc ASF across diverse mechanistic and target profiling assays revealed suppressed translation inhibition relative to that of other CSC-selective rocaglates, with enhanced targeting of the DEAD-box helicase DDX3X, a recently identified secondary target of rocaglates. Overall, these findings suggest a promising therapeutic strategy for targeting GBM CSCs.
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Affiliation(s)
- Zihao Wang
- Department
of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, United States
| | - Ritesh P. Thakare
- Department
of Molecular, Cell and Cancer Biology, University
of Massachusetts Chan Medical School, Worcester, Massachusetts 01605, United States
| | - Shalaka Chitale
- Department
of Molecular, Cell and Cancer Biology, University
of Massachusetts Chan Medical School, Worcester, Massachusetts 01605, United States
| | - Alok K. Mishra
- Department
of Molecular, Cell and Cancer Biology, University
of Massachusetts Chan Medical School, Worcester, Massachusetts 01605, United States
| | - Stanley I. Goldstein
- Boston
University Target Discovery Laboratory (BU-TDL), Boston, Massachusetts 02215, United States
- Department
of Pharmacology, Physiology, and Biophysics, Boston University, Boston, Massachusetts 02118, United States
| | - Alice C. Fan
- Department
of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, United States
- Boston
University Target Discovery Laboratory (BU-TDL), Boston, Massachusetts 02215, United States
| | - Rui Li
- Department
of Molecular, Cell and Cancer Biology, University
of Massachusetts Chan Medical School, Worcester, Massachusetts 01605, United States
- Department
of Molecular Medicine and Program in Bioinformatics and Integrative
Biology, University of Massachusetts Chan
Medical School, Worcester, Massachusetts 01605, United States
| | - Lihua Julie Zhu
- Department
of Molecular, Cell and Cancer Biology, University
of Massachusetts Chan Medical School, Worcester, Massachusetts 01605, United States
- Department
of Molecular Medicine and Program in Bioinformatics and Integrative
Biology, University of Massachusetts Chan
Medical School, Worcester, Massachusetts 01605, United States
| | - Lauren E. Brown
- Department
of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, United States
| | - Regina Cencic
- Department
of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
| | - Sidong Huang
- Department
of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
| | - Michael R. Green
- Department
of Molecular, Cell and Cancer Biology, University
of Massachusetts Chan Medical School, Worcester, Massachusetts 01605, United States
| | - Jerry Pelletier
- Department
of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
| | - Sunil K. Malonia
- Department
of Molecular, Cell and Cancer Biology, University
of Massachusetts Chan Medical School, Worcester, Massachusetts 01605, United States
| | - John A. Porco
- Department
of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, United States
- Boston
University Target Discovery Laboratory (BU-TDL), Boston, Massachusetts 02215, United States
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Lv X, Lan G, Guo Q. Identification of Subtypes in Triple-negative Breast Cancer Based on Shared Genes Between Immunity and Cancer Stemness. J Immunother 2024; 47:107-116. [PMID: 38369822 DOI: 10.1097/cji.0000000000000502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 12/13/2023] [Indexed: 02/20/2024]
Abstract
The correlation between triple-negative breast cancer (TNBC) and genes related to immunity and cancer stemness, particularly shared genes, remains unclear. This study aimed to investigate the correlation of immunity and cancer stemness with the molecular subtyping and survival rates in TNBC using bioinformatics approaches. Differential gene analysis was conducted to identify TNBC-associated differentially expressed genes (DEGs). Cancer stem cell (CSC)-related genes were obtained using weighted gene coexpression network analysis. Immune-related gene sets were retrieved from the literature. Venn analysis was performed to identify the shared DEGs between immunity and cancer stemness in TNBC. Cluster analysis and survival analysis based on the expression of these genes were conducted to identify TNBC subtypes with significant survival differences. A total of 5259 TNBC-associated DEGs, 2214 CSC-related genes, 1793 immune-related genes, and 44 shared DEGs between immunity and cancer stemness were obtained. Among them, 3 shared DEGs were closely associated with TNBC survival rates ( P <0.05). Cluster and survival analyses revealed that among 3 subtypes, cluster2 exhibited the best survival rate, and cluster3 showed the worst survival rate ( P <0.05). Dendritic cells were highly infiltrated in cluster2, while plasma cells and resting mast cells were highly infiltrated in cluster3 ( P <0.05). Genes shared by immunity and cancer stemness were capable of classifying TNBC samples. TNBC patients of different subtypes exhibited significant differences in immune profiles, genetic mutations, and drug sensitivity. These findings could provide new insights into the pathogenesis of TNBC, the immune microenvironment, and the selection of therapeutic targets for drug treatment.
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Affiliation(s)
- Xianmei Lv
- Department of Radiotherapy, Jinhua People's Hospital, Jinhua, China
| | - Gaochen Lan
- Department of Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Qiusheng Guo
- Department of Medical Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
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Wang Y, Liu Y, Zhang J, Peng Q, Wang X, Xiao X, Shi K. Nanomaterial-mediated modulation of the cGAS-STING signaling pathway for enhanced cancer immunotherapy. Acta Biomater 2024; 176:51-76. [PMID: 38237711 DOI: 10.1016/j.actbio.2024.01.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/30/2023] [Accepted: 01/09/2024] [Indexed: 01/27/2024]
Abstract
Despite the current promise of immunotherapy, many cancer patients still suffer from challenges such as poor immune response rates, resulting in unsatisfactory clinical efficacy of existing therapies. There is an urgent need to combine emerging biomedical discoveries and innovations in traditional therapies. Modulation of the cGAS-STING signalling pathway represents an important innate immunotherapy pathway that serves as a crucial DNA sensing mechanism in innate immunity and viral defense. It has attracted increasing attention as an emerging target for cancer therapy. The recent advancements in nanotechnology have led to the significant utilization of nanomaterials in cancer immunotherapy, owing to their exceptional physicochemical properties such as large specific surface area and efficient permeability. Given the rapid development of cancer immunotherapy driven by the cGAS-STING activation, this study reviews the latest research progress in employing nanomaterials to modulate this signaling pathway. Based on the introduction of the main activation mechanisms of cGAS-STING pathway, this review focuses on nanomaterials that mediate the agonists involved and effectively activate this signaling pathway. In addition, combination nanotherapeutics based on the activation of the cGAS-STING signaling pathway are also discussed, including emerging strategies combining nanoformulated agonists with chemotherapy, radiotherapy as well as other immunomodulation in tumor targeting therapy. STATEMENT OF SIGNIFICANCE: Given the rapid development of cancer immunotherapy driven by the cGAS / STING activation, this study reviews the latest research advances in the use of nanomaterials to modulate this signaling pathway. Based on the introduction of key cGAS-STING components and their activation mechanisms, this review focuses on nanomaterials that can mediate the corresponding agonists and effectively activate this signaling pathway. In addition, combination nanotherapies based on the activation of the cGAS-STING signaling pathway are also discussed, including emerging strategies combining nanoformulated agonists with chemotherapy, radiotherapy as well as immunomodulation in cancer therapy,.
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Affiliation(s)
- Yaxin Wang
- College of Pharmacy, Nankai University, Tianjin 300350, PR China
| | - Yunmeng Liu
- College of Pharmacy, Nankai University, Tianjin 300350, PR China
| | - Jincheng Zhang
- College of Pharmacy, Nankai University, Tianjin 300350, PR China
| | - Qikai Peng
- College of Pharmacy, Nankai University, Tianjin 300350, PR China
| | - Xingdong Wang
- College of Pharmacy, Nankai University, Tianjin 300350, PR China
| | - Xiyue Xiao
- College of Pharmacy, Nankai University, Tianjin 300350, PR China
| | - Kai Shi
- College of Pharmacy, Nankai University, Tianjin 300350, PR China.
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Batool A, Rashid W, Fatima K, Khan SU. Mechanisms of Cancer Resistance to Various Therapies. DRUG RESISTANCE IN CANCER: MECHANISMS AND STRATEGIES 2024:31-75. [DOI: 10.1007/978-981-97-1666-1_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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10
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Zheng L, Chen J, Ye W, Fan Q, Chen H, Yan H. An individualized stemness-related signature to predict prognosis and immunotherapy responses for gastric cancer using single-cell and bulk tissue transcriptomes. Cancer Med 2024; 13:e6908. [PMID: 38168907 PMCID: PMC10807574 DOI: 10.1002/cam4.6908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 12/01/2023] [Accepted: 12/22/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND Currently, many stemness-related signatures have been developed for gastric cancer (GC) to predict prognosis and immunotherapy outcomes. However, due to batch effects, these signatures cannot accurately analyze patients one by one, rendering them impractical in real clinical scenarios. Therefore, we aimed to develop an individualized and clinically applicable signature based on GC stemness. METHODS Malignant epithelial cells from single-cell RNA-Seq data of GC were used to identify stemness-related signature genes based on the CytoTRACE score. Using two bulk tissue datasets as training data, the enrichment scores of the signature genes were applied to classify samples into two subtypes. Then, using the identified subtypes as criteria, we developed an individualized stemness-related signature based on the within-sample relative expression orderings of genes. RESULTS We identified 175 stemness-related signature genes, which exhibited significantly higher AUCell scores in poorly differentiated GCs compared to differentiated GCs. In training datasets, GC samples were classified into two subtypes with significantly different survival times and genomic characteristics. Utilizing the two subtypes, an individualized signature was constructed containing 47 gene pairs. In four independent testing datasets, GC samples classified as high risk exhibited significantly shorter survival times, higher infiltration of M2 macrophages, and lower immune responses compared to low-risk samples. Moreover, the potential therapeutic targets and corresponding drugs were identified for the high-risk group, such as CD248 targeted by ontuxizumab. CONCLUSIONS We developed an individualized stemness-related signature, which can accurately predict the prognosis and efficacy of immunotherapy for each GC sample.
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Affiliation(s)
- Linyong Zheng
- Fujian Key Laboratory of Medical Bioinformatics, Department of Bioinformatics, School of Medical Technology and EngineeringFujian Medical UniversityFuzhouChina
| | - Jingyan Chen
- Fujian Key Laboratory of Medical Bioinformatics, Department of Bioinformatics, School of Medical Technology and EngineeringFujian Medical UniversityFuzhouChina
| | - Wenhai Ye
- Fujian Key Laboratory of Medical Bioinformatics, Department of Bioinformatics, School of Medical Technology and EngineeringFujian Medical UniversityFuzhouChina
| | - Qi Fan
- Fujian Key Laboratory of Medical Bioinformatics, Department of Bioinformatics, School of Medical Technology and EngineeringFujian Medical UniversityFuzhouChina
| | - Haifeng Chen
- Department of Gastrointestinal SurgeryFuzhou Second HospitalFuzhouChina
| | - Haidan Yan
- Fujian Key Laboratory of Medical Bioinformatics, Department of Bioinformatics, School of Medical Technology and EngineeringFujian Medical UniversityFuzhouChina
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, The School of Basic Medical SciencesFujian Medical UniversityFuzhouChina
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11
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Zhong C, Wang G, Guo M, Zhu N, Chen X, Yan Y, Li N, Yu W. The Role of Tumor Stem Cells in Colorectal Cancer Drug Resistance. Cancer Control 2024; 31:10732748241274196. [PMID: 39215442 PMCID: PMC11367616 DOI: 10.1177/10732748241274196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 07/09/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
Background: Colorectal cancer is a major cause of mortality among the prevalent malignant tumors of the gastrointestinal tract. Although chemotherapy is a standard treatment for colorectal cancer, its efficacy is limited by chemoresistance. Recent studies have investigated targeting tumor stem cells as a potential new therapeutic approach for addressing chemoresistance in colorectal cancer. Colorectal cancer frequently relapses, with tumor stem cells often representing one of the leading causes of treatment failure. Purpose: Understanding drug resistance in colorectal cancer stem cells is crucial for improving treatment outcomes. By focusing on developing targeted therapies that specifically address drug resistance in colorectal cancer stem cells, there is potential to make significant advancements in the treatment of colorectal cancer.This approach may lead to more effective and lasting outcomes in patients battling colorectal cancer. Research Design: In this review, a comprehensive overview of recent research on colorectal cancer stem cell treatment resistance is presented.Results: Elucidating the key underlying mechanisms. This review also highlights the potential benefits of targeted therapies in overcoming colorectal cancer resistance to treatment. Conclusions: CCSCs are key players in drug resistance of CRC, indicating their potential as targets for effective therapy. Elucidating their role in this process could aid in discovering tailored treatment strategies.The significance of signaling pathways, TME, and miRNA in regulating drug resistance in CCSCs is been highlighted.
