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Omid R, Khatami F, Rahimnia R, Taheri D, Mashhadi R, Mirzaei A, Hosseini SF, Hashemi Dougaheh SN, Oliveira Reis L, Aghamir SMK. Therapeutic Efficacy of Melatonin and Flutamide Combination in Safety for Prostate Cancer: An In Vitro Study. DNA Cell Biol 2025. [PMID: 40401443 DOI: 10.1089/dna.2025.0018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2025] Open
Abstract
The side effects associated with flutamide as a first-line drug treating prostate cancer, including hepatotoxicity, the aim of this research was to use melatonin as an anticancer candidate to reduce the dose of flutamide and reduce its side effects. We evaluated the effect of melatonin, flutamide, and melatonin-flutamide combination therapy in LNCaP, DU145, and PC3 cell lines. The assessment includes Hoechst dye staining, scratch-wound assay, colony formation assay, flow cytometric analysis of apoptosis and DNA cell cycle, real-time PCR (BAX [BCL2 Associated X]/B-cell lymphoma-2 [BCL2], E-cadherin, Zinc finger protein SNAI2 [SNAIL], Hypoxia Inducible Factor 1 Subunit Alpha [HIF1α], Vascular Endothelial Growth Factor C [VEGFC], and kallikrein-related peptidase 3 [KLK3] genes). To determine Half maximal inhibitory concentration (IC50) levels, cell lines were exposed to different concentrations of the drugs. Our data indicated that IC50 values for melatonin (75 µM) and three cell lines and flutamide (12 and 10 µM) for PC3 and LNCaP/DU145, respectively, with 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide were approved by flow cytometry in a dose and time-dependent manner which was as a consequence of cell cycle arrest at G0/G1 phase. Due to the efficacy of melatonin in combination with flutamide, we used 75 µM melatonin, and 5 µM flutamide instead of 12 µM in DU145, and 6 µM in PC3 and LNCaP, respectively. The combination of melatonin and flutamide significantly upregulated the expression of BAX/BCL2 ratio in all three cell lines (p < 0.0001) and downregulated the expression of KLK3 (p < 0.01), HIF1α (p < 0.01), VEGFC (p < 0.001), and epithelial-mesenchymal transition pathway genes in PC3 and LNCaP (p < 0.01). Melatonin in combination with flutamide reduced its dose and increased the sensitivity of prostate cancer cells to treatment.
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Affiliation(s)
- Reza Omid
- Urology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Khatami
- Urology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ramin Rahimnia
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Diana Taheri
- Urology Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Pathology, Isfahan Kidney Disease Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Rahil Mashhadi
- Urology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Akram Mirzaei
- Urology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | | | - Leonardo Oliveira Reis
- UroScience and Department of Surgery (Urology), School of Medical Sciences, University of Campinas, Unicamp, and Pontifical Catholic University of Campinas, PUC-Campinas, São Paulo, Brazil
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Harland AJ, Perks CM. IGFBP-2 and IGF-II: Key Components of the Neural Stem Cell Niche? Implications for Glioblastoma Pathogenesis. Int J Mol Sci 2025; 26:4749. [PMID: 40429889 DOI: 10.3390/ijms26104749] [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: 04/02/2025] [Revised: 05/09/2025] [Accepted: 05/12/2025] [Indexed: 05/29/2025] Open
Abstract
Glioblastoma is a fatal and aggressive cancer with no cure. It is becoming increasingly clear that glioblastoma initiation is a result of adult neural stem cell (NSC) transformation-most likely those within the subventricular zone (SVZ). Indeed, transcriptomic analysis indicates that glioblastomas are reminiscent of a neurodevelopmental hierarchy, in which neural stem and progenitor markers are widely expressed by tumour stem-like cells. However, NSC fates and the cues that drive them are poorly understood. Studying the crosstalk within NSC niches may better inform our understanding of glioblastoma initiation and development. Insulin-like growth factor binding protein 2 (IGFBP-2) has a well-established prognostic role in glioblastoma, and cell-based mechanistic studies show the independent activation of downstream oncogenic pathways. However, IGFBP-2 is more commonly recognised as a modulator of insulin-like growth factors (IGFs) for receptor tyrosine kinase signal propagation or attenuation. In the adult human brain, both IGFBP-2 and IGF-II expression are retained in the choroid plexus (ChP) and secreted into the cerebral spinal fluid (CSF). Moreover, secretion by closely associated cells and NSCs themselves position IGFBP-2 and IGF-II as interesting factors within the NSC niche. In this review, we will highlight the experimental findings that show IGFBP-2 and IGF-II influence NSC behaviour. Moreover, we will link this to glioblastoma biology and demonstrate the requirement for further analysis of these factors in glioma stem cells (GSCs).
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Affiliation(s)
- Abigail J Harland
- Cancer Endocrinology Group, Bristol Medical School, Translational Health Sciences, University of Bristol, Southmead Hospital, Bristol BS10 5NB, UK
| | - Claire M Perks
- Cancer Endocrinology Group, Bristol Medical School, Translational Health Sciences, University of Bristol, Southmead Hospital, Bristol BS10 5NB, UK
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Mahdi A, Aittaleb M, Tissir F. Targeting Glioma Stem Cells: Therapeutic Opportunities and Challenges. Cells 2025; 14:675. [PMID: 40358199 PMCID: PMC12072158 DOI: 10.3390/cells14090675] [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] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2025] [Revised: 04/25/2025] [Accepted: 05/03/2025] [Indexed: 05/15/2025] Open
Abstract
Glioblastoma (GBM), or grade 4 glioma, is the most common and aggressive primary brain tumor in adults with a median survival of 15 months. Increasing evidence suggests that GBM's aggressiveness, invasiveness, and therapy resistance are driven by glioma stem cells (GSCs), a subpopulation of tumor cells that share molecular and functional characteristics with neural stem cells (NSCs). GSCs are heterogeneous and highly plastic. They evade conventional treatments by shifting their state and entering in quiescence, where they become metabolically inactive and resistant to radiotherapy and chemotherapy. GSCs can exit quiescence and be reactivated to divide into highly proliferative tumor cells which contributes to recurrence. Understanding the molecular mechanisms regulating the biology of GSCs, their plasticity, and the switch between quiescence and mitotic activity is essential to shape new therapeutic strategies. This review examines the latest evidence on GSC biology, their role in glioblastoma progression and recurrence, emerging therapeutic approaches aimed at disrupting their proliferation and survival, and the mechanisms underlying their resistance to therapy.
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Affiliation(s)
| | | | - Fadel Tissir
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Education City, Doha P.O. Box 5825, Qatar; (A.M.); (M.A.)
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Chatterjee O, Kaur GA, Shukla N, Balayan S, Singh PK, Chatterjee S, Tiwari A. Multifaceted arsenal in SELEX nanomedicine. Adv Colloid Interface Sci 2025; 342:103540. [PMID: 40344950 DOI: 10.1016/j.cis.2025.103540] [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: 02/06/2025] [Revised: 04/25/2025] [Accepted: 04/28/2025] [Indexed: 05/11/2025]
Abstract
Aptamers, short oligonucleotide sequences that bind specifically to cellular proteins and receptors, are emerging as versatile tools in molecular nanomedicine. Unlike passive tumor targeting via the enhanced permeability and retention (EPR) effect, aptamers enable precise drug delivery, enhancing therapeutic efficacy while minimizing side effects. Developed through the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) process, aptamers offer compact size, robust structure, chemical versatility, and cost-effective synthesis. They serve as effective delivery vehicles for therapeutic molecules, including miRNA, siRNA, and small-molecule drugs, and function as antibody-like ligands for applications in cancer, diabetes, and autoimmune disorders. Since the approval of Macugen, the first aptamer targeting VEGF, aptamers have also shown promise as diagnostic sensors and theranostic agents. This review explores SELEX-derived aptamers in nanomedicine, focusing on their therapeutic and diagnostic roles, particularly in precision cancer therapies. It also addresses challenges such as degradation and clinical translation alongside prospects in vaccines, tissue engineering, and regenerative medicine.
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Affiliation(s)
- Oishika Chatterjee
- Institute of Advanced Materials, IAAM, Gammalkilsvägen 18, Ulrika 590 53, Sweden; Department of Biological Sciences, Bose Institute Unified Academic Campus EN 80, Sector 5, Bidhan Nagar (Salt Lake City) Kolkata 700 091, WB, India
| | - Gun Anit Kaur
- Institute of Advanced Materials, IAAM, Gammalkilsvägen 18, Ulrika 590 53, Sweden
| | - Nutan Shukla
- Institute of Advanced Materials, IAAM, Gammalkilsvägen 18, Ulrika 590 53, Sweden
| | - Sapna Balayan
- Institute of Advanced Materials, IAAM, Gammalkilsvägen 18, Ulrika 590 53, Sweden
| | - Pravin Kumar Singh
- Institute of Advanced Materials, IAAM, Gammalkilsvägen 18, Ulrika 590 53, Sweden
| | - Subhrangsu Chatterjee
- Department of Biological Sciences, Bose Institute Unified Academic Campus EN 80, Sector 5, Bidhan Nagar (Salt Lake City) Kolkata 700 091, WB, India.
| | - Ashutosh Tiwari
- Institute of Advanced Materials, IAAM, Gammalkilsvägen 18, Ulrika 590 53, Sweden.
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Wang Z, Zhang J, Luo L, Zhang C, Huang X, Liu S, Chen H, Miao W. Nucleoporin 93 Regulates Cancer Cell Growth and Stemness in Bladder Cancer via Wnt/β-Catenin Signaling. Mol Biotechnol 2025; 67:2072-2084. [PMID: 38744786 DOI: 10.1007/s12033-024-01184-9] [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: 11/29/2023] [Accepted: 04/16/2024] [Indexed: 05/16/2024]
Abstract
Bladder cancer (BLCA) is a prevalent cancer type with an unmet need for new therapeutic strategies. Nucleoporin 93 (Nup93) is implicated in the pathophysiology of several cancers, but its relationship with bladder cancer remains unclear. Nup93 expression was analyzed in TCGA datasets and 88 BLCA patient samples. Survival analysis and Cox regression models evaluated the association between Nup93 levels and patient prognosis. BLCA cells were used to investigate the effects of Nup93 overexpression or knockdown on cell growth, invasion, stemness (sphere formation and ALDH2 + cancer stem cell marker), and Wnt/β-catenin signaling in vitro. The Wnt activator BML-284 was used to confirm the involvement of Wnt/β-catenin signaling pathway. A xenograft mouse model validated the in vitro findings. Nup93 was highly expressed in BLCA tissues and cell lines, and high Nup93 expression correlated with poor prognosis in BLCA patients. Nup93 silencing inhibited BLCA cell proliferation, Wnt/β-catenin activation, and cancer cell stemness. Conversely, Nup93 overexpression promoted these effects. BML-284 partially rescued the reduction in cell growth and stemness markers caused by Nup93 knockdown. Nup93 knockdown also suppressed the tumor formation of BLCA cells in vivo. Nup93 regulates BLCA cell growth and stemness via the Wnt/β-catenin pathway, suggesting its potential as a prognostic marker and therapeutic target in BLCA.
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Affiliation(s)
- Zhe Wang
- Urology Department, The First Affiliated Hospital of Hebei North University, No. 12, Changqing Road, Zhangjiakou, 050051, Hebei Province, China
| | - Jing Zhang
- Department of Medical Oncology, The First Affiliated Hospital of Hebei North University, No. 12, Changqing Road, Zhangjiakou, 050051, Hebei Province, China
| | - Lina Luo
- Urology Department, The First Affiliated Hospital of Hebei North University, No. 12, Changqing Road, Zhangjiakou, 050051, Hebei Province, China
| | - Chao Zhang
- Urology Department, The First Affiliated Hospital of Hebei North University, No. 12, Changqing Road, Zhangjiakou, 050051, Hebei Province, China
| | - Xiaomeng Huang
- Medical Department, The First Affiliated Hospital of Hebei North University, No. 12, Changqing Road, Zhangjiakou, 050051, Hebei Province, China
| | - Shuo Liu
- Urology Department, The First Affiliated Hospital of Hebei North University, No. 12, Changqing Road, Zhangjiakou, 050051, Hebei Province, China
| | - Huaian Chen
- Urology Department, The First Affiliated Hospital of Hebei North University, No. 12, Changqing Road, Zhangjiakou, 050051, Hebei Province, China
| | - Wenlong Miao
- Urology Department, The First Affiliated Hospital of Hebei North University, No. 12, Changqing Road, Zhangjiakou, 050051, Hebei Province, China.
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Borlongan MC, Rodriguez T, Putthanbut N, Wang H, Lee JY. Modeling of cancer stem cells and the tumor microenvironment Via NT2/D1 cells to probe pathology and treatment for cancer and beyond. Discov Oncol 2025; 16:605. [PMID: 40272656 PMCID: PMC12022208 DOI: 10.1007/s12672-025-02158-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 03/17/2025] [Indexed: 04/27/2025] Open
Abstract
INTRODUCTION Unique from the other tumor cells, tumorigenic cancer stem cells (CSCs) manifest as a subpopulation of cells within the tumor that exhibit genetic and phenotypic features and signaling processes, which escape traditional anti-oncogenic treatments, thereby triggering metastases and relapses of cancers. Critical to cancer biology is the crosstalk between CSCs and tumor microenvironment (TME), implicating a CSC-based cancer immunotherapy. Cognizant of CSCs' significant role in cancer pathology and treatment, finding a biological model that recapitulates CSCs and TME may allow a better understanding of tumor onset and progression for testing CSC-based therapies. In this review paper, we examined the CSC and TME characteristics of the human embryonal carcinoma NTERA-2 clonal cell line called NTERA-2 cl.D1 or NT2/D1 cells and discussed their potential utility for research and development of treatments for cancer and central nervous system (CNS) disorders. METHODS To probe our hypotheses that NT2/D1 cells display CSC and TME properties key to tumor development, which can serve as a screening platform to test cancer and CNS therapeutics, we conducted a literature review over a 10-year period (2014-2024), focusing on PUBMED and Science Direct published articles on cellular models of cancer, with emphasis on milestone research discoveries on NT2/D1 cells relevant to CSCs and TME. We categorized the studies under pre-clinical and clinical investigations in supporting the existence of CSC and TME features in NT2/D1 cells and providing a laboratory-to-clinic translational basis for cancer and CNS therapeutics. CONCLUSIONS NT2/D1 cells stand as a feasible biological model that recapitulates the crosstalk of CSCs and TME, which may critically contribute to our understanding of cancer and CNS biology and therapeutics. Designing therapeutics against CSCs' distinct self-renewal and differentiation capacities within the TME opens new avenues for treating cancers and CNS disorders.
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Affiliation(s)
- Mia C Borlongan
- California Northstate University College of Medicine, Elk Grove, CA, 95757, USA
| | - Thomas Rodriguez
- Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA
| | - Napasiri Putthanbut
- Center of Aging and Brain Repair, Department of Neurosurgery, University of South Florida, Tampa, FL, 33612, USA
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Hongbin Wang
- California Northstate University College of Pharmacy, Elk Grove, CA, 95757, USA
| | - Jea-Young Lee
- Center of Aging and Brain Repair, Department of Neurosurgery, University of South Florida, Tampa, FL, 33612, USA.
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Rajan SS, Merlin JPJ, Abrahamse H. Breaking the Resistance: Photodynamic Therapy in Cancer Stem Cell-Driven Tumorigenesis. Pharmaceutics 2025; 17:559. [PMID: 40430852 DOI: 10.3390/pharmaceutics17050559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Revised: 04/11/2025] [Accepted: 04/21/2025] [Indexed: 05/29/2025] Open
Abstract
Cancer stem cells (CSCs) are essential for the growth of malignancies because they encourage resistance to cancer therapy and make metastasis and relapse easier. To effectively tackle the obstacles presented by CSCs, novel therapeutic approaches are required. Photodynamic therapy (PDT) is a promising treatment option for cancer cells, which uses light-sensitive medications that are activated by light wavelengths. This review investigates the use of PDT to overcome malignancies driven by CSCs that have innate resistance mechanisms. PDT works by causing tumor cells to accumulate photosensitizers (PSs) selectively. The reactive oxygen species (ROS), which kill cells, are released by these PSs when they are stimulated by light. According to recent developments in PDT, its efficacy may go beyond traditional tumor cells, providing a viable remedy for the resistance shown by CSCs. Researchers want to improve the targeted elimination and selective targeting of CSCs by combining PDT with new PSs and customized delivery systems. Studies emphasize how PDT affects CSCs as well as bulk tumor cells. According to studies, PDT not only limits CSC growth but also modifies their microenvironment, which lowers the possibility of recovery. Additionally, studies are being conducted on the utilization of PDT and immunotherapeutic techniques to improve treatment efficacy and overcome inherent resistance of CSCs. In conclusion, PDT is a viable strategy for treating carcinogenesis driven by CSCs. By applying the most recent advancements in PDT technologies and recognizing how it interacts with CSCs, this treatment has the potential to surpass traditional resistance mechanisms and improve the future of cancer patients. Clinical and preclinical studies highlight that combining PDT with CSC-targeted approaches has the potential to overcome current therapy limitations. Future efforts should focus on clinical validation, optimizing light delivery and PS use, and developing effective combination strategies to target CSCs.
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Affiliation(s)
- Sheeja S Rajan
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, Doornfontein, P.O. Box 17011, Johannesburg 2028, South Africa
| | - J P Jose Merlin
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, Doornfontein, P.O. Box 17011, Johannesburg 2028, South Africa
| | - Heidi Abrahamse
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, Doornfontein, P.O. Box 17011, Johannesburg 2028, South Africa
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Tang J, Amin MA, Campian JL. Glioblastoma Stem Cells at the Nexus of Tumor Heterogeneity, Immune Evasion, and Therapeutic Resistance. Cells 2025; 14:562. [PMID: 40277888 PMCID: PMC12025403 DOI: 10.3390/cells14080562] [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: 03/15/2025] [Revised: 04/05/2025] [Accepted: 04/06/2025] [Indexed: 04/26/2025] Open
Abstract
Glioblastoma (GBM) is an exceedingly aggressive primary brain tumor defined by rapid growth, extensive infiltration, and resistance to standard therapies. A central factor driving these malignancies is the subpopulation of glioblastoma stem cells (GSCs), which possess self-renewal capacity, multipotency, and the ability to regenerate tumor heterogeneity. GSCs contribute to key hallmarks of GBM pathobiology, including relentless progression, resistance to chemotherapy and radiotherapy, and inevitable recurrence. GSCs exhibit distinct molecular signatures, enhanced DNA repair, and metabolic adaptations that protect them against conventional treatments. Moreover, they reside within specialized niches-such as perivascular or hypoxic microenvironments-that sustain stemness, promote immunosuppression, and facilitate angiogenesis. Recent discoveries highlight signaling pathways like Notch, Wnt/β-catenin, Hedgehog, STAT3-PARN, and factors such as TFPI2 and HML-2 as critical regulators of GSC maintenance, plasticity, and immune evasion. These findings underscore the complexity of GSC biology and their pivotal role in driving GBM heterogeneity and therapeutic failure. Emerging therapeutic strategies aim to target GSCs through multiple avenues, including surface markers, immunotherapeutics (e.g., CAR T cells), metabolic vulnerabilities, and combination regimens. Advances in patient-derived organoids, single-cell omics, and 3D co-culture models enable more accurate representation of the tumor ecosystem and personalized therapeutic approaches. Ultimately, improved understanding of GSC-specific targets and the tumor microenvironment promises more effective interventions, paving the way toward better clinical outcomes for GBM patients.
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Affiliation(s)
- Justin Tang
- Department of Biomedical Science, University of Guelph, Guelph, ON N1G 2W1, Canada
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; (M.A.A.); (J.L.C.)
| | - Md Al Amin
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; (M.A.A.); (J.L.C.)
| | - Jian L. Campian
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; (M.A.A.); (J.L.C.)
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Turlej E, Domaradzka A, Radzka J, Drulis-Fajdasz D, Kulbacka J, Gizak A. Cross-Talk Between Cancer and Its Cellular Environment-A Role in Cancer Progression. Cells 2025; 14:403. [PMID: 40136652 PMCID: PMC11940884 DOI: 10.3390/cells14060403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 02/27/2025] [Accepted: 03/06/2025] [Indexed: 03/27/2025] Open
Abstract
The tumor microenvironment is a dynamic and complex three-dimensional network comprising the extracellular matrix and diverse non-cancerous cells, including fibroblasts, adipocytes, endothelial cells and various immune cells (lymphocytes T and B, NK cells, dendritic cells, monocytes/macrophages, myeloid-derived suppressor cells, and innate lymphoid cells). A constantly and rapidly growing number of studies highlight the critical role of these cells in shaping cancer survival, metastatic potential and therapy resistance. This review provides a synthesis of current knowledge on the modulating role of the cellular microenvironment in cancer progression and response to treatment.
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Affiliation(s)
- Eliza Turlej
- Departament of Molecular Physiology and Neurobiology, University of Wrocław, ul. Sienkiewicza 21, 50-335 Wrocław, Poland; (E.T.); (A.D.); (J.R.)
| | - Aleksandra Domaradzka
- Departament of Molecular Physiology and Neurobiology, University of Wrocław, ul. Sienkiewicza 21, 50-335 Wrocław, Poland; (E.T.); (A.D.); (J.R.)
| | - Justyna Radzka
- Departament of Molecular Physiology and Neurobiology, University of Wrocław, ul. Sienkiewicza 21, 50-335 Wrocław, Poland; (E.T.); (A.D.); (J.R.)
| | - Dominika Drulis-Fajdasz
- Departament of Molecular Physiology and Neurobiology, University of Wrocław, ul. Sienkiewicza 21, 50-335 Wrocław, Poland; (E.T.); (A.D.); (J.R.)
| | - Julita Kulbacka
- Departament of Molecular and Cellular Biology, Faculty of Pharmacy, Wrocław Medical University, Borowska 211A, 50-556 Wrocław, Poland;
- Department of Immunology and Bioelectrochemistry, State Research Institute Centre for Innovative Medicine, LT-08406 Vilnius, Lithuania
| | - Agnieszka Gizak
- Departament of Molecular Physiology and Neurobiology, University of Wrocław, ul. Sienkiewicza 21, 50-335 Wrocław, Poland; (E.T.); (A.D.); (J.R.)
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Xu J, Zhang H, Nie Z, He W, Zhao Y, Huang Z, Jia L, Du Z, Zhang B, Xia S. Cancer stem-like cells stay in a plastic state ready for tumor evolution. Neoplasia 2025; 61:101134. [PMID: 39919692 PMCID: PMC11851212 DOI: 10.1016/j.neo.2025.101134] [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: 08/01/2024] [Accepted: 01/31/2025] [Indexed: 02/09/2025]
Abstract
Cell plasticity emerges as a novel cancer hallmark and is pivotal in driving tumor heterogeneity and adaptive resistance to different therapies. Cancer stem-like cells (CSCs) are considered the root of cancer. While first defined as tumor-initiating cells with the potential to develop a heterogeneous tumor, CSCs further demonstrate their roles in cancer metastasis and adaptive therapeutic resistance. Generally, CSCs come from the malignant transformation of somatic stem cells or the de-differentiation of other cancer cells. The resultant cells gain more plasticity and are ready to differentiate into different cell states, enabling them to adapt to therapies and metastatic ecosystems. Therefore, CSCs are likely the nature of tumor cells that gain cell plasticity. However, the phenotypic plasticity of CSCs has never been systematically discussed. Here, we review the distinct intrinsic signaling pathways and unique microenvironmental niches that endow CSC plasticity in solid tumors to adapt to stressful conditions, as well as emerging opportunities for CSC-targeted therapy.
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Affiliation(s)
- Jiali Xu
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China
| | - Houde Zhang
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China
| | - Zhihao Nie
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China
| | - Wenyou He
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China
| | - Yichao Zhao
- Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Zhenhui Huang
- College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, Guangdong, China
| | - Lin Jia
- College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, Guangdong, China.
| | - Zhiye Du
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, China.
| | - Baotong Zhang
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.
| | - Siyuan Xia
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.
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Leck LYW, Abd El-Aziz YS, McKelvey KJ, Park KC, Sahni S, Lane DJR, Skoda J, Jansson PJ. Cancer stem cells: Masters of all traits. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167549. [PMID: 39454969 DOI: 10.1016/j.bbadis.2024.167549] [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: 02/05/2024] [Revised: 10/01/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024]
Abstract
Cancer is a heterogeneous disease, which contributes to its rapid progression and therapeutic failure. Besides interpatient tumor heterogeneity, tumors within a single patient can present with a heterogeneous mix of genetically and phenotypically distinct subclones. These unique subclones can significantly impact the traits of cancer. With the plasticity that intratumoral heterogeneity provides, cancers can easily adapt to changes in their microenvironment and therapeutic exposure. Indeed, tumor cells dynamically shift between a more differentiated, rapidly proliferating state with limited tumorigenic potential and a cancer stem cell (CSC)-like state that resembles undifferentiated cellular precursors and is associated with high tumorigenicity. In this context, CSCs are functionally located at the apex of the tumor hierarchy, contributing to the initiation, maintenance, and progression of tumors, as they also represent the subpopulation of tumor cells most resistant to conventional anti-cancer therapies. Although the CSC model is well established, it is constantly evolving and being reshaped by advancing knowledge on the roles of CSCs in different cancer types. Here, we review the current evidence of how CSCs play a pivotal role in providing the many traits of aggressive tumors while simultaneously evading immunosurveillance and anti-cancer therapy in several cancer types. We discuss the key traits and characteristics of CSCs to provide updated insights into CSC biology and highlight its implications for therapeutic development and improved treatment of aggressive cancers.