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Affiliation(s)
- Chen Zhong
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Guojuan Wang
- Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China
| | - Min Guo
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Naicheng Zhu
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Xiudan Chen
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Yuwei Yan
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Nanxin Li
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Wenyan Yu
- Jiangxi University of Chinese Medicine, Nanchang, China
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12
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Jalil AT, Abdulhadi MA, Al Jawadri AMH, Talib HA, Al-Azzawi AKJ, Zabibah RS, Ali A. Cancer Stem Cells in Colorectal Cancer: Implications for Targeted Immunotherapies. J Gastrointest Cancer 2023; 54:1046-1057. [PMID: 37247115 DOI: 10.1007/s12029-023-00945-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/13/2023] [Indexed: 05/30/2023]
Abstract
PURPOSE Colorectal cancers are composed of heterogeneous cell populations in the concepts of genetic and functional degrees that among them cancer stem cells are identified with their self-renewal and stemness capability mediating primary tumorigenesis, metastasize, therapeutic resistance, and tumor recurrence. Therefore, understanding the key mechanisms of stemness in colorectal cancer stem cells (CRCSCs) provides opportunities to discover new treatments or improve existing therapeutic regimens. METHODS We review the biological significance of stemness and the results of potential CRCSC-based targeted immunotherapies. Then, we pointed out the barriers to targeting CRCSCs in vivo and highlight new strategies based on synthetic and biogenic nanocarriers for the development of future anti-CRCSC trials. RESULTS The CSCs' surface markers, antigens, neoantigens, and signaling pathways supportive CRCSCs or immune cells that are interacted with CRCSCs could be targeted by immune monotherapy or in formulation with developed nanocarriers to overcome the resistant mechanisms in immune evader CRCSCs. CONCLUSION Identification molecular and cellular cues supporting stemness in CRCSCs and their targeting by nanoimmunotherpy can improve the efficacy of existed therapies or explore novel therapeutic options in future.
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Affiliation(s)
- Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq.
| | | | | | - Hayder Abdullah Talib
- College of Agriculture, National University of Science and Technology, Dhi Qar, Iraq
| | | | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Ahmed Ali
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
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13
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Agüero EI, Belgorosky D, García-Silva JI, Booth R, Lerner B, Pérez MS, Eiján AM. Microdevices for cancer stem cell culture as a predictive chemotherapeutic response platform. J Mol Med (Berl) 2023; 101:1465-1475. [PMID: 37755493 DOI: 10.1007/s00109-023-02375-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 08/20/2023] [Accepted: 09/13/2023] [Indexed: 09/28/2023]
Abstract
Microfluidic platforms for clinical use are a promising translational strategy for cancer research specially for drug screening. Identifying cancer stem cells (CSC) using sphere culture techniques in microfluidic devices (MDs) showed to be better reproducing physiological responses than other in vitro models and allow the optimization of samples and reagents. We evaluated individual sphere proliferation and stemness toward chemotherapeutic treatment (CT) with doxorubicin and cisplatin in bladder cancer cell lines (MB49-I and J82) cultured in MDs used as CSC treatment response platform. Our results confirm the usefulness of this device to evaluate the CT effect in sphere-forming efficiency, size, and growth rate from individual spheres within MDs and robust information comparable to conventional culture plates was obtained. The expression of pluripotency genetic markers (Oct4, Sox2, Nanog, and CD44) could be analyzed by qPCR and immunofluorescence in spheres growing directly in MDs. MDs are a suitable platform for sphere isolation from tumor samples and can provide information about CT response. Microfluidic-based CSC studies could provide information about treatment response of cancer patients from small samples and can be a promising tool for CSC-targeted specific treatment with potential in precision medicine. KEY MESSAGES: We have designed a microfluidic platform for CSC enriched culture by tumor sphere formation. Using MDs, we could quantify and determine sphere response after CT using murine and human cell lines as a proof of concept. MDs can be used as a tumor-derived sphere isolation platform to test the effect of antitumoral compounds in sphere proliferation.
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Affiliation(s)
- Eduardo Imanol Agüero
- Facultad de Ciencias Médicas, Instituto de Oncología "Ángel H. Roffo", Área de Investigación, Universidad de Buenos Aires, C1417DTB, Ciudad Autónoma de Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), C1425FQB, Ciudad Autónoma de Buenos Aires, Argentina
| | - Denise Belgorosky
- Facultad de Ciencias Médicas, Instituto de Oncología "Ángel H. Roffo", Área de Investigación, Universidad de Buenos Aires, C1417DTB, Ciudad Autónoma de Buenos Aires, Argentina
| | - Julio Israel García-Silva
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), C1425FQB, Ciudad Autónoma de Buenos Aires, Argentina
| | - Ross Booth
- Roche Sequencing Solutions, Santa Clara, CA, 95050, USA
| | - Betiana Lerner
- Department of Electrical and Computer Engineering, Florida International University (FIU), Miami, FL, 33174, USA
- Collaborative Research Institute Intelligent Oncology (CRIION), Freiburg im Breisgau, Germany
- Universidad Tecnológica Nacional (UTN), Centro IREN, B1706EAH, Buenos Aires, Argentina
- Facultad de Ingeniería, Instituto de Ingeniería Biomédica, Universidad de Buenos Aires, C1063ACV, Ciudad Autónoma de Buenos Aires, Argentina
| | - Maximiliano Sebastián Pérez
- Department of Electrical and Computer Engineering, Florida International University (FIU), Miami, FL, 33174, USA.
- Collaborative Research Institute Intelligent Oncology (CRIION), Freiburg im Breisgau, Germany.
- Universidad Tecnológica Nacional (UTN), Centro IREN, B1706EAH, Buenos Aires, Argentina.
- Facultad de Ingeniería, Instituto de Ingeniería Biomédica, Universidad de Buenos Aires, C1063ACV, Ciudad Autónoma de Buenos Aires, Argentina.
| | - Ana María Eiján
- Facultad de Ciencias Médicas, Instituto de Oncología "Ángel H. Roffo", Área de Investigación, Universidad de Buenos Aires, C1417DTB, Ciudad Autónoma de Buenos Aires, Argentina.
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), C1425FQB, Ciudad Autónoma de Buenos Aires, Argentina.
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14
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Zhong Q, Wang H, Yang J, Tu R, Li A, Zeng G, Zheng Q, Yu Liu Z, Shang‐Guan Z, Bo Huang X, Huang Q, Li Y, Zheng H, Lin G, Huang Z, Xu K, Qiu W, Jiang M, Zhao Y, Lin J, Huang Z, Huang J, Li P, Xie J, Zheng C, Chen Q, Huang C. Loss of ATOH1 in Pit Cell Drives Stemness and Progression of Gastric Adenocarcinoma by Activating AKT/mTOR Signaling through GAS1. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2301977. [PMID: 37824217 PMCID: PMC10646280 DOI: 10.1002/advs.202301977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 08/19/2023] [Indexed: 10/14/2023]
Abstract
Gastric cancer stem cells (GCSCs) are self-renewing tumor cells that govern chemoresistance in gastric adenocarcinoma (GAC), whereas their regulatory mechanisms remain elusive. Here, the study aims to elucidate the role of ATOH1 in the maintenance of GCSCs. The preclinical model and GAC sample analysis indicate that ATOH1 deficiency is correlated with poor GAC prognosis and chemoresistance. ScRNA-seq reveals that ATOH1 is downregulated in the pit cells of GAC compared with those in paracarcinoma samples. Lineage tracing reveals that Atoh1 deletion strongly confers pit cell stemness. ATOH1 depletion significantly accelerates cancer stemness and chemoresistance in Tff1-CreERT2; Rosa26Tdtomato and Tff1-CreERT2; Apcfl/fl ; p53fl/fl (TcPP) mouse models and organoids. ATOH1 deficiency downregulates growth arrest-specific protein 1 (GAS1) by suppressing GAS1 promoter transcription. GAS1 forms a complex with RET, which inhibits Tyr1062 phosphorylation, and consequently activates the RET/AKT/mTOR signaling pathway by ATOH1 deficiency. Combining chemotherapy with drugs targeting AKT/mTOR signaling can overcome ATOH1 deficiency-induced chemoresistance. Moreover, it is confirmed that abnormal DNA hypermethylation induces ATOH1 deficiency. Taken together, the results demonstrate that ATOH1 loss promotes cancer stemness through the ATOH1/GAS1/RET/AKT/mTOR signaling pathway in GAC, thus providing a potential therapeutic strategy for AKT/mTOR inhibitors in GAC patients with ATOH1 deficiency.
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15
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Landry J, Shows K, Jagdeesh A, Shah A, Pokhriyal M, Yakovlev V. Regulatory miRNAs in cancer cell recovery from therapy exposure and its implications as a novel therapeutic strategy for preventing disease recurrence. Enzymes 2023; 53:113-196. [PMID: 37748835 DOI: 10.1016/bs.enz.2023.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/27/2023]
Abstract
The desired outcome of cancer therapies is the eradication of disease. This can be achieved when therapy exposure leads to therapy-induced cancer cell death as the dominant outcome. Theoretically, a permanent therapy-induced growth arrest could also contribute to a complete response, which has the potential to lead to remission. However, preclinical models have shown that therapy-induced growth arrest is not always durable, as recovering cancer cell populations can contribute to the recurrence of cancer. Significant research efforts have been expended to develop strategies focusing on the prevention of recurrence. Recovery of cells from therapy exposure can occur as a result of several cell stress adaptations. These include cytoprotective autophagy, cellular quiescence, a reversable form of senescence, and the suppression of apoptosis and necroptosis. It is well documented that microRNAs regulate the response of cancer cells to anti-cancer therapies, making targeting microRNAs therapeutically a viable strategy to sensitization and the prevention of recovery. We propose that the use of microRNA-targeting therapies in prolonged sequence, that is, a significant period after initial therapy exposure, could reduce toxicity from the standard combination strategy, and could exploit new epigenetic states essential for cancer cells to recover from therapy exposure. In a step toward supporting this strategy, we survey the available scientific literature to identify microRNAs which could be targeted in sequence to eliminate residual cancer cell populations that were arrested as a result of therapy exposure. It is our hope that by successfully identifying microRNAs which could be targeted in sequence we can prevent disease recurrence.