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Affiliation(s)
- Lionel Y W Leck
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Yomna S Abd El-Aziz
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt
| | - Kelly J McKelvey
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Kyung Chan Park
- Proteina Co., Ltd./Seoul National University, Seoul, South Korea
| | - Sumit Sahni
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Darius J R Lane
- Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Jan Skoda
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
| | - Patric J Jansson
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
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12
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Park J, Jang HJ, Jung WK, Kang DY, Gong YL, Kim HJ, Kang JS, Yang JW, Byun Y, Park SK. Suppression of dopamine receptor 2 inhibits the formation of human prostate cancer PC‑3‑derived cancer stem cell‑like cells through AMPK inhibition. Oncol Lett 2025; 29:142. [PMID: 39850721 PMCID: PMC11755227 DOI: 10.3892/ol.2025.14888] [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] [Received: 10/10/2024] [Accepted: 01/02/2025] [Indexed: 01/25/2025] Open
Abstract
Cancer stem cells (CSCs) contribute to the resistance of intractable prostate cancer, and dopamine receptor (DR)D2 antagonists exhibit anticancer activity against prostate cancer and CSCs. Human prostate cancer PC-3 cells were used to generate CSC-like cells, serving as a surrogate system to identify the specific DR subtype the inhibition of which significantly affects prostate-derived CSCs. Additionally, the present study aimed to determine the downstream signaling molecules of this DR subtype that exert more profound effects compared with other DR subtypes. The inhibitory effects of specific antagonists or small interfering (si)RNAs on DR subtypes were compared by analyzing morphological changes of cells, expression patterns of pluripotency markers, cell growth inhibitory activities and in vitro cell invasion. L-741,626, a specific DRD2 antagonist, induced morphological changes in PC-3-derived CSC-like cells, suppressed the expression of Oct4 (a pluripotency marker), and inhibited the growth of cells and tumors. The proliferation of heterozygous null PC-3 cells, generated using the CRISPR/Cas9 method, was slow, and their sphere-forming ability was substantially reduced, indicating a diminished capacity to produce CSCs. In addition, the phosphorylation of AMPK was suppressed by DRD2 siRNA and the heterozygous knockout of DRD2 in PC-3 cells, indicating that AMPK may be a putative downstream signaling molecule involved in the production and maintenance of PC-3-derived CSC-like cells. Specific inhibition or suppression of DRD2 caused PC-3-derived CSC-like cells to lose their properties and inhibited the formation of PC-3-derived CSC-like cells, followed by inhibition of the phosphorylation of AMPK, which is considered a putative downstream signaling molecule of DRD2. Further understanding of the mechanisms by which DRD2 regulates AMPK and the effects of AMPK inhibition on the properties of PC-3-derived CSC-like cells may provide valuable insights into the identification of molecular targets for treating intractable prostate cancer wherein AMPK is constitutively activated.
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Affiliation(s)
- Juyeon Park
- College of Pharmacy, Korea University, Sejong 30019, Republic of Korea
| | - Hee Jun Jang
- College of Pharmacy, Korea University, Sejong 30019, Republic of Korea
| | - Won Ki Jung
- College of Pharmacy, Korea University, Sejong 30019, Republic of Korea
| | - Da Yeon Kang
- College of Pharmacy, Korea University, Sejong 30019, Republic of Korea
| | - You Li Gong
- College of Pharmacy, Korea University, Sejong 30019, Republic of Korea
| | - Hee-Jeong Kim
- College of Pharmacy, Korea University, Sejong 30019, Republic of Korea
| | - Jong Soon Kang
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungbuk 28116, Republic of Korea
| | - Jeong Wook Yang
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungbuk 28116, Republic of Korea
| | - Youngjoo Byun
- College of Pharmacy, Korea University, Sejong 30019, Republic of Korea
- Biomedical Research Center of Guro Hoipital, Research-Driven Hospital, Korea University, Seoul 08308, Republic of Korea
| | - Song-Kyu Park
- College of Pharmacy, Korea University, Sejong 30019, Republic of Korea
- Biomedical Research Center of Guro Hoipital, Research-Driven Hospital, Korea University, Seoul 08308, Republic of Korea
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13
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Pham DX, Hsu T. Tumor-initiating and metastasis-initiating cells of clear-cell renal cell carcinoma. J Biomed Sci 2025; 32:17. [PMID: 39920694 PMCID: PMC11806631 DOI: 10.1186/s12929-024-01111-9] [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: 10/02/2024] [Accepted: 12/11/2024] [Indexed: 02/09/2025] Open
Abstract
Clear-cell renal cell carcinoma (ccRCC) is the most common subtype of kidney malignancy. ccRCC is considered a major health concern worldwide because its numbers of incidences and deaths continue to rise and are predicted to continue rising in the foreseeable future. Therefore new strategy for early diagnosis and therapeutics for this disease is urgently needed. The discovery of cancer stem cells (CSCs) offers hope for early cancer detection and treatment. However, there has been no definitive identification of these cancer progenitors for ccRCC. A majority of ccRCC is characterized by the loss of the von Hippel-Lindau (VHL) tumor suppressor gene function. Recent advances in genome analyses of ccRCC indicate that in ccRCC, tumor-initiating cells (TICs) and metastasis-initiating cells (MICs) are two distinct groups of progenitors. MICs result from various genetic changes during subclonal evolution, while TICs reside in the stem of the ccRCC phylogenetic tree of clonal development. TICs likely originate from kidney tubule progenitor cells bearing VHL gene inactivation, including chromatin 3p loss. Recent studies also point to the importance of microenvironment reconstituted by the VHL-deficient kidney tubule cells in promoting ccRCC initiation and progression. These understandings should help define the progenitors of ccRCC and facilitate early detection and treatment of this disease.
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Affiliation(s)
- Dinh-Xuan Pham
- Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan, ROC
| | - Tien Hsu
- Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan, ROC.
- Graduate Institute of Biomedical Sciences, China Medical University-Taiwan, No. 91 Hsueh-Shih Road, Taichung, 40402, Taiwan, ROC.
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14
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Ragab EM, Gamal DME, El-Najjar FF, Elkomy HA, Ragab MA, Elantary MA, Basyouni OM, Moustafa SM, El-Naggar SA, Elsherbiny AS. New insights into Notch signaling as a crucial pathway of pancreatic cancer stem cell behavior by chrysin-polylactic acid-based nanocomposite. Discov Oncol 2025; 16:107. [PMID: 39891818 PMCID: PMC11787125 DOI: 10.1007/s12672-025-01846-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 01/21/2025] [Indexed: 02/03/2025] Open
Abstract
Pancreatic cancer is an extremely deadly illness for which there are few reliable treatments. Recent research indicates that malignant tumors are highly variable and consist of a tiny subset of unique cancer cells, known as cancer stem cells (CSCs), which are responsible for the beginning and spread of tumors. These cells are typically identified by the expression of specific cell surface markers. A population of pancreatic cancer stem cells with aberrantly active developmental signaling pathways has been identified in recent studies of human pancreatic tumors. Among these Notch signaling pathway has been identified as a key regulator of CSCs self-renewal, making it an attractive target for therapeutic intervention. Chrysin-loaded polylactic acid (PLA) as polymeric nanoparticles systems have been growing interest in using as platforms for improved drug delivery. This review aims to explore innovative strategies for targeted therapy and optimized drug delivery in pancreatic CSCs by manipulating the Notch pathway and leveraging PLA-based drug delivery systems. Furthermore, we will assess the capability of PLA nanoparticles to enhance the bioavailability and effectiveness of gemcitabine in pancreatic cancer cells. The insights gained from this review have the potential to contribute to the development of novel treatment approaches that combine targeted therapy with advanced drug delivery utilizing biodegradable polymeric nanoparticles.
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Affiliation(s)
- Eman M Ragab
- Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta, 31527, Egypt.
| | - Doaa M El Gamal
- Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta, 31527, Egypt
| | - Fares F El-Najjar
- Chemistry/Biochemistry Division, chemistry department, Faculty of Science, Tanta University, Tanta, 31527, Egypt
| | - Hager A Elkomy
- Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta, 31527, Egypt
| | - Mahmoud A Ragab
- Chemistry/Biochemistry Division, chemistry department, Faculty of Science, Tanta University, Tanta, 31527, Egypt
| | - Mariam A Elantary
- Chemistry/Biochemistry Division, chemistry department, Faculty of Science, Tanta University, Tanta, 31527, Egypt
| | - Omar M Basyouni
- Chemistry/Zoology Division, chemistry department, Faculty of Science, Tanta University, Tanta, 31527, Egypt
| | - Sherif M Moustafa
- Chemistry/Biochemistry Division, chemistry department, Faculty of Science, Tanta University, Tanta, 31527, Egypt
| | - Shimaa A El-Naggar
- Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta, 31527, Egypt
| | - Abeer S Elsherbiny
- Chemistry Department, Faculty of Science, Tanta University, Tanta, 31527, Egypt
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15
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Nuñez-Rios JD, Ulrich H, Díaz-Muñoz M, Lameu C, Vázquez-Cuevas FG. Purinergic system in cancer stem cells. Purinergic Signal 2025; 21:23-38. [PMID: 37966629 PMCID: PMC11904000 DOI: 10.1007/s11302-023-09976-5] [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: 06/10/2023] [Accepted: 10/25/2023] [Indexed: 11/16/2023] Open
Abstract
Accumulating evidence supports the idea that cancer stem cells (CSCs) are those with the capacity to initiate tumors, generate phenotypical diversity, sustain growth, confer drug resistance, and orchestrate the spread of tumor cells. It is still controversial whether CSCs originate from normal stem cells residing in the tissue or cancer cells from the tumor bulk that have dedifferentiated to acquire stem-like characteristics. Although CSCs have been pointed out as key drivers in cancer, knowledge regarding their physiology is still blurry; thus, research focusing on CSCs is essential to designing novel and more effective therapeutics. The purinergic system has emerged as an important autocrine-paracrine messenger system with a prominent role at multiple levels of the tumor microenvironment, where it regulates cellular aspects of the tumors themselves and the stromal and immune systems. Recent findings have shown that purinergic signaling also participates in regulating the CSC phenotype. Here, we discuss updated information regarding CSCs in the purinergic system and present evidence supporting the idea that elements of the purinergic system expressed by this subpopulation of the tumor represent attractive pharmacological targets for proposing innovative anti-cancer therapies.
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Affiliation(s)
- J D Nuñez-Rios
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Boulevard Juriquilla #3001, Juriquilla Querétaro, Querétaro, CP 76230, México
| | - H Ulrich
- Department of Biochemistry, Chemistry Institute, University of São Paulo (USP), São Paulo, Brazil
| | - M Díaz-Muñoz
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Boulevard Juriquilla #3001, Juriquilla Querétaro, Querétaro, CP 76230, México
| | - C Lameu
- Department of Biochemistry, Chemistry Institute, University of São Paulo (USP), São Paulo, Brazil
| | - F G Vázquez-Cuevas
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Boulevard Juriquilla #3001, Juriquilla Querétaro, Querétaro, CP 76230, México.
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16
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Hakala S, Hämäläinen A, Sandelin S, Giannareas N, Närvä E. Detection of Cancer Stem Cells from Patient Samples. Cells 2025; 14:148. [PMID: 39851576 PMCID: PMC11764358 DOI: 10.3390/cells14020148] [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] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/16/2025] [Accepted: 01/17/2025] [Indexed: 01/26/2025] Open
Abstract
The existence of cancer stem cells (CSCs) in various tumors has become increasingly clear in addition to their prominent role in therapy resistance, metastasis, and recurrence. For early diagnosis, disease progression monitoring, and targeting, there is a high demand for clinical-grade methods for quantitative measurement of CSCs from patient samples. Despite years of active research, standard measurement of CSCs has not yet reached clinical settings, especially in the case of solid tumors. This is because detecting this plastic heterogeneous population of cells is not straightforward. This review summarizes various techniques, highlighting their benefits and limitations in detecting CSCs from patient samples. In addition, methods designed to detect CSCs based on secreted and niche-associated signaling factors are reviewed. Spatial and single-cell methods for analyzing patient tumor tissues and noninvasive techniques such as liquid biopsy and in vivo imaging are discussed. Additionally, methods recently established in laboratories, preclinical studies, and clinical assays are covered. Finally, we discuss the characteristics of an ideal method as we look toward the future.