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Affiliation(s)
- Joseph Landry
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA, United States.
| | - Kathryn Shows
- Department of Biology, Virginia State University, Petersburg, VA, United States
| | - Akash Jagdeesh
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
| | - Aashka Shah
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
| | - Mihir Pokhriyal
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
| | - Vasily Yakovlev
- Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA, United States.
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16
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Cierpikowski P, Leszczyszyn A, Bar J. The Role of Hedgehog Signaling Pathway in Head and Neck Squamous Cell Carcinoma. Cells 2023; 12:2083. [PMID: 37626893 PMCID: PMC10453169 DOI: 10.3390/cells12162083] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/12/2023] [Accepted: 08/15/2023] [Indexed: 08/27/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth leading malignancy worldwide, with a poor prognosis and limited treatment options. Molecularly targeted therapies for HNSCC are still lacking. However, recent reports provide novel insights about many molecular alterations in HNSCC that may be useful in future therapies. Therefore, it is necessary to identify new biomarkers that may provide a better prediction of the disease and promising targets for personalized therapy. The poor response of HNSCC to therapy is attributed to a small population of tumor cells called cancer stem cells (CSCs). Growing evidence indicates that the Hedgehog (HH) signaling pathway plays a crucial role in the development and maintenance of head and neck tissues. The HH pathway is normally involved in embryogenesis, stem cell renewal, and tissue regeneration. However, abnormal activation of the HH pathway is also associated with carcinogenesis and CSC regulation. Overactivation of the HH pathway was observed in several tumors, including basal cell carcinoma, that are successfully treated with HH inhibitors. However, clinical studies about HH pathways in HNSCC are still rare. In this review, we summarize the current knowledge and recent advances regarding the HH pathway in HNSCC and discuss its possible implications for prognosis and future therapy.
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Affiliation(s)
- Piotr Cierpikowski
- Department of Maxillofacial Surgery, The Ludwik Rydygier Specialist Hospital, Osiedle Zlotej Jesieni 1, 31-826 Krakow, Poland
| | - Anna Leszczyszyn
- Dental Surgery Outpatient Clinic, 4th Military Clinical Hospital, Weigla 5, 53-114 Wroclaw, Poland;
| | - Julia Bar
- Department of Immunopathology and Molecular Biology, Wroclaw Medical University, Bujwida 44, 50-345 Wroclaw, Poland
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17
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Andreescu M. Risk of Infections Secondary to the Use of Targeted Therapies in Hematological Malignancies. Life (Basel) 2023; 13:1272. [PMID: 37374055 DOI: 10.3390/life13061272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/24/2023] [Accepted: 05/27/2023] [Indexed: 06/29/2023] Open
Abstract
Concurrent infections in hematological malignancies (HM) are major contributors to adverse clinical outcomes, including prolonged hospitalization and reduced life expectancy. Individuals diagnosed with HM are particularly susceptible to infectious pathogens due to immunosuppression, which can either be inherent to the hematological disorder or induced by specific therapeutic strategies. Over the years, the treatment paradigm for HM has witnessed a tremendous shift, from broad-spectrum treatment approaches to more specific targeted therapies. At present, the therapeutic landscape of HM is constantly evolving due to the advent of novel targeted therapies and the enhanced utilization of these agents for treatment purposes. By initiating unique molecular pathways, these agents hinder the proliferation of malignant cells, consequently affecting innate and adaptive immunity, which increases the risk of infectious complications. Due to the complexity of novel targeted therapies and their associated risks of infection, it often becomes a daunting task for physicians to maintain updated knowledge in their clinical practice. The situation is further aggravated by the fact that most of the initial clinical trials on targeted therapies provide inadequate information to determine the associated risk of infection. In such a scenario, a cumulative body of evidence is paramount in guiding clinicians regarding the infectious complications that can arise following targeted therapies. In this review, I summarize the recent knowledge on infectious complications arising in the context of targeted therapies for HM.
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Affiliation(s)
- Mihaela Andreescu
- Department of Clinical Sciences, Hematology, Faculty of Medicine, Titu Maiorescu University of Bucharest, 040051 Bucharest, Romania
- Department of Hematology, Colentina Clinical Hospital, 020125 Bucharest, Romania
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18
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Bu J, Zhang Y, Wu S, Li H, Sun L, Liu Y, Zhu X, Qiao X, Ma Q, Liu C, Niu N, Xue J, Chen G, Yang Y, Liu C. KK-LC-1 as a therapeutic target to eliminate ALDH + stem cells in triple negative breast cancer. Nat Commun 2023; 14:2602. [PMID: 37147285 PMCID: PMC10163259 DOI: 10.1038/s41467-023-38097-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 04/14/2023] [Indexed: 05/07/2023] Open
Abstract
Failure to achieve complete elimination of triple negative breast cancer (TNBC) stem cells after adjuvant therapy is associated with poor outcomes. Aldehyde dehydrogenase 1 (ALDH1) is a marker of breast cancer stem cells (BCSCs), and its enzymatic activity regulates tumor stemness. Identifying upstream targets to control ALDH+ cells may facilitate TNBC tumor suppression. Here, we show that KK-LC-1 determines the stemness of TNBC ALDH+ cells via binding with FAT1 and subsequently promoting its ubiquitination and degradation. This compromises the Hippo pathway and leads to nuclear translocation of YAP1 and ALDH1A1 transcription. These findings identify the KK-LC-1-FAT1-Hippo-ALDH1A1 pathway in TNBC ALDH+ cells as a therapeutic target. To reverse the malignancy due to KK-LC-1 expression, we employ a computational approach and discover Z839878730 (Z8) as an small-molecule inhibitor which may disrupt KK-LC-1 and FAT1 binding. We demonstrate that Z8 suppresses TNBC tumor growth via a mechanism that reactivates the Hippo pathway and decreases TNBC ALDH+ cell stemness and viability.
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Affiliation(s)
- Jiawen Bu
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Yixiao Zhang
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Sijin Wu
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
- Shenzhen Jingtai Technology Co., Ltd. (XtalPi), International Biomedical Industrial Park (Phase II) 3F, 2 Hongliu Rd, Futian District, 16023, Shenzhen, China
| | - Haonan Li
- School of Bioengineering, Dalian University of Technology, 116023, Dalian, China
| | - Lisha Sun
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Yang Liu
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 110016, Shenyang, China
- Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, 110016, Shenyang, China
| | - Xudong Zhu
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Xinbo Qiao
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Qingtian Ma
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Chao Liu
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Nan Niu
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Jinqi Xue
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Guanglei Chen
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Yongliang Yang
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China.
- School of Bioengineering, Dalian University of Technology, 116023, Dalian, China.
| | - Caigang Liu
- Cancer Stem Cell and Translation Medicine Lab, Department of Oncology, Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shengjing Hospital of China Medical University, 110004, Shenyang, China.
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Preclinical and Clinical Trials of New Treatment Strategies Targeting Cancer Stem Cells in Subtypes of Breast Cancer. Cells 2023; 12:cells12050720. [PMID: 36899854 PMCID: PMC10001180 DOI: 10.3390/cells12050720] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/01/2023] [Accepted: 02/09/2023] [Indexed: 02/26/2023] Open
Abstract
Breast cancer (BC) can be classified into various histological subtypes, each associated with different prognoses and treatment options, including surgery, radiation, chemotherapy, and endocrine therapy. Despite advances in this area, many patients still face treatment failure, the risk of metastasis, and disease recurrence, which can ultimately lead to death. Mammary tumors, like other solid tumors, contain a population of small cells known as cancer stem-like cells (CSCs) that have high tumorigenic potential and are involved in cancer initiation, progression, metastasis, tumor recurrence, and resistance to therapy. Therefore, designing therapies specifically targeting at CSCs could help to control the growth of this cell population, leading to increased survival rates for BC patients. In this review, we discuss the characteristics of CSCs, their surface biomarkers, and the active signaling pathways associated with the acquisition of stemness in BC. We also cover preclinical and clinical studies that focus on evaluating new therapy systems targeted at CSCs in BC through various combinations of treatments, targeted delivery systems, and potential new drugs that inhibit the properties that allow these cells to survive and proliferate.
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20
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Zhou Y, Cheng L, Liu L, Li X. NK cells are never alone: crosstalk and communication in tumour microenvironments. Mol Cancer 2023; 22:34. [PMID: 36797782 PMCID: PMC9933398 DOI: 10.1186/s12943-023-01737-7] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 01/30/2023] [Indexed: 02/18/2023] Open
Abstract
Immune escape is a hallmark of cancer. The dynamic and heterogeneous tumour microenvironment (TME) causes insufficient infiltration and poor efficacy of natural killer (NK) cell-based immunotherapy, which becomes a key factor triggering tumour progression. Understanding the crosstalk between NK cells and the TME provides new insights for optimising NK cell-based immunotherapy. Here, we present new advances in direct or indirect crosstalk between NK cells and 9 specialised TMEs, including immune, metabolic, innervated niche, mechanical, and microbial microenvironments, summarise TME-mediated mechanisms of NK cell function inhibition, and highlight potential targeted therapies for NK-TME crosstalk. Importantly, we discuss novel strategies to overcome the inhibitory TME and provide an attractive outlook for the future.
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Affiliation(s)
- Yongqiang Zhou
- grid.32566.340000 0000 8571 0482The First School of Clinical Medicine, Lanzhou University, 222 Tianshui South Road, Lanzhou, 730000 China ,grid.412643.60000 0004 1757 2902Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China ,Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
| | - Lu Cheng
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
| | - Lu Liu
- grid.412643.60000 0004 1757 2902Department of Pediatrics, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, 222 Tianshui South Road, Lanzhou, 730000, China. .,Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China. .,Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China.
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21
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Ding Y, Pan Q, Gao W, Pu Y, Luo K, He B. Reactive oxygen species-upregulating nanomedicines towards enhanced cancer therapy. Biomater Sci 2023; 11:1182-1214. [PMID: 36606593 DOI: 10.1039/d2bm01833k] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Reactive oxygen species (ROS) play a crucial role in physiological and pathological processes, emerging as a therapeutic target in cancer. Owing to the high concentration of ROS in solid tumor tissues, ROS-based treatments, such as photodynamic therapy and chemodynamic therapy, and ROS-responsive drug delivery systems have been widely explored to powerfully and specifically suppress tumors. However, their anticancer efficacy is still hampered by the heterogeneous ROS levels, and thus comprehensively upregulating the ROS levels in tumor tissues can ensure an enhanced therapeutic effect, which can further sensitize and/or synergize with other therapies to inhibit tumor growth and metastasis. Herein, we review the recently emerging drug delivery strategies and technologies for increasing the H2O2, ˙OH, 1O2, and ˙O2- concentrations in cancer cells, including the efficient delivery of natural enzymes, nanozymes, small molecular biological molecules, and nanoscale Fenton-reagents and semiconductors and neutralization of intracellular antioxidant substances and localized input of mechanical and electromagnetic waves (such as ultrasound, near infrared light, microwaves, and X-rays). The applications of these ROS-upregulating nanosystems in enhancing and synergizing cancer therapies including chemotherapy, chemodynamic therapy, phototherapy, and immunotherapy are surveyed. In addition, we discuss the challenges of ROS-upregulating systems and the prospects for future studies.