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Affiliation(s)
| | | | | | | | - Elisa Närvä
- Institute of Biomedicine and FICAN West Cancer Centre Laboratory, University of Turku and Turku University Hospital, FI-20520 Turku, Finland; (S.H.); (A.H.); (S.S.); (N.G.)
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17
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Filippi A, Deculescu-Ioniță T, Hudiță A, Baldasici O, Gălățeanu B, Mocanu MM. Molecular Mechanisms of Dietary Compounds in Cancer Stem Cells from Solid Tumors: Insights into Colorectal, Breast, and Prostate Cancer. Int J Mol Sci 2025; 26:631. [PMID: 39859345 PMCID: PMC11766403 DOI: 10.3390/ijms26020631] [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: 11/21/2024] [Revised: 01/10/2025] [Accepted: 01/11/2025] [Indexed: 01/27/2025] Open
Abstract
Cancer stem cells (CSC) are known to be the main source of tumor relapse, metastasis, or multidrug resistance and the mechanisms to counteract or eradicate them and their activity remain elusive. There are different hypotheses that claim that the origin of CSC might be in regular stem cells (SC) and, due to accumulation of mutations, these normal cells become malignant, or the source of CSC might be in any malignant cell that, under certain environmental circumstances, acquires all the qualities to become CSC. Multiple studies indicate that lifestyle and diet might represent a source of wellbeing that can prevent and ameliorate the malignant phenotype of CSC. In this review, after a brief introduction to SC and CSC, we analyze the effects of phenolic and non-phenolic dietary compounds and we highlight the molecular mechanisms that are shown to link diets to CSC activation in colon, breast, and prostate cancer. We focus the analysis on specific markers such as sphere formation, CD surface markers, epithelial-mesenchymal transition (EMT), Oct4, Nanog, Sox2, and aldehyde dehydrogenase 1 (ALDH1) and on the major signaling pathways such as PI3K/Akt/mTOR, NF-κB, Notch, Hedgehog, and Wnt/β-catenin in CSC. In conclusion, a better understanding of how bioactive compounds in our diets influence the dynamics of CSC can raise valuable awareness towards reducing cancer risk.
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Affiliation(s)
- Alexandru Filippi
- Department of Biochemistry and Biophysics, “Carol Davila” University of Medicine and Pharmacy of Bucharest, 050474 Bucharest, Romania;
| | - Teodora Deculescu-Ioniță
- Department of Pharmacognosy, Phytochemistry and Phytotherapy, “Carol Davila” University of Medicine and Pharmacy of Bucharest, 050474 Bucharest, Romania;
| | - Ariana Hudiță
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania; (A.H.); (B.G.)
| | - Oana Baldasici
- Department of Genetics, Genomics and Experimental Pathology, The Oncology Institute “Prof. Dr. Ion Chiricuță”, 400015 Cluj-Napoca, Romania;
| | - Bianca Gălățeanu
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania; (A.H.); (B.G.)
| | - Maria-Magdalena Mocanu
- Department of Biochemistry and Biophysics, “Carol Davila” University of Medicine and Pharmacy of Bucharest, 050474 Bucharest, Romania;
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18
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Velapure P, Kansal D, Bobade C. Tumor microenvironment-responsive nanoformulations for breast cancer. DISCOVER NANO 2024; 19:212. [PMID: 39708097 DOI: 10.1186/s11671-024-04122-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 10/07/2024] [Indexed: 12/23/2024]
Abstract
Nanomedicine, the most promising approach for regulated and targeted drug delivery, is frequently applied in cancer treatment. Essentially, accumulating evidence indicates that nanomedicine has positive results in the treatment of breast cancer (BC), with many BC patients benefiting from nanomedicine-related treatments. Currently, nanodrug delivery systems based on stimulus responses are gaining popularity because of their additional ability to manage drug release depending on the interior environment of the cancer. This review includes a synopsis of several types of internal (pH, redox, enzyme, reactive oxygen species, and hypoxia) stimuli-responsive nanoparticle drug delivery systems as well as perspectives for forthcoming times. Stimulus-responsive nanoparticles can remain stable under physiological conditions while being rapidly activated to release drugs in response to specific stimuli, prolonging blood circulation and increasing cancer cellular uptake, resulting in excellent therapeutic performance and improved biosafety. In this paper, we discuss tumor microenvironment responsive Nanoformulation for breast cancer treatment.
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Affiliation(s)
- Pallavi Velapure
- School of Health Science and Technology, Dr. Vishwanath Karad MIT World Peace University, S.No. 124, MIT Campus, Paud Road, Kothrud, Pune, 411038, Maharashtra, India
| | - Divyanshi Kansal
- School of Health Science and Technology, Dr. Vishwanath Karad MIT World Peace University, S.No. 124, MIT Campus, Paud Road, Kothrud, Pune, 411038, Maharashtra, India
| | - Chandrashekhar Bobade
- School of Health Science and Technology, Dr. Vishwanath Karad MIT World Peace University, S.No. 124, MIT Campus, Paud Road, Kothrud, Pune, 411038, Maharashtra, India.
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19
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Oguic R, Grskovic A, Spanjol J, Mikolasevic I, Djordjevic G. CD44 Immunohistochemical Expression in Central and Peripheral Parts of Prostatic Adenocarcinoma: An Institutional Study. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:2032. [PMID: 39768912 PMCID: PMC11728140 DOI: 10.3390/medicina60122032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 11/18/2024] [Accepted: 11/27/2024] [Indexed: 01/16/2025]
Abstract
Background and Objectives: Prostate cancer is one of the most commonly diagnosed cancers in the male population and the fifth leading cause of cancer death worldwide in men as of 2022. One of the potential biomarkers that can predict the progression of the disease is the transmembrane adhesion molecule CD44s. The aims of this study were to determine the expression of CD44s in prostate cancer in the central tumor mass and in the tumor periphery of the disease and to compare it with the clinicopathological parameters (PSA, Gleason score, surgical margins, and biochemical recurrence of the disease) in patients treated with radical prostatectomy. Materials and Methods: The research was randomized retrospectively during the period from 2001 to 2006. Tissue microarrays of 121 archival acinar prostate carcinoma samples were immunohistochemically evaluated for CD44s expression. The immunoexpression was determined semiquantitatively, taking into account the percentage (0 (0-5%), 1 (6-24%), 2 (26-75%), and 3 (76-100%) and intensity of the membranous staining of the tumor cells (0 absent; 1 weak at 400×; 2 intermediates at 100×; 3 strong at 40×) and calculated to obtain a final score (0-3 were regarded as negative; 4-6 were regarded as positive). Results: For statistical purposes, we divided the tumors into two categories: Gleason grade group 1 makes up 80.7% and grade group 2, which includes all the remaining Gleason grade groups (out of 2-5), accounts for 19.3% of the tumors. Grade group 1 had the highest incidence of score 4 (positive expression). There were statistically significantly more positive expressions in those tumors with negative prostatectomy margins (chi square: p = 0.001; Cramer V: 0.319). There was no correlation between CD44s expression and biochemical recurrence (p = 0.218), nor with the preoperative PSA values (p = 0.165). In the grade group 1 tumors, the CD44s immunoexpression and status of prostatectomy margin were statistically significantly related with negative margins (p = 0.028). An analysis of the expression of CD44s according to the localization in the central part of the tumor mass and on the periphery of the cancer in the group of tumors with a positive margin did not show a significant correlation because the sample was too small. Descriptively, it can be noted that the expression on the periphery was higher, and the central/peripheral expression ratio was higher in favor of the periphery. Conclusions: Our results provide insight into the possible value of CD44s expression for predicting the behavior of prostate tumors and the justification of therapy after a prostatectomy. Also hypothetically, they indicate a protective role of CD44s in a group of well-differentiated tumors at the periphery of the tumor mass. Therefore, it is useful to study the CD44s molecule further in this sense.
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Affiliation(s)
- Romano Oguic
- Department of Urology, University Hospital Rijeka, 51000 Rijeka, Croatia; (R.O.); (A.G.); (J.S.)
| | - Antun Grskovic
- Department of Urology, University Hospital Rijeka, 51000 Rijeka, Croatia; (R.O.); (A.G.); (J.S.)
| | - Josip Spanjol
- Department of Urology, University Hospital Rijeka, 51000 Rijeka, Croatia; (R.O.); (A.G.); (J.S.)
| | - Ivana Mikolasevic
- Clinical Institute of Oncology and Radiotherapy, University Hospital Centre Rijeka, 51000 Rijeka, Croatia;
| | - Gordana Djordjevic
- Department of Pathology and Cytology, University Hospital Center Rijeka, 51000 Rijeka, Croatia
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20
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Louati K, Maalej A, Kolsi F, Kallel R, Gdoura Y, Borni M, Hakim LS, Zribi R, Choura S, Sayadi S, Chamkha M, Mnif B, Khemakhem Z, Boudawara TS, Boudawara MZ, Bouraoui A, Kraiem J, Safta F. A Shotgun Proteomic-Based Approach with a Q-Exactive Hybrid Quadrupole-Orbitrap High-Resolution Mass Spectrometer for the Assessment of Pesticide Mixture-Induced Neurotoxicity on a 3D-Developed Neurospheroid Model from Human Brain Meningiomas: Identification of Trityl-Post-Translational Modification. J Proteome Res 2024; 23:5554-5576. [PMID: 39556108 PMCID: PMC11629387 DOI: 10.1021/acs.jproteome.4c00804] [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: 09/16/2024] [Revised: 10/14/2024] [Accepted: 10/31/2024] [Indexed: 11/19/2024]
Abstract
The widespread use of pesticides, particularly in combinations, has resulted in enhanced hazardous health effects. However, little is known about their molecular mechanism of interactions. The aim of this study was to assess the neurotoxicity effect of pesticides in mixtures by adopting a 3D in vitro developed neurospheroid model, followed by treatment by increased concentrations of pesticides for 24 h and analysis by a shotgun proteomic-based approach with high-resolution tandem mass spectrometry. Three proteins, namely, glyceraldehyde-3-phosphate-dehydrogenase (GAPDH), α-enolase, and phosphoglycerate-kinase-1, were selected as key targets in the metabolic process. Only high doses of pesticides mitigated cell-density proliferation with the occurrence of apoptotic cells, which unlikely makes any neurological alterations in environmental regulatory exposures. The proteomic analysis showed that majority of altered proteins were implicated in cell metabolism. De novo peptide sequencing revealed ion losses and adduct formation, namely, a trityl-post-translational modification in the active site of 201-GAPDH protein. The study also highlights the plausible role of pyrethroids to be implicated in the deleterious effects of pesticides in a mixture. To the best of our knowledge, our finding is the first in toxicoproteomics to deeply elucidate pesticides' molecular interactions and their ability to adduct proteins as a pivotal role in the neurotoxicity mechanism.
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Affiliation(s)
- Kaouthar Louati
- Laboratory
of Chemical, Galenic and Pharmacological Drug Development- LR12ES09, University of Monastir, Road Avicenne , 5000Monastir, Tunisia
| | - Amina Maalej
- Laboratory
of Environmental Bioprocesses, Centre of
Biotechnology of Sfax, Road of Sidi-Mansour, P.O. Box 1177 , 3018Sfax, Tunisia
| | - Fatma Kolsi
- Department
of Neurosurgery, Habib Bourguiba University
Hospital, Road El Ain
km 1.5, Avenue of Ferdaous, 3089Sfax, Tunisia
- Faculty
of Medicine, University of Sfax, Avenue of Majida Boulila, 3029Sfax, Tunisia
| | - Rim Kallel
- Laboratory
of Pathological Anatomy and Cytology, Habib
Bourguiba University Hospital, Road El Ain km 1.5, Avenue of Ferdaous, 3089 Sfax, Tunisia
- Faculty
of Medicine, University of Sfax, Avenue of Majida Boulila, 3029Sfax, Tunisia
| | - Yassine Gdoura
- Department
of Neurosurgery, Habib Bourguiba University
Hospital, Road El Ain
km 1.5, Avenue of Ferdaous, 3089Sfax, Tunisia
- Faculty
of Medicine, University of Sfax, Avenue of Majida Boulila, 3029Sfax, Tunisia
| | - Mahdi Borni
- Department
of Neurosurgery, Habib Bourguiba University
Hospital, Road El Ain
km 1.5, Avenue of Ferdaous, 3089Sfax, Tunisia
- Faculty
of Medicine, University of Sfax, Avenue of Majida Boulila, 3029Sfax, Tunisia
| | - Leila Sellami Hakim
- Laboratory
of Pathological Anatomy and Cytology, Habib
Bourguiba University Hospital, Road El Ain km 1.5, Avenue of Ferdaous, 3089 Sfax, Tunisia
| | - Rania Zribi
- Faculty
of Letters and Humanities, University of
Sfax, Airport Road, Km
4.5, 3023 Sfax, Tunisia
| | - Sirine Choura
- Laboratory
of Environmental Bioprocesses, Centre of
Biotechnology of Sfax, Road of Sidi-Mansour, P.O. Box 1177 , 3018Sfax, Tunisia
| | - Sami Sayadi
- Biotechnology
Program, Center for Sustainable Development, College of Arts and Sciences, Qatar University, 2713 Doha, Qatar
| | - Mohamed Chamkha
- Laboratory
of Environmental Bioprocesses, Centre of
Biotechnology of Sfax, Road of Sidi-Mansour, P.O. Box 1177 , 3018Sfax, Tunisia
| | - Basma Mnif
- Department
of Bacteriology, Habib Bourguiba University
Hospital, Road El Ain km 1.5, Avenue of Ferdaous, 3089Sfax, Tunisia
- Faculty
of Medicine, University of Sfax, Avenue of Majida Boulila, 3029Sfax, Tunisia
| | - Zouheir Khemakhem
- Legal
Medicine
Department, Habib Bourguiba University Hospital, Road El Ain km 1.5, Avenue of Ferdaous, 3089 Sfax, Tunisia
- Faculty
of Medicine, University of Sfax, Avenue of Majida Boulila, 3029Sfax, Tunisia
| | - Tahya Sellami Boudawara
- Laboratory
of Pathological Anatomy and Cytology, Habib
Bourguiba University Hospital, Road El Ain km 1.5, Avenue of Ferdaous, 3089 Sfax, Tunisia
- Faculty
of Medicine, University of Sfax, Avenue of Majida Boulila, 3029Sfax, Tunisia
| | - Mohamed Zaher Boudawara
- Department
of Neurosurgery, Habib Bourguiba University
Hospital, Road El Ain
km 1.5, Avenue of Ferdaous, 3089Sfax, Tunisia
- Faculty
of Medicine, University of Sfax, Avenue of Majida Boulila, 3029Sfax, Tunisia
| | - Abderrahman Bouraoui
- Laboratory
of Chemical, Galenic and Pharmacological Drug Development- LR12ES09, University of Monastir, Road Avicenne , 5000Monastir, Tunisia
| | - Jamil Kraiem
- Laboratory
of Chemical, Galenic and Pharmacological Drug Development- LR12ES09, University of Monastir, Road Avicenne , 5000Monastir, Tunisia
| | - Fathi Safta
- Laboratory
of Chemical, Galenic and Pharmacological Drug Development- LR12ES09, University of Monastir, Road Avicenne , 5000Monastir, Tunisia
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21
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Park J, Kim J. CRISPR/Cas9 Technology Providing the Therapeutic Landscape of Metastatic Prostate Cancer. Pharmaceuticals (Basel) 2024; 17:1589. [PMID: 39770431 PMCID: PMC11676443 DOI: 10.3390/ph17121589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 01/11/2025] Open
Abstract
Prostate cancer (PCa) is the most prevalent malignancy and the second leading cause of cancer-related death in men. Although current therapies can effectively manage the primary tumor, most patients with late-stage disease manifest with metastasis in different organs. From surgery to treatment intensification (TI), several combinations of therapies are administered to improve the prognosis of patients with metastatic PCa. Due to the high frequency of the mutation during the metastatic phase, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated nuclease 9 (Cas9) genetic engineering tool can accelerate the effects of TI by enhancing targeted gene therapy or immunotherapy. This review describes the genetic background of metastatic PCa and how CRISPR/Cas9 technology can contribute to the field of PCa treatment development. It also discusses the current limitations of conventional PCa therapy and the potential of CRISPR-based PCa therapy.
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Affiliation(s)
- Jieun Park
- Department of Neurology, College of Medicine, Dongguk University, Ilsan, Goyang 10326, Republic of Korea;
| | - Jaehong Kim
- Department of Biochemistry, College of Medicine, Gachon University, Incheon 21999, Republic of Korea
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22
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Tao Y, Du M, Zhu M, Wang Y, Fei Y, Zhao YQ, Ma J, Fan R, Dai F, Chen J, Yin J, Fan B, Zeng G. Antitumor Effect of Peptide-Camptothecin Conjugate Targeting CD133 Protein. Bioconjug Chem 2024; 35:1859-1869. [PMID: 39527780 DOI: 10.1021/acs.bioconjchem.4c00485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
The peptide-drug conjugate (PDC) has emerged as one of the new approaches for cancer therapy, which has the advantages of improved drug target ability and reduced adverse effects compared with the traditional chemotherapy. CD133 is a surface antigen specific to cancer stem cells, which are thought to be responsible for the self-renewal, proliferation, metastasis, and chemoresistance of cancer cells. A PDC for CD133 was designed by us, and it consists of CD133 targeting peptide LS-7 (amino acid sequence LQNAPRS), a pH-sensitive linker (succinyl), and a cytotoxic payload, the cytotoxic molecule camptothecin (CPT) with potent toxicity in vivo and in vitro. An antitumor study exhibited that the conjugate LS-7-CPT has not only improved its cytotoxicity in tumor cells but also retained its anticancer effect in vivo. In addition, the acute toxicity in mice of LS-7-CPT has been improved and the maximum tolerated dose has been increased by at least 56.2-fold. Pull-down and in vivo fluorescent imaging results indicated that LS-7-CPT was enriched in mice tumors by targeting CD133 protein. As far as we know, this is the first report for a PDC molecule designed for CD133, which is important for the study of CPT drug development.
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Affiliation(s)
- Yang Tao
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Maoxin Du
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Meihua Zhu
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Yinyue Wang
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Yusong Fei
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
| | - Yu-Qiang Zhao
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
| | - Junjie Ma
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Ruifeng Fan
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Fang Dai
- School of Chemistry and Environmental Engineering, Qujing Normal University, Qujing 655011, China
| | - Jingchao Chen
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Junlin Yin
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Baomin Fan
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
| | - Guangzhi Zeng
- Yunnan Key Laboratory of Chiral Functional Substance Research and Application, Yunnan Minzu University, Kunming 650504, China
- Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China
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23
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Chow ST, Fan J, Zhang X, Wang Y, Li Y, Ng CF, Pei X, Zheng Q, Wang F, Wu D, Chan FL. Nuclear receptor TLX functions to promote cancer stemness and EMT in prostate cancer via its direct transactivation of CD44 and stem cell-regulatory transcription factors. Br J Cancer 2024; 131:1450-1462. [PMID: 39322688 PMCID: PMC11519473 DOI: 10.1038/s41416-024-02843-z] [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: 08/25/2023] [Revised: 08/27/2024] [Accepted: 08/28/2024] [Indexed: 09/27/2024] Open
Abstract
BACKGROUND Prostate cancer stem cells (PCSCs) play crucial roles in therapy-resistance and metastasis in castration-resistant prostate cancer (CRPC). Certain functional link between cancer stemness and epithelial-mesenchymal transition (EMT) is involved in CRPC. However, up-stream regulators controlling these two processes in PCSCs are still poorly understood. Recently, we have shown that orphan nuclear receptor TLX can promote tumour initiation and progression in CRPC by repressing androgen receptor and oncogene-induced senescence. METHODS PCSCs were isolated from various prostate cancer cell lines and clinical tumour tissues using multiple methods for various in vitro and in vivo oncogenic growth analyses. Direct targets of TLX involved in stemness and EMT regulation were determined by specific reporter gene assays and ligand-driven modulation of TLX activity. RESULTS PCSCs isolated from various sources exhibited increased expression of TLX. Functional and molecular characterisation showed that TLX could function to promote cancer stemness and EMT in prostate cancer cells via its direct transactivation of CD44, SOX2, POU5F1 and NANOG, which share certain functional crosstalk in these two cellular processes. CONCLUSIONS TLX could act as a key up-stream regulator in transcriptional control of stemness and EMT in PCSCs, which contribute to their tumorigenicity, castration-resistance and metastasis potentials in advanced prostate cancer.
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Affiliation(s)
- Sin Ting Chow
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China
| | - Jiaqi Fan
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China
| | - Xingxing Zhang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China
| | - Yuliang Wang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China
| | - Youjia Li
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China
| | - Chi-Fai Ng
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China
| | - Xiaojuan Pei
- Department of Pathology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guandong, China
| | - Qingyou Zheng
- Department of Urology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong Province, China
| | - Fei Wang
- Department of Urology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, China
| | - Dinglan Wu
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China.
- Department of Urology and The Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, China.
| | - Franky Leung Chan
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China.
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24
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Galassi C, Esteller M, Vitale I, Galluzzi L. Epigenetic control of immunoevasion in cancer stem cells. Trends Cancer 2024; 10:1052-1071. [PMID: 39244477 DOI: 10.1016/j.trecan.2024.08.004] [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: 03/30/2024] [Revised: 07/24/2024] [Accepted: 08/12/2024] [Indexed: 09/09/2024]
Abstract
Cancer stem cells (CSCs) are a poorly differentiated population of malignant cells that (at least in some neoplasms) is responsible for tumor progression, resistance to therapy, and disease relapse. According to a widely accepted model, all stages of cancer progression involve the ability of neoplastic cells to evade recognition or elimination by the host immune system. In line with this notion, CSCs are not only able to cope with environmental and therapy-elicited stress better than their more differentiated counterparts but also appear to better evade tumor-targeting immune responses. We summarize epigenetic modifications of DNA and histones through which CSCs evade immune recognition or elimination, and propose that such alterations constitute promising therapeutic targets to increase the sensitivity of some malignancies to immunotherapy.
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Affiliation(s)
- Claudia Galassi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Manel Esteller
- Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain; Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain; Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Catalonia, Spain
| | - Ilio Vitale
- Italian Institute for Genomic Medicine, Istituto di Ricovero e Cura a Carattere Scientifico (IRCSS) Candiolo, Torino, Italy; Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy.
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA; Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA.
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25
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Lorusso B, Nogara A, Fioretzaki R, Corradini E, Bove R, Roti G, Gherli A, Montanaro A, Monica G, Cavazzini F, Bonomini S, Graiani G, Silini EM, Gnetti L, Pilato FP, Cerasoli G, Quaini F, Lagrasta CAM. CD26 Is Differentially Expressed throughout the Life Cycle of Infantile Hemangiomas and Characterizes the Proliferative Phase. Int J Mol Sci 2024; 25:9760. [PMID: 39337249 PMCID: PMC11432178 DOI: 10.3390/ijms25189760] [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: 07/09/2024] [Revised: 08/30/2024] [Accepted: 09/07/2024] [Indexed: 09/30/2024] Open
Abstract
Infantile hemangiomas (IHs) are benign vascular neoplasms of childhood (prevalence 5-10%) due to the abnormal proliferation of endothelial cells. IHs are characterized by a peculiar natural life cycle enclosing three phases: proliferative (≤12 months), involuting (≥13 months), and involuted (up to 4-7 years). The mechanisms underlying this neoplastic disease still remain uncovered. Twenty-seven IH tissue specimens (15 proliferative and 12 involuting) were subjected to hematoxylin and eosin staining and a panel of diagnostic markers by immunohistochemistry. WT1, nestin, CD133, and CD26 were also analyzed. Moreover, CD31pos/CD26pos proliferative hemangioma-derived endothelial cells (Hem-ECs) were freshly isolated, exposed to vildagliptin (a DPP-IV/CD26 inhibitor), and tested for cell survival and proliferation by MTT assay, FACS analysis, and Western blot assay. All IHs displayed positive CD31, GLUT1, WT1, and nestin immunostaining but were negative for D2-40. Increased endothelial cell proliferation in IH samples was documented by ki67 labeling. All endothelia of proliferative IHs were positive for CD26 (100%), while only 10 expressed CD133 (66.6%). Surprisingly, seven involuting IH samples (58.3%) exhibited coexisting proliferative and involuting aspects in the same hemangiomatous lesion. Importantly, proliferative areas were characterized by CD26 immunolabeling, at variance from involuting sites that were always CD26 negative. Finally, in vitro DPP-IV pharmacological inhibition by vildagliptin significantly reduced Hem-ECs proliferation through the modulation of ki67 and induced cell cycle arrest associated with the upregulation of p21 protein expression. Taken together, our findings suggest that CD26 might represent a reliable biomarker to detect proliferative sites and unveil non-regressive IHs after a 12-month life cycle.
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Affiliation(s)
- Bruno Lorusso
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (B.L.); (A.N.); (R.F.); (E.C.); (R.B.); (G.R.); (A.G.); (A.M.); (G.M.); (F.C.); (F.Q.)
| | - Antonella Nogara
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (B.L.); (A.N.); (R.F.); (E.C.); (R.B.); (G.R.); (A.G.); (A.M.); (G.M.); (F.C.); (F.Q.)
| | - Rodanthi Fioretzaki
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (B.L.); (A.N.); (R.F.); (E.C.); (R.B.); (G.R.); (A.G.); (A.M.); (G.M.); (F.C.); (F.Q.)