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Affiliation(s)
- Yuanyuan Ding
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
| | - Qingqing Pan
- School of Preclinical Medicine, Chengdu University, Chengdu 610106, China
| | - Wenxia Gao
- College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou 325027, China
| | - Yuji Pu
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
| | - Kui Luo
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Functional and molecular imaging Key Laboratory of Sichuan Province, Sichuan University, Chengdu 610041, China
| | - Bin He
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
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22
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Shu Y, Lan J, Hu Z, Liu W, Song R. Epigenetic regulation of RARB overcomes the radio-resistance of colorectal carcinoma cells via cancer stem cells. JOURNAL OF RADIATION RESEARCH 2023; 64:11-23. [PMID: 36214504 PMCID: PMC9855330 DOI: 10.1093/jrr/rrac060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 07/19/2022] [Indexed: 06/16/2023]
Abstract
Cancer stem cells (CSCs) are able to survive after cancer therapies, leading to cancer progression and recurrence in colorectal carcinoma (CRC). Therapies targeting CSCs are believed to be promising strategies for efficiently eradicating cancers. This study was to investigate that how retinoic acid receptor beta (RARB) affected the biological characteristics of CSCs and radio-resistance in CRC and the epigenetic mechanism. The sensitivity of CSCs isolated from HCT116 cells to radiotherapy was reduced compared with the parental cells. Using database querying, we found that RARB was one of the most significantly downregulated gene in radio-resistant cells in CRC. Also, RARB was poorly expressed in our isolated CSCs, and overexpression of RARB inhibited the properties of CSCs and enhanced radiotherapy sensitivity. Mechanistically, the methylation of RARB was higher in CSCs compared with HCT116 cells, which was significantly reduced after the application of DNA methylation inhibitor 5-azacytidine (5-azaC). DNA methyltransferases (DNMT1) was found to be recruited into the RARB promoter. 5-AzaC treatment inhibited DNMT1 activity and improved radiotherapy sensitivity by promoting RARB expression. Our results imply that inhibition of DNMT1 can display a new mechanism for the epigenetic mediation of RARB in radio-resistant CRC.
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Affiliation(s)
- Yuxian Shu
- Department of Comprehensive Radiotherapy, Jiangxi Cancer Hospital, Nanchang 330029, Jiangxi, P.R. China
| | - Jun Lan
- Department 1 of General Surgery, Jiangxi Gao’an People’s Hospital, Gao’an 330800, Jiangxi, P.R. China
| | - Zhaobing Hu
- Department of Oncology, Jingdezhen Second People’s Hospital, Jingdezhen 333000, Jiangxi, P.R. China
| | - Weiguo Liu
- Department of Gastroenterology, Jiangxi Cancer Hospital, Nanchang 330029, Jiangxi, P.R. China
| | - Rongfeng Song
- Corresponding author. Department of Gastroenterology, Jiangxi Cancer Hospital, No. 519, Beijing East Road, Qingshanhu District, Nanchang 330029, Jiangxi, P.R. China. ; Tel/Fax: 13879172671
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23
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Sai S, Koto M, Yamada S. Basic and translational research on carbon-ion radiobiology. Am J Cancer Res 2023; 13:1-24. [PMID: 36777517 PMCID: PMC9906076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 11/16/2022] [Indexed: 02/14/2023] Open
Abstract
Carbon-ion beam irradiation (IR) has evident advantages over the conventional photon beams in treating tumors. It releases enormous amount of energy in a well-defined range with insignificant scatter in surrounding tissues based on well-localized energy deposition. Over the past 28 years, more than 14,000 patients with various types of cancer have been treated by carbon ion radiotherapy (CIRT) with promising results at QST. I have provided an overview of the basic and translational research on carbon-ion radiobiology including mechanisms underlying high linear energy transfer (LET) carbon-ion IR-induced cell death (apoptosis, autophagy, senescence, mitotic catastrophe etc.) and high radiocurability produced by carbon-ion beams in combination with DNA damaging drugs or with molecular-targeted drugs, micro-RNA therapeutics and immunotherapy. Additionally, I have focused on the application of these treatment in human cancer cells, especially cancer stem cells (CSCs). Finally, I have summarized the current studies on the application of basic carbon-ion beam IR according to the cancer types and clinical outcomes.
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Affiliation(s)
- Sei Sai
- Department of Charged Particle Therapy Research, Institute of Quantum Medical Science, National Institutes for Quantum Science and Technology (QST)Chiba, Japan
| | - Masashi Koto
- Department of Charged Particle Therapy Research, Institute of Quantum Medical Science, National Institutes for Quantum Science and Technology (QST)Chiba, Japan,QST Hospital, National Institutes for Quantum Science and Technology (QST)Chiba, Japan
| | - Shigeru Yamada
- QST Hospital, National Institutes for Quantum Science and Technology (QST)Chiba, Japan
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24
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The Expanding Role of Cancer Stem Cell Marker ALDH1A3 in Cancer and Beyond. Cancers (Basel) 2023; 15:cancers15020492. [PMID: 36672441 PMCID: PMC9857290 DOI: 10.3390/cancers15020492] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/08/2023] [Accepted: 01/11/2023] [Indexed: 01/15/2023] Open
Abstract
Aldehyde dehydrogenase 1A3 (ALDH1A3) is one of 19 ALDH enzymes expressed in humans, and it is critical in the production of hormone receptor ligand retinoic acid (RA). We review the role of ALDH1A3 in normal physiology, its identification as a cancer stem cell marker, and its modes of action in cancer and other diseases. ALDH1A3 is often over-expressed in cancer and promotes tumor growth, metastasis, and chemoresistance by altering gene expression, cell signaling pathways, and glycometabolism. The increased levels of ALDH1A3 in cancer occur due to genetic amplification, epigenetic modifications, post-transcriptional regulation, and post-translational modification. Finally, we review the potential of targeting ALDH1A3, with both general ALDH inhibitors and small molecules specifically designed to inhibit ALDH1A3 activity.
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25
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Tsochantaridis I, Roupas A, Mohlin S, Pappa A, Voulgaridou GP. The Concept of Cancer Stem Cells: Elaborating on ALDH1B1 as an Emerging Marker of Cancer Progression. LIFE (BASEL, SWITZERLAND) 2023; 13:life13010197. [PMID: 36676146 PMCID: PMC9863106 DOI: 10.3390/life13010197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 12/29/2022] [Accepted: 01/03/2023] [Indexed: 01/11/2023]
Abstract
Cancer is a multifactorial, complex disease exhibiting extraordinary phenotypic plasticity and diversity. One of the greatest challenges in cancer treatment is intratumoral heterogeneity, which obstructs the efficient eradication of the tumor. Tumor heterogeneity is often associated with the presence of cancer stem cells (CSCs), a cancer cell sub-population possessing a panel of stem-like properties, such as a self-renewal ability and multipotency potential. CSCs are associated with enhanced chemoresistance due to the enhanced efflux of chemotherapeutic agents and the existence of powerful antioxidant and DNA damage repair mechanisms. The distinctive characteristics of CSCs make them ideal targets for clinical therapeutic approaches, and the identification of efficient and specific CSCs biomarkers is of utmost importance. Aldehyde dehydrogenases (ALDHs) comprise a wide superfamily of metabolic enzymes that, over the last years, have gained increasing attention due to their association with stem-related features in a wide panel of hematopoietic malignancies and solid cancers. Aldehyde dehydrogenase 1B1 (ALDH1B1) is an isoform that has been characterized as a marker of colon cancer progression, while various studies suggest its importance in additional malignancies. Here, we review the basic concepts related to CSCs and discuss the potential role of ALDH1B1 in cancer development and its contribution to the CSC phenotype.
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Affiliation(s)
- Ilias Tsochantaridis
- Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - Angelos Roupas
- Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - Sofie Mohlin
- Division of Pediatrics, Clinical Sciences, Lund Stem Cell Center, Lund University Cancer Center, 22384 Lund, Sweden
| | - Aglaia Pappa
- Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - Georgia-Persephoni Voulgaridou
- Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece
- Correspondence:
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26
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Appiah CO, Singh M, May L, Bakshi I, Vaidyanathan A, Dent P, Ginder G, Grant S, Bear H, Landry J. The epigenetic regulation of cancer cell recovery from therapy exposure and its implications as a novel therapeutic strategy for preventing disease recurrence. Adv Cancer Res 2023; 158:337-385. [PMID: 36990536 DOI: 10.1016/bs.acr.2022.11.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The ultimate goal of cancer therapy is the elimination of disease from patients. Most directly, this occurs through therapy-induced cell death. Therapy-induced growth arrest can also be a desirable outcome, if prolonged. Unfortunately, therapy-induced growth arrest is rarely durable and the recovering cell population can contribute to cancer recurrence. Consequently, therapeutic strategies that eliminate residual cancer cells reduce opportunities for recurrence. Recovery can occur through diverse mechanisms including quiescence or diapause, exit from senescence, suppression of apoptosis, cytoprotective autophagy, and reductive divisions resulting from polyploidy. Epigenetic regulation of the genome represents a fundamental regulatory mechanism integral to cancer-specific biology, including the recovery from therapy. Epigenetic pathways are particularly attractive therapeutic targets because they are reversible, without changes in DNA, and are catalyzed by druggable enzymes. Previous use of epigenetic-targeting therapies in combination with cancer therapeutics has not been widely successful because of either unacceptable toxicity or limited efficacy. The use of epigenetic-targeting therapies after a significant interval following initial cancer therapy could potentially reduce the toxicity of combination strategies, and possibly exploit essential epigenetic states following therapy exposure. This review examines the feasibility of targeting epigenetic mechanisms using a sequential approach to eliminate residual therapy-arrested populations, that might possibly prevent recovery and disease recurrence.
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Affiliation(s)
- Christiana O Appiah
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA, United States; Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA, United States
| | - Manjulata Singh
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
| | - Lauren May
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
| | - Ishita Bakshi
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
| | - Ashish Vaidyanathan
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
| | - Paul Dent
- Department of Biochemistry and Molecular Biology, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Gordon Ginder
- Department of Internal Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Steven Grant
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA, United States; Department of Internal Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States; Department of Biochemistry and Molecular Biology, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States; Department of Microbiology & Immunology, Virginia Commonwealth University School of Medicine, Massey Cancer Center, Richmond, Richmond, VA, United States
| | - Harry Bear
- Department of Surgery, Virginia Commonwealth University School of Medicine, Massey Cancer Center, Richmond, VA, United States; Department of Microbiology & Immunology, Virginia Commonwealth University School of Medicine, Massey Cancer Center, Richmond, Richmond, VA, United States
| | - Joseph Landry
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA, United States.