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, 185 37 Piraeus, Greece
| | - Emilia Corradini
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (B.L.); (A.N.); (R.F.); (E.C.); (R.B.); (G.R.); (A.G.); (A.M.); (G.M.); (F.C.); (F.Q.)
| | - Roberta Bove
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (B.L.); (A.N.); (R.F.); (E.C.); (R.B.); (G.R.); (A.G.); (A.M.); (G.M.); (F.C.); (F.Q.)
| | - Giovanni Roti
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (B.L.); (A.N.); (R.F.); (E.C.); (R.B.); (G.R.); (A.G.); (A.M.); (G.M.); (F.C.); (F.Q.)
- Translational Hematology and Chemogenomics (THEC), University of Parma, 43126 Parma, Italy
- Hematology and BMT Unit, University Hospital of Parma, 43126 Parma, Italy;
| | - Andrea Gherli
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (B.L.); (A.N.); (R.F.); (E.C.); (R.B.); (G.R.); (A.G.); (A.M.); (G.M.); (F.C.); (F.Q.)
- Translational Hematology and Chemogenomics (THEC), University of Parma, 43126 Parma, Italy
| | - Anna Montanaro
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (B.L.); (A.N.); (R.F.); (E.C.); (R.B.); (G.R.); (A.G.); (A.M.); (G.M.); (F.C.); (F.Q.)
- Translational Hematology and Chemogenomics (THEC), University of Parma, 43126 Parma, Italy
| | - Gregorio Monica
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (B.L.); (A.N.); (R.F.); (E.C.); (R.B.); (G.R.); (A.G.); (A.M.); (G.M.); (F.C.); (F.Q.)
- Translational Hematology and Chemogenomics (THEC), University of Parma, 43126 Parma, Italy
| | - Filippo Cavazzini
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (B.L.); (A.N.); (R.F.); (E.C.); (R.B.); (G.R.); (A.G.); (A.M.); (G.M.); (F.C.); (F.Q.)
- Translational Hematology and Chemogenomics (THEC), University of Parma, 43126 Parma, Italy
| | - Sabrina Bonomini
- Hematology and BMT Unit, University Hospital of Parma, 43126 Parma, Italy;
| | - Gallia Graiani
- Center of Dental Medicine, University of Parma, 43126 Parma, Italy;
| | - Enrico Maria Silini
- Pathology Section, University Hospital of Parma, 43126 Parma, Italy; (E.M.S.); (L.G.); (F.P.P.)
| | - Letizia Gnetti
- Pathology Section, University Hospital of Parma, 43126 Parma, Italy; (E.M.S.); (L.G.); (F.P.P.)
| | - Francesco Paolo Pilato
- Pathology Section, University Hospital of Parma, 43126 Parma, Italy; (E.M.S.); (L.G.); (F.P.P.)
| | - Giuseppe Cerasoli
- Pediatric Surgery, Ospedale dei Bambini of Parma, University Hospital of Parma, 43126 Parma, Italy;
| | - Federico Quaini
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (B.L.); (A.N.); (R.F.); (E.C.); (R.B.); (G.R.); (A.G.); (A.M.); (G.M.); (F.C.); (F.Q.)
| | - Costanza Anna Maria Lagrasta
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (B.L.); (A.N.); (R.F.); (E.C.); (R.B.); (G.R.); (A.G.); (A.M.); (G.M.); (F.C.); (F.Q.)
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26
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Hawly J, Murcar MG, Schcolnik-Cabrera A, Issa ME. Glioblastoma stem cell metabolism and immunity. Cancer Metastasis Rev 2024; 43:1015-1035. [PMID: 38530545 DOI: 10.1007/s10555-024-10183-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 03/09/2024] [Indexed: 03/28/2024]
Abstract
Despite enormous efforts being invested in the development of novel therapies for brain malignancies, there remains a dire need for effective treatments, particularly for pediatric glioblastomas. Their poor prognosis has been attributed to the fact that conventional therapies target tumoral cells, but not glioblastoma stem cells (GSCs). GSCs are characterized by self-renewal, tumorigenicity, poor differentiation, and resistance to therapy. These characteristics represent the fundamental tools needed to recapitulate the tumor and result in a relapse. The mechanisms by which GSCs alter metabolic cues and escape elimination by immune cells are discussed in this article, along with potential strategies to harness effector immune cells against GSCs. As cellular immunotherapy is making significant advances in a variety of cancers, leveraging this underexplored reservoir may result in significant improvements in the treatment options for brain malignancies.
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Affiliation(s)
- Joseph Hawly
- Faculty of Medicine and Medical Sciences, University of Balamand, Dekouaneh, Lebanon
| | - Micaela G Murcar
- Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA
| | | | - Mark E Issa
- Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
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27
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Luo Y, Yu J, Lin Z, Wang X, Zhao J, Liu X, Qin W, Xu G. Metabolic characterization of sphere-derived prostate cancer stem cells reveals aberrant urea cycle in stemness maintenance. Int J Cancer 2024; 155:742-755. [PMID: 38647131 DOI: 10.1002/ijc.34967] [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: 11/27/2023] [Revised: 03/06/2024] [Accepted: 03/19/2024] [Indexed: 04/25/2024]
Abstract
Alteration of cell metabolism is one of the essential characteristics of tumor growth. Cancer stem cells (CSCs) are the initiating cells of tumorigenesis, proliferation, recurrence, and other processes, and play an important role in therapeutic resistance and metastasis. Thus, identification of the metabolic profiles in prostate cancer stem cells (PCSCs) is critical to understanding prostate cancer progression. Using untargeted metabolomics and lipidomics methods, we show distinct metabolic differences between prostate cancer cells and PCSCs. Urea cycle is the most significantly altered metabolic pathway in PCSCs, the key metabolites arginine and proline are evidently elevated. Proline promotes cancer stem-like characteristics via the JAK2/STAT3 signaling pathway. Meanwhile, the enzyme pyrroline-5-carboxylate reductase 1 (PYCR1), which catalyzes the conversion of pyrroline-5-carboxylic acid to proline, is highly expressed in PCSCs, and the inhibition of PYCR1 suppresses the stem-like characteristics of prostate cancer cells and tumor growth. In addition, carnitine and free fatty acid levels are significantly increased, indicating reprogramming of fatty acid metabolism in PCSCs. Reduced sphingolipid levels and increased triglyceride levels are also observed. Collectively, our data illustrate the comprehensive landscape of the metabolic reprogramming of PCSCs and provide potential therapeutic strategies for prostate cancer.
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Affiliation(s)
- Yuanyuan Luo
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
- State Key Laboratory of Medical Proteomics, Beijing, China
- Liaoning Province Key Laboratory of Metabolomics, Dalian, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jiachuan Yu
- Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zhikun Lin
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
- State Key Laboratory of Medical Proteomics, Beijing, China
- Liaoning Province Key Laboratory of Metabolomics, Dalian, China
| | - Xiaolin Wang
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
- State Key Laboratory of Medical Proteomics, Beijing, China
- Liaoning Province Key Laboratory of Metabolomics, Dalian, China
| | - Jinhui Zhao
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
- State Key Laboratory of Medical Proteomics, Beijing, China
- Liaoning Province Key Laboratory of Metabolomics, Dalian, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xinyu Liu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
- State Key Laboratory of Medical Proteomics, Beijing, China
- Liaoning Province Key Laboratory of Metabolomics, Dalian, China
| | - Wangshu Qin
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
- State Key Laboratory of Medical Proteomics, Beijing, China
- Liaoning Province Key Laboratory of Metabolomics, Dalian, China
| | - Guowang Xu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
- State Key Laboratory of Medical Proteomics, Beijing, China
- Liaoning Province Key Laboratory of Metabolomics, Dalian, China
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28
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Aria H, Azizi M, Nazem S, Mansoori B, Darbeheshti F, Niazmand A, Daraei A, Mansoori Y. Competing endogenous RNAs regulatory crosstalk networks: The messages from the RNA world to signaling pathways directing cancer stem cell development. Heliyon 2024; 10:e35208. [PMID: 39170516 PMCID: PMC11337742 DOI: 10.1016/j.heliyon.2024.e35208] [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: 02/10/2024] [Revised: 07/08/2024] [Accepted: 07/24/2024] [Indexed: 08/23/2024] Open
Abstract
Cancer stem cells (CSCs) are one of the cell types that account for cancer heterogeneity. The cancer cells arrest in G0 and generate non-CSC progeny through self-renewal and pluripotency, resulting in tumor recurrence, metastasis, and resistance to chemotherapy. They can stimulate tumor relapse and re-grow a metastatic tumor. So, CSCs is a promising target for eradicating tumors, and developing an anti-CSCs therapy has been considered. In recent years competing endogenous RNA (ceRNA) has emerged as a significant class of post-transcriptional regulators that affect gene expression via competition for microRNA (miRNA) binding. Furthermore, aberrant ceRNA expression is associated with tumor progression. Recent findings show that ceRNA network can cause tumor progression through the effect on CSCs. To overcome therapeutic resistance due to CSCs, we need to improve our current understanding of the mechanisms by which ceRNAs are implicated in CSC-related relapse. Thus, this review was designed to discuss the role of ceRNAs in CSCs' function. Targeting ceRNAs may open the path for new cancer therapeutic targets and can be used in clinical research.
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Affiliation(s)
- Hamid Aria
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahdieh Azizi
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shima Nazem
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Behnam Mansoori
- Pediatrics Department, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Farzaneh Darbeheshti
- Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Anoosha Niazmand
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Abdolreza Daraei
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
- Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Yaser Mansoori
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
- Department of Medical Genetics, Fasa University of Medical Sciences, Fasa, Iran
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29
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Obaid Saleh R, Shbeer AM, Jetti R, Ahmed Robadi I, Hjazi A, Hussein Kareem A, Noori Shakir M, Qasim Alasheqi M, Alawadi A, Haslany A. Association between lncRNAs with stem cells in cancer; a particular focus on lncRNA-CSCs axis in cancer immunopathogenesis. Int Immunopharmacol 2024; 136:112306. [PMID: 38833843 DOI: 10.1016/j.intimp.2024.112306] [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: 04/02/2024] [Revised: 05/10/2024] [Accepted: 05/16/2024] [Indexed: 06/06/2024]
Abstract
A unique population of cells known as cancer stem cells (CSCs) is essential to developing and spreading cancer. Cancer initiation, maintenance, and progression are all believed to be significantly impacted by the distinct characteristics these cells exhibit regarding self-renewal, proliferation, and differentiation. Transcriptional, post-transcriptional, and translational processes are the only steps of gene expression that lncRNAs can affect. As a result, these proteins participate in numerous biological processes, including the repair of DNA damage, inflammatory reactions, metabolic control, the survival of cells, intercellular communication, and the development and specialization of cells. Studies have indicated that lncRNAs are important for controlling the increase in the subset of CSCs contributing to cancer development. The knowledge that is currently available about lncRNAs and their critical role in maintaining the biological properties of CSCs is highlighted in this study.
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Affiliation(s)
- Raed Obaid Saleh
- Department of Medical Laboratory Techniques, Al-Maarif University College, Al-Anbar, Iraq
| | - Abdullah M Shbeer
- Department of Surgery, Faculty of Medicine, Jazan University, Jazan, Saudi Arabia.
| | - Raghu Jetti
- Department of Basic Medical Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Ibrahim Ahmed Robadi
- Department of Pathology, Faculty of Medicine, Jazan University, Jazan, Saudi Arabia
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | | | - Maha Noori Shakir
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
| | | | - Ahmed Alawadi
- College of Technical Engineering, the Islamic University, Najaf, Iraq; College of Technical Engineering, the Islamic University of Al Diwaniyah, Iraq; College of Technical Engineering, the Islamic University of Babylon, Iraq
| | - Ali Haslany
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq
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30
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Chen H, Fang S, Zhu X, Liu H. Cancer-associated fibroblasts and prostate cancer stem cells: crosstalk mechanisms and implications for disease progression. Front Cell Dev Biol 2024; 12:1412337. [PMID: 39092186 PMCID: PMC11291335 DOI: 10.3389/fcell.2024.1412337] [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: 04/07/2024] [Accepted: 07/05/2024] [Indexed: 08/04/2024] Open
Abstract
The functional heterogeneity and ecological niche of prostate cancer stem cells (PCSCs), which are major drivers of prostate cancer development and treatment resistance, have attracted considerable research attention. Cancer-associated fibroblasts (CAFs), which are crucial components of the tumor microenvironment (TME), substantially affect PCSC stemness. Additionally, CAFs promote PCSC growth and survival by releasing signaling molecules and modifying the surrounding environment. Conversely, PCSCs may affect the characteristics and behavior of CAFs by producing various molecules. This crosstalk mechanism is potentially crucial for prostate cancer progression and the development of treatment resistance. Using organoids to model the TME enables an in-depth study of CAF-PCSC interactions, providing a valuable preclinical tool to accurately evaluate potential target genes and design novel treatment strategies for prostate cancer. The objective of this review is to discuss the current research on the multilevel and multitarget regulatory mechanisms underlying CAF-PCSC interactions and crosstalk, aiming to inform therapeutic approaches that address challenges in prostate cancer treatment.