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27
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Patel SG, Patel A, Patel N, Raiya B, Vora H, Jain N. Investigating the resistance mechanism of 5-fluorouracil in colorectal cancer based on surface markers of cancer stemness and cytokine level: A pre-clinical study. J Cancer Res Ther 2023; 19:S560-S568. [PMID: 38384019 DOI: 10.4103/jcrt.jcrt_1299_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 07/04/2022] [Indexed: 02/23/2024]
Abstract
BACKGROUND Colorectal cancer (CRC) is the deadliest malignancy in the world. The first-line chemotherapy used for CRC is 5-fluorouracil (5-FU). 5-FU completely eradicates rapidly proliferating and terminally differentiated tumor cells but fails to target cancer stem cells (CSCs). As a result, the tumor may shrink temporarily, but remnant CSC multiplies and forms a tumor again more aggressively. The recurrence and resistance lead to metastasis. METHODOLOGY CRC was induced in 12 Sprague-Dawley (RPCP/IAEC/2019-20/R2) rats by 1,2 dimethyl hydrazine. Later, animals were treated with 5-FU for 7 weeks at a 10 mg/kg dose by the subcutaneous route. At the end of treatment, half population was sacrificed (6), whereas the remaining half (6) was left without treatment of 5-FU for 5 weeks and then sacrificed. Parameters such as body weight, complete blood count (CBC), immune cell subset (CD4, CD8, and NK cells), colon length to weight index, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) level, occult blood in stool, tumor multiplicity, and liver metastasis were estimated. In addition, the dissected colon was fixed in formalin and sent to the histology lab for hematoxylin-eosin staining and immunohistochemistry at both intervals. RESULTS All blood and tissue-based markers have shown significant differences (p < 0.05) between the animals sacrificed at the end of the 27th week and the end of the 32nd week for 5-FU treatment. CONCLUSION It can be concluded that 5-FU up-regulates inflammatory cytokines and cell surface markers of CSC that promote CRC stemness via the Wnt/β-catenin pathway. Also, involvement of Nf-κB, fibronectin, MMP-9, and RANKL leads to tumorigenesis, disease aggressiveness, metastasis, and resistance.
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Affiliation(s)
- Samir G Patel
- Department of Pharmaceutical Chemistry, Ramanbhai Patel College of Pharmacy, Charotar University of Science & Technology, Changa, India
| | - Alkeshkumar Patel
- Department of Pharmacology, Ramanbhai Patel College of Pharmacy, Charotar University of Science & Technology, Changa, India
| | - Nupur Patel
- Department of Cancer Biology, Immunohaematology Lab, Gujarat Cancer and Research Institute, Cancer Civil Hospital, Ahmedabad, India
| | - Birva Raiya
- Department of Cancer Biology, Immunohaematology Lab, Gujarat Cancer and Research Institute, Cancer Civil Hospital, Ahmedabad, India
| | - Hemangini Vora
- Department of Cancer Biology, Immunohaematology Lab, Gujarat Cancer and Research Institute, Cancer Civil Hospital, Ahmedabad, India
| | - Neeraj Jain
- Department of Biological Sciences, P D Patel Institute of Applied Sciences, Charotar University of Science & Technology, Changa, Anand, Gujarat, India
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28
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Chou YJ, Lin CC, Hsu YC, Syu JL, Tseng LM, Chiu JH, Lo JF, Lin CH, Fu SL. Andrographolide suppresses the malignancy of triple-negative breast cancer by reducing THOC1-promoted cancer stem cell characteristics. Biochem Pharmacol 2022; 206:115327. [PMID: 36330949 DOI: 10.1016/j.bcp.2022.115327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 10/11/2022] [Accepted: 10/19/2022] [Indexed: 12/14/2022]
Abstract
Triple-negative breast cancers (TNBCs) are difficult to cure and currently lack of effective treatment strategies. Cancer stem cells (CSCs) are highly associated with the poor clinical outcome of TNBCs. Thoc1 is a core component of the THO complex (THOC) that regulates the elongation, processing and nuclear export of mRNA. The function of thoc1 in TNBC and whether Thoc1 serves as a drug target are poorly understood. In this study, we demonstrated that thoc1 expression is elevated in TNBC cell lines and human TNBC patient tissues. Knockdown of thoc1 decreased cancer stem cell populations, reduced mammosphere formation, impaired THOC function, and downregulated the expression of stemness-related proteins. Moreover, the thoc1-knockdown 4T1 cells showed less lung metastasis in an orthotopic breast cancer mouse model. Overexpression of Thoc1 promoted TNBC malignancy and the mRNA export of stemness-related genes. Furthermore, treatment of TNBC cells with the natural compound andrographolide reduced the expression of Thoc1 expression, impaired homeostasis of THOC, suppressed CSC properties, and delayed tumor growth in a 4T1-implanted orthotopic mouse model. Andrographolide also reduced the activity of NF-κB, an upstream transcriptional regulator of Thoc1. Notably, thoc1 overexpression attenuates andrographolide-suppressed cellular proliferation. Altogether, our results demonstrate that THOC1 promotes cancer stem cell characteristics of TNBC, and andrographolide is a potential natural compound for eliminating CSCs of TNBCs by downregulating the NF-κB-thoc1 axis.
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Affiliation(s)
- Yi-Ju Chou
- Program in Molecular Medicine, School of Life Sciences, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 11221, Taiwan
| | - Ching-Cheng Lin
- Institute of Microbiology and Immunology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Ya-Chi Hsu
- Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Jia-Ling Syu
- Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Ling-Ming Tseng
- Comprehensive Breast Health Center, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jen-Hwey Chiu
- Comprehensive Breast Health Center, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jeng-Fan Lo
- Institute of Oral Biology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Chao-Hsiung Lin
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Shu-Ling Fu
- Program in Molecular Medicine, School of Life Sciences, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 11221, Taiwan; Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan.
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29
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Mayani H, Chávez-González A, Vázquez-Santillan K, Contreras J, Guzman ML. Cancer Stem Cells: Biology and Therapeutic Implications. Arch Med Res 2022; 53:770-784. [PMID: 36462951 DOI: 10.1016/j.arcmed.2022.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/14/2022] [Accepted: 11/22/2022] [Indexed: 12/05/2022]
Abstract
It is well recognized that most cancers derive and progress from transformation and clonal expansion of a single cell that possesses stem cell properties, i.e., self-renewal and multilineage differentiation capacities. Such cancer stem cells (CSCs) are usually present at very low frequencies and possess properties that make them key players in tumor development. Indeed, besides having the ability to initiate tumor growth, CSCs drive tumor progression and metastatic dissemination, are resistant to most cancer drugs, and are responsible for cancer relapse. All of these features make CSCs attractive targets for the development of more effective oncologic treatments. In the present review article, we have summarized recent advances in the biology of CSCs, including their identification through their immunophenotype, and their physiology, both in vivo and in vitro. We have also analyzed some molecular markers that might become targets for developing new therapies aiming at hampering CSCs regeneration and cancer relapse.
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Affiliation(s)
- Hector Mayani
- Unidad de Investigaci..n en Enfermedades Oncol..gicas, Hospital de Oncolog.ía, Centro M..dico Nacional SXXI, Instituto Mexicano del Seguro Social. Ciudad de M..xico, M..xico.
| | - Antonieta Chávez-González
- Unidad de Investigaci..n en Enfermedades Oncol..gicas, Hospital de Oncolog.ía, Centro M..dico Nacional SXXI, Instituto Mexicano del Seguro Social. Ciudad de M..xico, M..xico
| | | | - Jorge Contreras
- Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medicine, New York, NY, USA
| | - Monica L Guzman
- Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medicine, New York, NY, USA
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30
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Manni W, Min W. Signaling pathways in the regulation of cancer stem cells and associated targeted therapy. MedComm (Beijing) 2022; 3:e176. [PMID: 36226253 PMCID: PMC9534377 DOI: 10.1002/mco2.176] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/20/2022] [Accepted: 08/22/2022] [Indexed: 11/07/2022] Open
Abstract
Cancer stem cells (CSCs) are defined as a subpopulation of malignant tumor cells with selective capacities for tumor initiation, self-renewal, metastasis, and unlimited growth into bulks, which are believed as a major cause of progressive tumor phenotypes, including recurrence, metastasis, and treatment failure. A number of signaling pathways are involved in the maintenance of stem cell properties and survival of CSCs, including well-established intrinsic pathways, such as the Notch, Wnt, and Hedgehog signaling, and extrinsic pathways, such as the vascular microenvironment and tumor-associated immune cells. There is also intricate crosstalk between these signal cascades and other oncogenic pathways. Thus, targeting pathway molecules that regulate CSCs provides a new option for the treatment of therapy-resistant or -refractory tumors. These treatments include small molecule inhibitors, monoclonal antibodies that target key signaling in CSCs, as well as CSC-directed immunotherapies that harness the immune systems to target CSCs. This review aims to provide an overview of the regulating networks and their immune interactions involved in CSC development. We also address the update on the development of CSC-directed therapeutics, with a special focus on those with application approval or under clinical evaluation.
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Affiliation(s)
- Wang Manni
- Department of Biotherapy, Cancer Center, West China HospitalSichuan UniversityChengduP. R. China
| | - Wu Min
- Department of Biomedical Sciences, School of Medicine and Health SciencesUniversity of North DakotaGrand ForksNorth DakotaUSA
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31
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Dual-drug loaded nanomedicine hydrogel as a therapeutic platform to target both residual glioblastoma and glioma stem cells. Int J Pharm 2022; 628:122341. [DOI: 10.1016/j.ijpharm.2022.122341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 10/19/2022] [Accepted: 10/22/2022] [Indexed: 11/06/2022]
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32
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Chen J, Li H, Zhang B, Xiong Z, Jin Z, Chen J, Zheng Y, Zhu X, Zhang S. ABI2-mediated MEOX2/KLF4-NANOG axis promotes liver cancer stem cell and drives tumour recurrence. Liver Int 2022; 42:2562-2576. [PMID: 36017822 PMCID: PMC9825985 DOI: 10.1111/liv.15412] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/19/2022] [Accepted: 08/23/2022] [Indexed: 01/11/2023]
Abstract
Tumour recurrence and drug resistance in hepatocellular carcinoma remain challenging. Cancer stem cells (CSCs) are responsible for tumour initiation because of their stemness characteristics. CSCs accounting for drug resistance and tumour relapse are promising therapeutic targets. We report that Abelson interactor 2 (ABI2) is a novel therapeutic target of HCC CSCs. First, ABI2 was upregulated in HCC tissues compared with liver tissues and was associated with tumour size, pathological grade, liver cirrhosis, worse prognosis and a high recurrence rate. Functional studies illustrate that ABI2 knockdown suppresses cell growth, migration, invasion and sorafenib resistance in vitro. Furthermore, ABI2 knockdown inhibited HCC sphere formation and decreased the CD24+ , CD133+ and CD326+ CSCs populations, suggesting the suppression of HCC stemness characteristics. A tumour xenograft model and limiting dilution assay demonstrated the inhibition of tumorigenicity and tumour initiation. Moreover, molecular mechanism studies showed that ABI2 recruits and directly interacts with the transcription factor MEOX2, which binds to the KLF4 and NANOG promoter regions to activate their transcription. Furthermore, overexpression of MEOX2 restored HCC malignant behaviour and the CSC population. The ABI2-mediated transcriptional axis MEOX2/KLF4-NANOG promotes HCC growth, metastasis and sorafenib resistance by maintaining the CSC population, suggesting that ABI2 is a promising CSC target in HCC treatment.
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Affiliation(s)
- Jiandi Chen
- Department of RadiologyThe First Affiliated Hospital of Jinan UniversityGuangzhouChina
| | - Huizi Li
- Department of General SurgeryThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Bin Zhang
- Department of RadiologyThe First Affiliated Hospital of Jinan UniversityGuangzhouChina
| | - Zhiyuan Xiong
- Department of RadiologyThe First Affiliated Hospital of Jinan UniversityGuangzhouChina
| | - Zhe Jin
- Department of RadiologyThe First Affiliated Hospital of Jinan UniversityGuangzhouChina
| | - Jiaxi Chen
- Department of General SurgeryThe Fourth Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Yang Zheng
- Department of General SurgeryThe Fourth Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Xiangnan Zhu
- Department of General SurgeryThe Fourth Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Shuixing Zhang
- Department of RadiologyThe First Affiliated Hospital of Jinan UniversityGuangzhouChina
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33
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Swati K, Agrawal K, Raj S, Kumar R, Prakash A, Kumar D. Molecular mechanism(s) of regulations of cancer stem cell in brain cancer propagation. Med Res Rev 2022; 43:441-463. [PMID: 36205299 DOI: 10.1002/med.21930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 06/01/2022] [Accepted: 09/11/2022] [Indexed: 11/12/2022]
Abstract
Brain tumors are most often diagnosed with solid neoplasms and are the primary reason for cancer-related deaths in both children and adults worldwide. With recent developments in the progression of novel targeted chemotherapies, the prognosis of malignant glioma remains dismal. However, the high recurrence rate and high mortality rate remain unresolved and are closely linked to the biological features of cancer stem cells (CSCs). Research on tumor biology has reached a new age with more understanding of CSC features. CSCs, a subpopulation of whole tumor cells, are now regarded as candidate therapeutic targets. Therefore, in the diagnosis and treatment of tumors, recognizing the biological properties of CSCs is of considerable significance. Here, we have discussed the concept of CSCs and their significant role in brain cancer growth and propagation. We have also discussed personalized therapeutic development and immunotherapies for brain cancer by specifically targeting CSCs.
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Affiliation(s)
- Kumari Swati
- Department of Biotechnology, School of Life Science, Mahatma Gandhi Central University, Motihari, Bihar, India
| | - Kirti Agrawal
- School of Health Sciences and Technology (SoHST), UPES University, Dehradun, India.,Amity Institute of Molecular Medicine and Stem Cell Research, Amity University Uttar Pradesh, Noida, India
| | - Sibi Raj
- School of Health Sciences and Technology (SoHST), UPES University, Dehradun, India.,Amity Institute of Molecular Medicine and Stem Cell Research, Amity University Uttar Pradesh, Noida, India
| | - Rajeev Kumar
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India
| | - Anand Prakash
- Department of Biotechnology, School of Life Science, Mahatma Gandhi Central University, Motihari, Bihar, India
| | - Dhruv Kumar
- School of Health Sciences and Technology (SoHST), UPES University, Dehradun, India.,Amity Institute of Molecular Medicine and Stem Cell Research, Amity University Uttar Pradesh, Noida, India
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34
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Cámara-Sánchez P, Díaz-Riascos ZV, García-Aranda N, Gener P, Seras-Franzoso J, Giani-Alonso M, Royo M, Vázquez E, Schwartz S, Abasolo I. Selectively Targeting Breast Cancer Stem Cells by 8-Quinolinol and Niclosamide. Int J Mol Sci 2022; 23:ijms231911760. [PMID: 36233074 PMCID: PMC9570236 DOI: 10.3390/ijms231911760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/19/2022] [Accepted: 09/26/2022] [Indexed: 12/01/2022] Open
Abstract
Cancer maintenance, metastatic dissemination and drug resistance are sustained by cancer stem cells (CSCs). Triple negative breast cancer (TNBC) is the breast cancer subtype with the highest number of CSCs and the poorest prognosis. Here, we aimed to identify potential drugs targeting CSCs to be further employed in combination with standard chemotherapy in TNBC treatment. The anti-CSC efficacy of up to 17 small drugs was tested in TNBC cell lines using cell viability assays on differentiated cancer cells and CSCs. Then, the effect of 2 selected drugs (8-quinolinol -8Q- and niclosamide -NCS-) in the cancer stemness features were evaluated using mammosphere growth, cell invasion, migration and anchorage-independent growth assays. Changes in the expression of stemness genes after 8Q or NCS treatment were also evaluated. Moreover, the potential synergism of 8Q and NCS with PTX on CSC proliferation and stemness-related signaling pathways was evaluated using TNBC cell lines, CSC-reporter sublines, and CSC-enriched mammospheres. Finally, the efficacy of NCS in combination with PTX was analyzed in vivo using an orthotopic mouse model of MDA-MB-231 cells. Among all tested drug candidates, 8Q and NCS showed remarkable specific anti-CSC activity in terms of CSC viability, migration, invasion and anchorage independent growth reduction in vitro. Moreover, specific 8Q/PTX and NCS/PTX ratios at which both drugs displayed a synergistic effect in different TNBC cell lines were identified. The sole use of PTX increased the relative presence of CSCs in TNBC cells, whereas the combination of 8Q and NCS counteracted this pro-CSC activity of PTX while significantly reducing cell viability. In vivo, the combination of NCS with PTX reduced tumor growth and limited the dissemination of the disease by reducing circulating tumor cells and the incidence of lung metastasis. The combination of 8Q and NCS with PTX at established ratios inhibits both the proliferation of differentiated cancer cells and the viability of CSCs, paving the way for more efficacious TNBC treatments.
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Affiliation(s)
- Patricia Cámara-Sánchez
- Drug Delivery and Targeting Group, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Zamira V. Díaz-Riascos
- Drug Delivery and Targeting Group, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Functional Validation & Preclinical Research (FVPR), Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
| | - Natalia García-Aranda
- Drug Delivery and Targeting Group, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Functional Validation & Preclinical Research (FVPR), Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
| | - Petra Gener
- Drug Delivery and Targeting Group, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Joaquin Seras-Franzoso
- Drug Delivery and Targeting Group, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Micaela Giani-Alonso
- Drug Delivery and Targeting Group, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
| | - Miriam Royo
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Institute for Advanced Chemistry (IQAC-CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain
| | - Esther Vázquez
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
- Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
| | - Simó Schwartz
- Drug Delivery and Targeting Group, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Ibane Abasolo
- Drug Delivery and Targeting Group, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Functional Validation & Preclinical Research (FVPR), Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
- Correspondence:
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Harbiyeli IFC, Burtea DE, Ivan ET, Streață I, Nicoli ER, Uscatu D, Șerbănescu MS, Ioana M, Vilmann P, Săftoiu A. Assessing Putative Markers of Colorectal Cancer Stem Cells: From Colonoscopy to Gene Expression Profiling. Diagnostics (Basel) 2022; 12:diagnostics12102280. [PMID: 36291969 PMCID: PMC9601164 DOI: 10.3390/diagnostics12102280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 11/16/2022] Open
Abstract
Cancer stem cells (CSCs) are proposed to be involved in colorectal cancer (CRC) initiation, growth, and metastasis. The aim of our pilot study was to assess possible correlations between the clinicopathological characteristics of CRC patients and CSCs gene expression patterns, in order to provide insight into new methods for patient stratification and targeted therapeutic strategies. Our study involved 60 CRC patients, and the following three specific CSC genes were targeted: PROM1/CD133, ALCAM/CD166 and HCAM /CD44. Data are presented as relative mRNA expression of target genes to GAPDH. The expression of total CD133 and CD166 was assessed in paired samples of CRC tumors and adjacent tissue, while CD44 was assessed in similar samples. The qRT-PCR analysis detected all three targeted genes to different extents, in both normal and tumor tissue. In nine cases (15.69%), total CD133 had a higher expression in tumor tissue, whilst in 28 cases (47.06%) the expression was higher in non-malignant peritumor tissue. The total CD166 expression was increased in tumor tissue compared with paired non-invaded peritumor samples in eight cases (13.73%), whilst in eight cases (13.73%) the expression was higher in non-malignant peritumor tissue. Total CD44 expression was higher in tumor tissue compared with paired non-invaded peritumor samples in 47 cases (78.95%). In the remaining cases the difference between paired samples was biologically insignificant. In conclusion, our study suggests that qRT-PCR is feasible in assessing the gene expression profiles of CSCs from CRC, and a promising pathway to be followed for determining how often a person needs screening by colonoscopy and at which age to start. This could improve CRC diagnosis and early patient stratification, and open the way for new oncologic treatment development.
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Affiliation(s)
- Irina Florina Cherciu Harbiyeli
- Research Center of Gastroenterology and Hepatology Craiova, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania
| | - Daniela Elena Burtea
- Research Center of Gastroenterology and Hepatology Craiova, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania
- Correspondence:
| | - Elena Tatiana Ivan
- Research Center of Gastroenterology and Hepatology Craiova, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania
| | - Ioana Streață
- Human Genomics Laboratory, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Elena Raluca Nicoli
- Human Genomics Laboratory, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Daniel Uscatu
- Human Genomics Laboratory, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Mircea-Sebastian Șerbănescu
- Department of Medical Informatics and Biostatistics, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Mihai Ioana
- Human Genomics Laboratory, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Peter Vilmann
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, 2730 Herlev, Denmark
| | - Adrian Săftoiu
- Research Center of Gastroenterology and Hepatology Craiova, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania
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Gimple RC, Yang K, Halbert ME, Agnihotri S, Rich JN. Brain cancer stem cells: resilience through adaptive plasticity and hierarchical heterogeneity. Nat Rev Cancer 2022; 22:497-514. [PMID: 35710946 DOI: 10.1038/s41568-022-00486-x] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/03/2022] [Indexed: 02/07/2023]
Abstract
Malignant brain tumours are complex ecosystems containing neoplastic and stromal components that generate adaptive and evolutionarily driven aberrant tissues in the central nervous system. Brain cancers are cultivated by a dynamic population of stem-like cells that enforce intratumoural heterogeneity and respond to intrinsic microenvironment or therapeutically guided insults through proliferation, plasticity and restructuring of neoplastic and stromal components. Far from a rigid hierarchy, heterogeneous neoplastic populations transition between cellular states with differential self-renewal capacities, endowing them with powerful resilience. Here we review the biological machinery used by brain tumour stem cells to commandeer tissues in the intracranial space, evade immune responses and resist chemoradiotherapy. Through recent advances in single-cell sequencing, improved models to investigate the role of the tumour microenvironment and a deeper understanding of the fundamental role of the immune system in cancer biology, we are now better equipped to explore mechanisms by which these processes can be exploited for therapeutic benefit.
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Affiliation(s)
- Ryan C Gimple
- Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
| | - Kailin Yang
- Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA
| | - Matthew E Halbert
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Sameer Agnihotri
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jeremy N Rich
- University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA.
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
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Liu H, Heller-Trulli D, Moore CL. Targeting the mRNA endonuclease CPSF73 inhibits breast cancer cell migration, invasion, and self-renewal. iScience 2022; 25:104804. [PMID: 35992060 PMCID: PMC9385686 DOI: 10.1016/j.isci.2022.104804] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 05/26/2022] [Accepted: 07/15/2022] [Indexed: 12/02/2022] Open
Abstract
Cleavage by the endonuclease CPSF73 and polyadenylation of nascent RNA is an essential step in co-transcriptional mRNA maturation. Recent work has surprisingly identified CPSF73 as a promising drug target for inhibiting the growth of specific cancers, triggering further studies on understanding CPSF73 regulation and functions in cells. Here, we report that a HECT-like E3 ligase, UBE3D, participates in stabilizing CPFS73 protein by preventing its ubiquitin-mediated degradation by the proteasome. Depletion of UBE3D leads to CPSF73 downregulation, a pre-mRNA cleavage defect, and dysregulated gene expression in cells. UBE3D dysfunction or chemical inactivation of CPSF73 inhibited migration and invasion as well as stem cell renewal phenotypes in vitro in triple-negative breast cancer cells. In addition, genetic overexpression of CPSF73 promoted breast cancer stemness and knocking down CPSF73 inhibited stem cell renewal properties. Together, our findings indicate that targeting the pre-mRNA processing nuclease CPSF73 has potential for breast cancer therapy.