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Affiliation(s)
| | | | | | - Hao Liu
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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31
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Chu X, Tian W, Ning J, Xiao G, Zhou Y, Wang Z, Zhai Z, Tanzhu G, Yang J, Zhou R. Cancer stem cells: advances in knowledge and implications for cancer therapy. Signal Transduct Target Ther 2024; 9:170. [PMID: 38965243 PMCID: PMC11224386 DOI: 10.1038/s41392-024-01851-y] [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: 10/02/2023] [Revised: 03/27/2024] [Accepted: 04/28/2024] [Indexed: 07/06/2024] Open
Abstract
Cancer stem cells (CSCs), a small subset of cells in tumors that are characterized by self-renewal and continuous proliferation, lead to tumorigenesis, metastasis, and maintain tumor heterogeneity. Cancer continues to be a significant global disease burden. In the past, surgery, radiotherapy, and chemotherapy were the main cancer treatments. The technology of cancer treatments continues to develop and advance, and the emergence of targeted therapy, and immunotherapy provides more options for patients to a certain extent. However, the limitations of efficacy and treatment resistance are still inevitable. Our review begins with a brief introduction of the historical discoveries, original hypotheses, and pathways that regulate CSCs, such as WNT/β-Catenin, hedgehog, Notch, NF-κB, JAK/STAT, TGF-β, PI3K/AKT, PPAR pathway, and their crosstalk. We focus on the role of CSCs in various therapeutic outcomes and resistance, including how the treatments affect the content of CSCs and the alteration of related molecules, CSCs-mediated therapeutic resistance, and the clinical value of targeting CSCs in patients with refractory, progressed or advanced tumors. In summary, CSCs affect therapeutic efficacy, and the treatment method of targeting CSCs is still difficult to determine. Clarifying regulatory mechanisms and targeting biomarkers of CSCs is currently the mainstream idea.
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Affiliation(s)
- Xianjing Chu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Wentao Tian
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jiaoyang Ning
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Gang Xiao
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yunqi Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Ziqi Wang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zhuofan Zhai
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Guilong Tanzhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Jie Yang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Rongrong Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China.
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32
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Li K, Wang Q, Tang X, Akakuru OU, Li R, Wang Y, Zhang R, Jiang Z, Yang Z. Advances in Prostate Cancer Biomarkers and Probes. CYBORG AND BIONIC SYSTEMS 2024; 5:0129. [PMID: 40353136 PMCID: PMC12063729 DOI: 10.34133/cbsystems.0129] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Accepted: 04/25/2024] [Indexed: 01/03/2025] Open
Abstract
Prostate cancer is one of the most prevalent malignant tumors in men worldwide, and early diagnosis is essential to improve patient survival. This review provides a comprehensive discussion of recent advances in prostate cancer biomarkers, including molecular, cellular, and exosomal biomarkers. The potential of various biomarkers such as gene fusions (TMPRSS2-ERG), noncoding RNAs (SNHG12), proteins (PSA, PSMA, AR), and circulating tumor cells (CTCs) in the diagnosis, prognosis, and targeted therapies of prostate cancer is emphasized. In addition, this review systematically explores how multi-omics data and artificial intelligence technologies can be used for biomarker discovery and personalized medicine applications. In addition, this review provides insights into the development of specific probes, including fluorescent, electrochemical, and radionuclide probes, for sensitive and accurate detection of prostate cancer biomarkers. In conclusion, this review provides a comprehensive overview of the status and future directions of prostate cancer biomarker research, emphasizing the potential for precision diagnosis and targeted therapy.
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Affiliation(s)
- Keyi Li
- Department of Endoscope, General Hospital of Northern Theater Command, Shenyang, Liaoning, P. R. China
- School of Medical Technology,
Beijing Institute of Technology, Beijing, P. R. China
| | - Qiao Wang
- Department of Endoscope, General Hospital of Northern Theater Command, Shenyang, Liaoning, P. R. China
| | - Xiaoying Tang
- School of Medical Technology,
Beijing Institute of Technology, Beijing, P. R. China
| | - Ozioma Udochukwu Akakuru
- Department of Chemical and Petroleum Engineering, Schulich School of Engineering,
University of Calgary, Alberta T2N 1N4, Canada
| | - Ruobing Li
- School of Medical Technology,
Beijing Institute of Technology, Beijing, P. R. China
| | - Yan Wang
- School of Medical Technology,
Beijing Institute of Technology, Beijing, P. R. China
| | - Renran Zhang
- School of Medical Technology,
Beijing Institute of Technology, Beijing, P. R. China
| | - Zhenqi Jiang
- School of Medical Technology,
Beijing Institute of Technology, Beijing, P. R. China
| | - Zhuo Yang
- Department of Endoscope, General Hospital of Northern Theater Command, Shenyang, Liaoning, P. R. China
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33
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Vo GV, Rao KM, Chung I, Ha CS, An SSA, Yun YH. Derivatization of Hyaluronan to Target Neuroblastoma and Neuroglioma Expressing CD44. Pharmaceutics 2024; 16:836. [PMID: 38931956 PMCID: PMC11207210 DOI: 10.3390/pharmaceutics16060836] [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: 04/26/2024] [Revised: 05/18/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
Therapeutics for actively targeting over-expressed receptors are of great interest because the majority of diseased tissues originate from normal cells and do not possess a unique receptor from which they can be differentiated. One such receptor is CD44, which has been shown to be highly overexpressed in many breast cancers and other types of cancer cells. While CD44 has been documented to express low levels in normal adult neurons, astrocytes, and microglia, this receptor may be overexpressed by neuroblastoma and neuroglioma. If differential expression exists between normal and cancerous cells, hyaluronan (HA) could be a useful carrier that targets carcinomas. Thus, HA was conjugated with resveratrol (HA-R), and its efficacy was tested on cortical-neuroblastoma hybrid, neuroblastoma, and neuroglioma cells. Confocal and flow cytometry showed these cells express CD44 and are able to bind and uptake HA-R. The toxicity of HA-R correlated well with CD44 expression in this study. Therefore, conjugating resveratrol and other chemotherapeutics to HA could minimize the side effects for normal cells within the brain and nervous system and could be a viable strategy for developing targeted therapies.
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Affiliation(s)
- Giau Van Vo
- Department of Bionano Technology, Gachon Bionano Research Institute, Gachon University, 1342 Seongnam-daero, Sujeong-gu, Seongnam-si 13120, Gyeonggi-do, Republic of Korea;
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA 92037, USA
| | - Kummara Madhusudana Rao
- School of Chemical Engineering, Yeungnam University, Gyeongsan-si 38541, Gyeongbuk-do, Republic of Korea;
- Department of Polymer Science and Engineering, Pusan National University, Busan 46241, Gyeongsangnam-do, Republic of Korea; (I.C.); (C.-S.H.)
| | - Ildoo Chung
- Department of Polymer Science and Engineering, Pusan National University, Busan 46241, Gyeongsangnam-do, Republic of Korea; (I.C.); (C.-S.H.)
| | - Chang-Sik Ha
- Department of Polymer Science and Engineering, Pusan National University, Busan 46241, Gyeongsangnam-do, Republic of Korea; (I.C.); (C.-S.H.)
| | - Seong Soo A. An
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA 92037, USA
| | - Yang H. Yun
- Department of Biomedical Engineering, The University of Akron, Akron, OH 44325-0302, USA
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34
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Rahman MA, Apu EH, Rakib-Uz-Zaman SM, Chakraborti S, Bhajan SK, Taleb SA, Shaikh MH, Jalouli M, Harrath AH, Kim B. Exploring Importance and Regulation of Autophagy in Cancer Stem Cells and Stem Cell-Based Therapies. Cells 2024; 13:958. [PMID: 38891090 PMCID: PMC11171866 DOI: 10.3390/cells13110958] [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: 05/04/2024] [Revised: 05/28/2024] [Accepted: 05/31/2024] [Indexed: 06/21/2024] Open
Abstract
Autophagy is a globally conserved cellular activity that plays a critical role in maintaining cellular homeostasis through the breakdown and recycling of cellular constituents. In recent years, there has been much emphasis given to its complex role in cancer stem cells (CSCs) and stem cell treatment. This study examines the molecular processes that support autophagy and how it is regulated in the context of CSCs and stem cell treatment. Although autophagy plays a dual role in the management of CSCs, affecting their removal as well as their maintenance, the intricate interaction between the several signaling channels that control cellular survival and death as part of the molecular mechanism of autophagy has not been well elucidated. Given that CSCs have a role in the development, progression, and resistance to treatment of tumors, it is imperative to comprehend their biological activities. CSCs are important for cancer biology because they also show a tissue regeneration model that helps with organoid regeneration. In other words, the manipulation of autophagy is a viable therapeutic approach in the treatment of cancer and stem cell therapy. Both synthetic and natural substances that target autophagy pathways have demonstrated promise in improving stem cell-based therapies and eliminating CSCs. Nevertheless, there are difficulties associated with the limitations of autophagy in CSC regulation, including resistance mechanisms and off-target effects. Thus, the regulation of autophagy offers a versatile strategy for focusing on CSCs and enhancing the results of stem cell therapy. Therefore, understanding the complex interactions between autophagy and CSC biology would be essential for creating therapeutic treatments that work in both regenerative medicine and cancer treatment.
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Affiliation(s)
- Md Ataur Rahman
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
- Global Biotechnology and Biomedical Research Network (GBBRN), Department of Biotechnology and Genetic Engineering, Faculty of Biological Sciences, Islamic University, Kushtia 7003, Bangladesh
| | - Ehsanul Hoque Apu
- Department of Biomedical Sciences, College of Dental Medicine, Lincoln Memorial University, Knoxville, TN 37923, USA;
- DeBusk College of Osteopathic Medicine, Lincoln Memorial University, Harrogate, TN 37752, USA
- Division of Hematology and Oncology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - S. M Rakib-Uz-Zaman
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA; (S.M.R.-U.-Z.); (S.C.)
- Biotechnology Program, Department of Mathematics and Natural Sciences, School of Data and Sciences, BRAC University, Dhaka 1212, Bangladesh
| | - Somdeepa Chakraborti
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA; (S.M.R.-U.-Z.); (S.C.)
| | - Sujay Kumar Bhajan
- Department of Biotechnology and Genetic Engineering, Bangabandhu Sheikh Mujibur Rahman Science & Technology University, Gopalganj 8100, Bangladesh;
| | - Shakila Afroz Taleb
- Department of Internal Medicine, Yale School of Medicine, Yale University, New Haven, CT 06510, USA;
| | - Mushfiq H. Shaikh
- Department of Otolaryngology—Head and Neck Surgery, Western University, London, ON N6A 4V2, Canada;
| | - Maroua Jalouli
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia;
| | - Abdel Halim Harrath
- Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Bonglee Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, 1-5 Hoegidong, Dongdaemun-gu, Seoul 02447, Republic of Korea
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
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35
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Wang J, Zhang N, Ding X, Fu C, Li X, Li B, Ding J, Sun T. Targeted nanostrategies eliminate pre-metastatic niche of cancer. NANO RESEARCH 2024; 17:5358-5373. [DOI: 10.1007/s12274-024-6412-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 12/08/2023] [Accepted: 12/11/2023] [Indexed: 05/14/2025]
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Satapathy BP, Sheoran P, Yadav R, Chettri D, Sonowal D, Dash CP, Dhaka P, Uttam V, Yadav R, Jain M, Jain A. The synergistic immunotherapeutic impact of engineered CAR-T cells with PD-1 blockade in lymphomas and solid tumors: a systematic review. Front Immunol 2024; 15:1389971. [PMID: 38799440 PMCID: PMC11116574 DOI: 10.3389/fimmu.2024.1389971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 04/11/2024] [Indexed: 05/29/2024] Open
Abstract
Currently, therapies such as chimeric antigen receptor-T Cell (CAR-T) and immune checkpoint inhibitors like programmed cell death protein-1 (PD-1) blockers are showing promising results for numerous cancer patients. However, significant advancements are required before CAR-T therapies become readily available as off-the-shelf treatments, particularly for solid tumors and lymphomas. In this review, we have systematically analyzed the combination therapy involving engineered CAR-T cells and anti PD-1 agents. This approach aims at overcoming the limitations of current treatments and offers potential advantages such as enhanced tumor inhibition, alleviated T-cell exhaustion, heightened T-cell activation, and minimized toxicity. The integration of CAR-T therapy, which targets tumor-associated antigens, with PD-1 blockade augments T-cell function and mitigates immune suppression within the tumor microenvironment. To assess the impact of combination therapy on various tumors and lymphomas, we categorized them based on six major tumor-associated antigens: mesothelin, disialoganglioside GD-2, CD-19, CD-22, CD-133, and CD-30, which are present in different tumor types. We evaluated the efficacy, complete and partial responses, and progression-free survival in both pre-clinical and clinical models. Additionally, we discussed potential implications, including the feasibility of combination immunotherapies, emphasizing the importance of ongoing research to optimize treatment strategies and improve outcomes for cancer patients. Overall, we believe combining CAR-T therapy with PD-1 blockade holds promise for the next generation of cancer immunotherapy.