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Affiliation(s)
- Huiyun Liu
- Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA
| | - Daniel Heller-Trulli
- Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA
| | - Claire L. Moore
- Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA
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38
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Sohn EJ. Differentially expression and function of circular RNAs in ovarian cancer stem cells. J Ovarian Res 2022; 15:97. [PMID: 35978436 PMCID: PMC9382745 DOI: 10.1186/s13048-022-01014-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 06/27/2022] [Indexed: 11/16/2022] Open
Abstract
Background Circular RNAs (circRNAs) are noncoding RNAs that regulate miRNA expression; however, their functions in cancer stem cells (CSCs) are not well known. Methods To determine the function of differentially expression of circRNAs associated with ovarian CSCs, circRNA profiling was conducted using a circRNA-based microarray on sphere-forming cells derived from A2780 and SKOV3 epithelial ovarian cancer cells termed A2780-SP and SKOV3-SP compared to monolayer cells such as A2780 and SKOV3 cells, respectively. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to predict the biological functions of the circRNAs expressed in CSCs. Results The circRNA-based microarray data showed that 159 circRNAs were significantly upregulated (fold change > 1.5) and 55 circRNAs were downregulated in ovarian CSCs compared to monolayer cells. GO and KEGG enrichment analysis of differentially expressed circRNAs in ovarian CSCs showed that they were mainly involved in cell cycle, histone modification, cellular protein metabolic process, cell cycle, apoptotic signaling pathway, and ubiquitin-mediated proteolysis in ovarian cancer. In addition, the hsa-circRNA000963-miRNA-mRNA regulatory network was constructed based on potential target of miRNAs. These analyses involved that the biological function of the hsa-circRNA00096/miRNA/mRNA network was involved in signaling pathways regulating pluripotency of stem cells, PI3K-Akt signaling pathway, cell cycle, p53 signaling pathway, Wnt signaling pathway, calcium modulating pathway, and production of miRNAs involved in gene silencing by miRNA. Conclusions Our data demonstrate the expression profiles of circRNAs in ovarian CSCs and suggest that circRNAs may be potential diagnostic and predictive biomarkers of ovarian cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s13048-022-01014-z.
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Affiliation(s)
- Eun Jung Sohn
- Pusan National University, Yangsan, 50612, Republic of Korea.
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Properties of Leukemic Stem Cells in Regulating Drug Resistance in Acute and Chronic Myeloid Leukemias. Biomedicines 2022; 10:biomedicines10081841. [PMID: 36009388 PMCID: PMC9405586 DOI: 10.3390/biomedicines10081841] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 07/26/2022] [Accepted: 07/27/2022] [Indexed: 11/17/2022] Open
Abstract
Notoriously known for their capacity to reconstitute hematological malignancies in vivo, leukemic stem cells (LSCs) represent key drivers of therapeutic resistance and disease relapse, posing as a major medical dilemma. Despite having low abundance in the bulk leukemic population, LSCs have developed unique molecular dependencies and intricate signaling networks to enable self-renewal, quiescence, and drug resistance. To illustrate the multi-dimensional landscape of LSC-mediated leukemogenesis, in this review, we present phenotypical characteristics of LSCs, address the LSC-associated leukemic stromal microenvironment, highlight molecular aberrations that occur in the transcriptome, epigenome, proteome, and metabolome of LSCs, and showcase promising novel therapeutic strategies that potentially target the molecular vulnerabilities of LSCs.
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40
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Kapoor-Narula U, Lenka N. Cancer stem cells and tumor heterogeneity: Deciphering the role in tumor progression and metastasis. Cytokine 2022; 157:155968. [PMID: 35872504 DOI: 10.1016/j.cyto.2022.155968] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 07/08/2022] [Accepted: 07/13/2022] [Indexed: 11/03/2022]
Abstract
Tumor heterogeneity, in principle, reflects the variation among different cancer cell populations. It can be termed inter- or intra-tumoral heterogeneity, respectively, based on its occurrence in various tissues from diverse patients or within a single tumor. The intra-tumoral heterogeneity is one of the leading causes of cancer progression and treatment failure, with the cancer stem cells (CSCs) contributing immensely to the same. These niche cells, similar to normal stem cells, possess the characteristics of self-renewal and differentiation into multiple cell types. Moreover, CSCs contribute to tumor growth and surveillance by promoting recurrence, metastasis, and therapeutic resistance. Diverse factors, including intracellular signalling pathways and tumor microenvironment (TME), play a vital role in regulating these CSCs. Although a panel of markers is considered to identify the CSC pool in various cancers, further research is needed to discriminate cancer-specific CSC markers in those. CSCs have also been found to be promising therapeutic targets for cancer therapy. Several small molecules, natural compounds, antibodies, chimeric antigen receptor T (CAR-T) cells, and CAR-natural killer (CAR-NK) cells have emerged as therapeutic tools for specific targeting of CSCs. Interestingly, many of these are in clinical trials too. Despite being a much-explored avenue of research for years, and we have come to understand its nitty-gritty, there is still a tremendous gap in our knowledge concerning its precise genesis and regulation. Hence, a concrete understanding is needed to assess the CSC-TME link and how to target different cancer-specific CSCs by designing newer tools. In this review, we have summarized CSC, its causative, different pathways and factors regulating its growth, association with tumor heterogeneity, and last but not least, discussed many of the promising CSC-targeted therapies for combating cancer metastasis.
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41
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Sharifi-Azad M, Fathi M, Cho WC, Barzegari A, Dadashi H, Dadashpour M, Jahanban-Esfahlan R. Recent advances in targeted drug delivery systems for resistant colorectal cancer. Cancer Cell Int 2022; 22:196. [PMID: 35590367 PMCID: PMC9117978 DOI: 10.1186/s12935-022-02605-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 05/02/2022] [Indexed: 01/05/2023] Open
Abstract
Colorectal cancer (CRC) is one of the deadliest cancers in the world, the incidences and morality rate are rising and poses an important threat to the public health. It is known that multiple drug resistance (MDR) is one of the major obstacles in CRC treatment. Tumor microenvironment plus genomic instability, tumor derived exosomes (TDE), cancer stem cells (CSCs), circulating tumor cells (CTCs), cell-free DNA (cfDNA), as well as cellular signaling pathways are important issues regarding resistance. Since non-targeted therapy causes toxicity, diverse side effects, and undesired efficacy, targeted therapy with contribution of various carriers has been developed to address the mentioned shortcomings. In this paper the underlying causes of MDR and then various targeting strategies including exosomes, liposomes, hydrogels, cell-based carriers and theranostics which are utilized to overcome therapeutic resistance will be described. We also discuss implication of emerging approaches involving single cell approaches and computer-aided drug delivery with high potential for meeting CRC medical needs.
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Affiliation(s)
- Masoumeh Sharifi-Azad
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Marziyeh Fathi
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China
| | - Abolfazl Barzegari
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Dadashi
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Dadashpour
- Department of Medical Biotechnology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran.
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran.
| | - Rana Jahanban-Esfahlan
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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42
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Thomas E, Thankan RS, Purushottamachar P, Huang W, Kane MA, Zhang Y, Ambulos N, Weber DJ, Njar VCO. Transcriptome profiling reveals that VNPP433-3β, the lead next-generation galeterone analog inhibits prostate cancer stem cells by downregulating epithelial-mesenchymal transition and stem cell markers. Mol Carcinog 2022; 61:643-654. [PMID: 35512605 PMCID: PMC9322274 DOI: 10.1002/mc.23406] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/04/2022] [Accepted: 03/23/2022] [Indexed: 02/06/2023]
Abstract
Cancer stem cells (CSCs) virtually present in all tumors albeit in small numbers are primarily responsible for driving cancer progression, metastasis, drug resistance, and recurrence. Prostate cancer (PCa) is the second most frequent cancer in men worldwide, and castration resistant prostate cancer (CRPC) remains a major challenge despite the tremendous advancements in medicine. Currently, none of the available treatment options are effective in treating CRPC. We earlier reported that VNPP433-3β, the lead next-generation galeterone analog is effective in treating preclinical in vivo models of CRPC. In this study using RNA-seq, cytological, and biochemical methods, we report that VNPP433-3β inhibits prostate CSCs by targeting key pathways critical to stemness and epithelial-mesenchymal transition. VNPP433-3β inhibits CSCs in PCa, presumably by degrading the androgen receptor (AR) thereby decreasing the AR-mediated transcription of several stem cell markers including BMI1 and KLF4. Transcriptome analyses by RNA-seq, Ingenuity Pathway Analysis, and Gene Set Enrichment Analysis demonstrate that VNPP433-3β inhibits transcription of several genes and functional pathways critical to the prostate CSCs thereby inhibiting CSCs in PCa besides targeting the bulk of the tumor.
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Affiliation(s)
- Elizabeth Thomas
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA.,The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Retheesh S Thankan
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA.,Isoprene Pharmaceuticals Inc., Baltimore, Maryland, USA.,Flavocure Biotech, Baltimore, Maryland, USA
| | - Puranik Purushottamachar
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA.,The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Weiliang Huang
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland, USA
| | - Maureen A Kane
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland, USA
| | - Yuji Zhang
- Division of Biostatistics and Bioinformatics, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, Maryland, USA.,Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Nicholas Ambulos
- Department of Microbiology and Immunology, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, Maryland, USA
| | - David J Weber
- The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland, USA.,Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.,Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Vincent C O Njar
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA.,The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland, USA.,Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
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More than a Bubble: Extracellular Vesicle microRNAs in Head and Neck Squamous Cell Carcinoma. Cancers (Basel) 2022; 14:cancers14051160. [PMID: 35267467 PMCID: PMC8909139 DOI: 10.3390/cancers14051160] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 02/18/2022] [Accepted: 02/22/2022] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Head and neck squamous cell carcinoma (HNSCC) is an aggressive and lethal disease. Despite diagnostic and therapeutic advances, the overall survival of patients with advanced HNSCC remains poor. Recently, microRNAs in extracellular vesicles (EV-miRNAs) have been proposed as essential regulatory molecules involved in HNSCC. EV-miRNAs may serve as disease biomarkers and represent a novel therapeutic target. This review summarizes the current understanding of the role of EV-miRNAs in HNSCC as well as their potential future clinical applications. Abstract MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that play a pivotal regulatory role in a broad variety of biological processes. Dysregulation of miRNAs is associated with several human diseases, particularly cancer. Extracellular vesicles (EVs) are crucial components in intercellular communication. As part of the cargo of EVs, miRNAs are involved in EV-mediated cell-to-cell interactions, including promotion or suppression of tumor development. The knowledge on the molecular mechanisms and clinical importance of EV-miRNAs in head and neck squamous cell carcinoma (HNSCC) has rapidly grown over the past years. In the present review, the current understanding regarding the effect of EV-miRNAs on HNSCC tumorigenesis is summarized, which includes effects on tumor proliferation, angiogenesis, invasion and metastasis, the tumor microenvironment, immune modulation, and treatment resistance. EV-miRNA-based biomarkers in liquid biopsies such as blood and saliva may open up new possibilities for employing EV-miRNAs for screening and early diagnostics as well as disease monitoring. Future perspectives include the promise of EV-miRNAs as a novel therapeutic target.
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Keyvani V, Riahi E, Yousefi M, Esmaeili SA, Shafabakhsh R, Moradi Hasan-Abad A, Mahjoubin-Tehran M, Hamblin MR, Mollazadeh S, Mirzaei H. Gynecologic Cancer, Cancer Stem Cells, and Possible Targeted Therapies. Front Pharmacol 2022; 13:823572. [PMID: 35250573 PMCID: PMC8888850 DOI: 10.3389/fphar.2022.823572] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Accepted: 01/19/2022] [Indexed: 11/13/2022] Open
Abstract
Gynecologic cancer is one of the main causes of death in women. In this type of cancer, several molecules (oncogenes or tumor suppressor genes) contribute to the tumorigenic process, invasion, metastasis, and resistance to treatment. Based on recent evidence, the detection of molecular changes in these genes could have clinical importance for the early detection and evaluation of tumor grade, as well as the selection of targeted treatment. Researchers have recently focused on cancer stem cells (CSCs) in the treatment of gynecologic cancer because of their ability to induce progression and recurrence of malignancy. This has highlighted the importance of a better understanding of the molecular basis of CSCs. The purpose of this review is to focus on the molecular mechanism of gynecologic cancer and the role of CSCs to discover more specific therapeutic approaches to gynecologic cancer treatment.
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Affiliation(s)
- Vahideh Keyvani
- Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Espanta Riahi
- Blood Borne Infections Research Center, Academic Center for Education, Culture and Research (ACECR), Mashhad, Iran; Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Meysam Yousefi
- Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyed-Alireza Esmaeili
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Rana Shafabakhsh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Amin Moradi Hasan-Abad
- Autoimmune Diseases Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Mahjoubin-Tehran
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, South Africa
| | - Samaneh Mollazadeh
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
- *Correspondence: Samaneh Mollazadeh, ; Hamed Mirzaei, ,
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- *Correspondence: Samaneh Mollazadeh, ; Hamed Mirzaei, ,
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45
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Sun ZG, Li ZN, Zhang JM, Hou XY, Yeh SM, Ming X. Recent Development of Flavonoids with Various Activities. Curr Top Med Chem 2022; 22:305-329. [PMID: 35040404 DOI: 10.2174/1568026622666220117111858] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 12/24/2021] [Accepted: 12/27/2021] [Indexed: 11/22/2022]
Abstract
Flavonoids, a series of compounds with C6-C3-C6 structure, mostly originate from plant metabolism. Flavonoids have shown beneficial effects on many aspects of human physiology and health. Recently, many flavonoids with various activities have been discovered, which has led to more and more studies focusing on their physiological and pharmacodynamic activities. The anti-cancer and anti-viral activities especially have attracted the attention of many researchers. Therefore, the discovery and development of flavonoids as anti-disease drugs has great potential and may make significant contribution to fighting diseases. This review focus on the discovery and development of flavonoids in medicinal chemistry in recent years.
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Affiliation(s)
- Zhi-Gang Sun
- Central Laboratory, Linyi Central Hospital, No.17 Jiankang Road, Linyi 276400, China
- Departments of Cancer Biology and Biomedical Engineering, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Zhi-Na Li
- Central Laboratory, Linyi Central Hospital, No.17 Jiankang Road, Linyi 276400, China
| | - Jin-Mai Zhang
- Room 205, BIO-X white house, Shanghai Jiao Tong University, No.1954 Huashan Road, Shanghai 200030, P.R. China
| | - Xiao-Yan Hou
- Qilu Pharmaceutical Co., Ltd, 8888 Lvyou Road, High-tech Zone, Jinan, 250104, P.R. China
| | - Stacy Mary Yeh
- Departments of Cancer Biology and Biomedical Engineering, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Xin Ming
- Departments of Cancer Biology and Biomedical Engineering, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
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Yang R, Qian L. Research on Gut Microbiota-Derived Secondary Bile Acids in Cancer Progression. Integr Cancer Ther 2022; 21:15347354221114100. [PMID: 35880833 PMCID: PMC9421216 DOI: 10.1177/15347354221114100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
The interaction between gut microbiota-derived metabolites and the body plays a
significant role in the occurrence and development of cancer. Secondary bile
acids (BAs) are the important products produced from gut microbial fermentation
of primary BAs, mainly deoxycholic acid (DCA) and lithocholic acid (LCA). In the
gut, they can influence the structure of the microbial communities. Several
studies have demonstrated that secondary BAs, as signaling molecules, can
activate a variety of signaling pathways. They can inhibit the apoptosis of
cancer cells, induce the progression of cancer cell cycles, enhance the ability
of metastasis and invasion of cancer cells, and promote the transformation of
cells into cancer stem cells (CSCs). Moreover, secondary BAs promote cancer by
regulating the function of immune cells. Therefore, targeted manipulation of gut
microbial and secondary BAs has the potential to be developed as for treatment
and prevention of various cancers.
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Affiliation(s)
- Rong Yang
- Medical College, Yangzhou University, Yangzhou, China
| | - Li Qian
- Medical College, Yangzhou University, Yangzhou, China
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47
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Zahra MH, Nawara HM, Hassan G, Afify SM, Seno A, Seno M. Cancer Stem Cells Contribute to Drug Resistance in Multiple Different Ways. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1393:125-139. [PMID: 36587305 DOI: 10.1007/978-3-031-12974-2_6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Many tumors are resistant to conventional cancer therapies because a tumor is composed of heterogeneous cell population. Especially, subpopulation of cancer stem cells, which have self-renewal and differentiation properties and responsible for the tumor initiation, is generally considered resistant to chemo-, radio-, and immune therapy. Understanding the mechanism of drug resistance in cancer stem cells should lead to establish more effective therapeutic strategies. Actually, different molecular mechanisms are conceivable for cancer stem cells acquiring drug resistance. These mechanisms include not only cytoplasmic signaling pathways but also the intercellular communications in the tumor microenvironment. Recently, a great deal of successful reports challenged to elucidate the mechanisms of drug resistance and to develop novel treatments targeting cancer stem cells.
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Affiliation(s)
- Maram H Zahra
- Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, 700-8530, Japan.
| | - Hend M Nawara
- Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, 700-8530, Japan.
| | - Ghmkin Hassan
- Department of Genomic Oncology and Oral Medicine, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, 734-8553, Japan
| | - Said M Afify
- Division of Biochemistry, Chemistry Department, Faculty of Science, Menoufia University, Shebin El Koum-Menoufia, Shebeen El-Kom, 32511, Egypt
| | - Akimasa Seno
- Laboratory of Natural Food & Medicine, Co., Ltd, Okayama University Incubator, Okayama, 700-8530, Japan
| | - Masaharu Seno
- Laboratory of Natural Food & Medicine, Co., Ltd, Okayama University Incubator, Okayama, 700-8530, Japan.
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48
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Zhao† Z, Deng† S, Wang Q, Jia C, Yang J. Novel Insight into Blocking Cancer Metastasis by Biological Nano Confinement through Altering the Cancer Microenvironment. CLINICAL CANCER INVESTIGATION JOURNAL 2022. [DOI: 10.51847/0ozasxscb1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Ogbu SC, Rojas S, Weaver J, Musich PR, Zhang J, Yao ZQ, Jiang Y. DSTYK Enhances Chemoresistance in Triple-Negative Breast Cancer Cells. Cells 2021; 11:97. [PMID: 35011659 PMCID: PMC8750327 DOI: 10.3390/cells11010097] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 12/14/2021] [Accepted: 12/22/2021] [Indexed: 12/14/2022] Open
Abstract
Breast cancer, as the most prevalent cancer in women, is responsible for more than 15% of new cancer cases and about 6.9% of all cancer-related death in the US. A major cause of therapeutic failure in breast cancer is the development of resistance to chemotherapy, especially for triple-negative breast cancer (TNBC). Therefore, how to overcome chemoresistance is the major challenge to improve the life expectancy of breast cancer patients. Our studies demonstrate that TNBC cells surviving the chronic treatment of chemotherapeutic drugs show significantly higher expression of the dual serine/threonine and tyrosine protein kinase (DSTYK) than non-treated parental cells. In our in vitro cellular models, DSTYK knockout via the CRISPR/Cas9-mediated technique results in apoptotic cell death of chemoresistant cells upon drug treatment. Moreover, DSTYK knockout promotes chemotherapeutic drug-induced tumor cell death in an orthotopic mouse model. These findings suggest that DSTYK exerts an important and previously unknown role in promoting chemoresistance. Our studies provide fundamental insight into the role of DSTYK in chemoresistance in TNBC cells and lay the foundation for the development of new strategies targeting DSTYK for improving TNBC therapy.
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Affiliation(s)
- Stella C. Ogbu
- Department of Biomedical Sciences, J. H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (S.C.O.); (S.R.); (J.W.); (P.R.M.)
| | - Samuel Rojas
- Department of Biomedical Sciences, J. H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (S.C.O.); (S.R.); (J.W.); (P.R.M.)
| | - John Weaver
- Department of Biomedical Sciences, J. H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (S.C.O.); (S.R.); (J.W.); (P.R.M.)
| | - Phillip R. Musich
- Department of Biomedical Sciences, J. H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (S.C.O.); (S.R.); (J.W.); (P.R.M.)
| | - Jinyu Zhang
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, ETSU, Johnson City, TN 37614, USA; (J.Z.); (Z.Q.Y.)
| | - Zhi Q. Yao
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, ETSU, Johnson City, TN 37614, USA; (J.Z.); (Z.Q.Y.)
| | - Yong Jiang
- Department of Biomedical Sciences, J. H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (S.C.O.); (S.R.); (J.W.); (P.R.M.)
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Resveratrol Analog 4-Bromo-Resveratrol Inhibits Gastric Cancer Stemness through the SIRT3-c-Jun N-Terminal Kinase Signaling Pathway. Curr Issues Mol Biol 2021; 44:63-72. [PMID: 35723384 PMCID: PMC8929134 DOI: 10.3390/cimb44010005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/16/2021] [Accepted: 12/17/2021] [Indexed: 12/24/2022] Open
Abstract
Chemotherapy is the treatment of choice for gastric cancer, but the currently available therapeutic drugs have limited efficacy. Studies have suggested that gastric cancer stem cells may play a key role in drug resistance in chemotherapy. Therefore, new agents that selectively target gastric cancer stem cells in gastric tumors are urgently required. Sirtuin-3 (SIRT3) is a deacetylase that regulates mitochondrial metabolic homeostasis to maintain stemness in glioma stem cells. Targeting the mitochondrial protein SIRT3 may provide a novel therapeutic option for gastric cancer treatment. However, the mechanism by which stemness is regulated through SIRT3 inhibition in gastric cancer remains unknown. We evaluated the stemness inhibition ability of the SIRT3 inhibitor 4′-bromo-resveratrol (4-BR), an analog of resveratrol in human gastric cancer cells. Our results suggested that 4-BR inhibited gastric cancer cell stemness through the SIRT3-c-Jun N-terminal kinase pathway and may aid in gastric cancer stem-cell–targeted therapy.
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