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Affiliation(s)
- Bibhu Prasad Satapathy
- Department of Zoology, Non-Coding RNA and Cancer Biology Laboratory, Central University of Punjab, Bathinda, Punjab, India
| | - Pooja Sheoran
- Department of Zoology, Non-Coding RNA and Cancer Biology Laboratory, Central University of Punjab, Bathinda, Punjab, India
| | - Rohit Yadav
- Department of Zoology, Non-Coding RNA and Cancer Biology Laboratory, Central University of Punjab, Bathinda, Punjab, India
| | - Dewan Chettri
- Department of Zoology, Non-Coding RNA and Cancer Biology Laboratory, Central University of Punjab, Bathinda, Punjab, India
| | - Dhruba Sonowal
- Department of Zoology, Non-Coding RNA and Cancer Biology Laboratory, Central University of Punjab, Bathinda, Punjab, India
| | - Chinmayee Priyadarsini Dash
- Department of Zoology, Non-Coding RNA and Cancer Biology Laboratory, Central University of Punjab, Bathinda, Punjab, India
| | - Prachi Dhaka
- Department of Zoology, Non-Coding RNA and Cancer Biology Laboratory, Central University of Punjab, Bathinda, Punjab, India
| | - Vivek Uttam
- Department of Zoology, Non-Coding RNA and Cancer Biology Laboratory, Central University of Punjab, Bathinda, Punjab, India
| | - Ritu Yadav
- Department of Zoology, Non-Coding RNA and Cancer Biology Laboratory, Central University of Punjab, Bathinda, Punjab, India
| | - Manju Jain
- Department of Biochemistry, School of Basic Sciences, Central University of Punjab, Bathinda, Punjab, India
| | - Aklank Jain
- Department of Zoology, Non-Coding RNA and Cancer Biology Laboratory, Central University of Punjab, Bathinda, Punjab, India
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Kwon JE, Jang Y, Yun BS, Kang S, Kim YH, Kim BG, Cho NH. MET overexpression in ovarian cancer via CD24-induced downregulation of miR-181a: A signalling for cellular quiescence-like state and chemoresistance in ovarian CSCs. Cell Prolif 2024; 57:e13582. [PMID: 38030594 PMCID: PMC11056702 DOI: 10.1111/cpr.13582] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 11/15/2023] [Accepted: 11/17/2023] [Indexed: 12/01/2023] Open
Abstract
Increased expression of CD24 and MET, markers for cancer stem-like cells (CSCs), are each associated with ovarian cancer severity. However, whether CD24 and MET are co-expressed in ovarian CSCs and, if so, how they are related to CSC phenotype manifestation remains unknown. Our immunohistochemistry analysis showed that the co-expression of CD24 and MET was associated with poorer patient survival in ovarian cancer than those without. In addition, analyses using KM plotter and ROC plotter presented that the overexpression of CD24 or MET in ovarian cancer patients was associated with resistance to platinum-based chemotherapy. In our miRNA transcriptome and putative target genes analyses, miR-181a was downregulated in CD24-high ovarian cancer cells compared to CD24-low and predicted to bind to CD24 and MET 3'UTRs. In OV90 and SK-OV-3 cells, CD24 downregulated miR-181a expression by Src-mediated YY1 activation, leading to increased expression of MET. And, CD24 or MET knockdown or miR-181a overexpression inhibited the manifestation of CSC phenotypes, cellular quiescence-like state and chemoresistance, in OV90 and SK-OV-3 cells: increased colony formation, decreased G0/G1 phase cell population and increased sensitivity to Cisplatin and Carboplatin. Our findings suggest that CD24-miR-181a-MET may consist of a signalling route for ovarian CSCs, therefore being a combinatory set of markers and therapeutic targets for ovarian CSCs.
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Affiliation(s)
- Ji Eun Kwon
- Department of PathologyAjou University School of MedicineSuwonKorea
- Brain Korea 21 Plus Project for Medical ScienceYonsei University College of MedicineSeoulKorea
| | - Yeonsue Jang
- Department of PathologyYonsei University College of MedicineSeoulKorea
| | - Bo Seong Yun
- Department of Gynecology Obstetrics and Gynecology, CHA Gangnam Medical CenterCHA UniversitySeoulKorea
| | - Suki Kang
- Department of PathologyYonsei University College of MedicineSeoulKorea
| | - Yon Hee Kim
- Department of PathologySoonchunhyang University HospitalSeoulKorea
| | - Baek Gil Kim
- Brain Korea 21 Plus Project for Medical ScienceYonsei University College of MedicineSeoulKorea
- Department of PathologyYonsei University College of MedicineSeoulKorea
| | - Nam Hoon Cho
- Brain Korea 21 Plus Project for Medical ScienceYonsei University College of MedicineSeoulKorea
- Department of PathologyYonsei University College of MedicineSeoulKorea
- Severance Biomedical Science Institute (SBSI)Yonsei University College of MedicineSeoulKorea
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38
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Lee JS, Lee HY. Ginseng-derived compounds as potential anticancer agents targeting cancer stem cells. J Ginseng Res 2024; 48:266-275. [PMID: 38707642 PMCID: PMC11068999 DOI: 10.1016/j.jgr.2024.03.003] [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] [Received: 09/20/2023] [Revised: 01/31/2024] [Accepted: 03/07/2024] [Indexed: 05/07/2024] Open
Abstract
Cancer stem cells (CSCs) are a rare subpopulation of cancer cells that exhibit stem cell-like characteristics, including self-renewal and differentiation in a multi-stage lineage state via symmetric or asymmetric division, causing tumor initiation, heterogeneity, progression, and recurrence and posing a major challenge to current anticancer therapy. Despite the importance of CSCs in carcinogenesis and cancer progression, currently available anticancer therapeutics have limitations for eradicating CSCs. Moreover, the efficacy and therapeutic windows of currently available anti-CSC agents are limited, suggesting the necessity to optimize and develop a novel anticancer agent targeting CSCs. Ginseng has been traditionally used for enhancing immunity and relieving fatigue. As ginseng's long history of use has demonstrated its safety, it has gained attention for its potential pharmacological properties, including anticancer effects. Several studies have identified the bioactive principles of ginseng, such as ginseng saponin (ginsenosides) and non-saponin compounds (e.g., polysaccharides, polyacetylenes, and phenolic compounds), and their pharmacological activities, including antioxidant, anticancer, antidiabetic, antifatigue, and neuroprotective effects. Notably, recent reports have shown the potential of ginseng-derived compounds as anti-CSC agents. This review investigates the biology of CSCs and efforts to utilize ginseng-derived components for cancer treatment targeting CSCs, highlighting their role in overcoming current therapeutic limitations.
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Affiliation(s)
- Ji-Sun Lee
- Department of Molecular, Cell & Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Ho-Young Lee
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, Republic of Korea
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
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39
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Pleskač P, Fargeas CA, Veselska R, Corbeil D, Skoda J. Emerging roles of prominin-1 (CD133) in the dynamics of plasma membrane architecture and cell signaling pathways in health and disease. Cell Mol Biol Lett 2024; 29:41. [PMID: 38532366 DOI: 10.1186/s11658-024-00554-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 02/22/2024] [Indexed: 03/28/2024] Open
Abstract
Prominin-1 (CD133) is a cholesterol-binding membrane glycoprotein selectively associated with highly curved and prominent membrane structures. It is widely recognized as an antigenic marker of stem cells and cancer stem cells and is frequently used to isolate them from biological and clinical samples. Recent progress in understanding various aspects of CD133 biology in different cell types has revealed the involvement of CD133 in the architecture and dynamics of plasma membrane protrusions, such as microvilli and cilia, including the release of extracellular vesicles, as well as in various signaling pathways, which may be regulated in part by posttranslational modifications of CD133 and its interactions with a variety of proteins and lipids. Hence, CD133 appears to be a master regulator of cell signaling as its engagement in PI3K/Akt, Src-FAK, Wnt/β-catenin, TGF-β/Smad and MAPK/ERK pathways may explain its broad action in many cellular processes, including cell proliferation, differentiation, and migration or intercellular communication. Here, we summarize early studies on CD133, as they are essential to grasp its novel features, and describe recent evidence demonstrating that this unique molecule is involved in membrane dynamics and molecular signaling that affects various facets of tissue homeostasis and cancer development. We hope this review will provide an informative resource for future efforts to elucidate the details of CD133's molecular function in health and disease.
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Affiliation(s)
- Petr Pleskač
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
| | - Christine A Fargeas
- Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Tatzberg 47/49, 01307, Dresden, Germany
- Tissue Engineering Laboratories, Medizinische Fakultät der Technischen Universität Dresden, Dresden, Germany
| | - Renata Veselska
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
| | - Denis Corbeil
- Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Tatzberg 47/49, 01307, Dresden, Germany.
- Tissue Engineering Laboratories, Medizinische Fakultät der Technischen Universität Dresden, Dresden, Germany.
| | - Jan Skoda
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic.
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
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40
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Beninato T, Lo Russo G, Leporati R, Roz L, Bertolini G. Circulating tumor cells in lung cancer: Integrating stemness and heterogeneity to improve clinical utility. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 392:1-66. [PMID: 40287216 DOI: 10.1016/bs.ircmb.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/29/2025]
Abstract
Circulating tumor cells (CTC), released by primary tumors into the bloodstream, represent a valuable source to inform on cancer heterogeneity, cancer progression, metastatic disease and therapy efficacy without the need of invasive tumor biopsies. However, the extreme rarity and heterogeneity of CTCs, occurring at genotypic, phenotypic and functional levels, poses a major challenge for the study of this population and explains the lack of standardized strategies of CTC isolation. Lung cancer, the leading causes of cancer-related death worldwide, is a paradigmatic example of how CTC heterogeneity can undermine the clinical utility of this biomarker, since contrasting data have been reported using different isolation technologies. Some evidences suggest that only a fraction of CTC, characterized by stem-like feature and partial epithelial-mesenchymal transition (EMT) phenotype, can sustain metastasis initiation. Cancer stem cells (CSCs) have the potential to maintain primary tumors, initiate metastasis and escape both chemotherapy and immunotherapy treatments. Moreover, a close connection has been reported in several tumor types among hybrid phenotype, characterized by retention of epithelial and mesenchymal traits, acquisition of CSC feature and increased metastatic potential. This review focuses on the phenotypic and functional heterogeneity of CTCs and the resulting implications for their isolation and clinical validation, especially in the setting of non-small cell lung cancer (NSCLC). In particular, we discuss the most relevant studies providing evidence for the presence and prognostic/predictive value of CTC subsets characterized by stem-like and hybrid EMT phenotype. Despite technical and conceptual issues, tracking circulating CSCs has the potential to improve the prognostic/predictive value of CTCs in NSCLC setting and could provide novel insights into the comprehension of the metastatic process and identification of novel therapeutic targets.
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Affiliation(s)
- Teresa Beninato
- Thoracic Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giuseppe Lo Russo
- Thoracic Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Rita Leporati
- Thoracic Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Luca Roz
- Unit of Epigenomics and Biomarkers of Solid Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giulia Bertolini
- Unit of Epigenomics and Biomarkers of Solid Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
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41
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Güler G, Acikgoz E, Mukhtarova G, Oktem G. Biomolecular fingerprints of the effect of zoledronic acid on prostate cancer stem cells: Comparison of 2D and 3D cell culture models. Arch Biochem Biophys 2024; 753:109920. [PMID: 38307315 DOI: 10.1016/j.abb.2024.109920] [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: 09/21/2023] [Revised: 12/23/2023] [Accepted: 01/30/2024] [Indexed: 02/04/2024]
Abstract
Revealing the potential of candidate drugs against different cancer types without disrupting normal cells depends on the drug mode of action. In the current study, the drug response of prostate cancer stem cells (PCSCs) to zoledronic acid (ZOL) grown in two-dimensional (2D) and three-dimensional (3D) culture systems was compared using Fourier transform-infrared (FT-IR) spectroscopy which is a vibrational spectroscopic technique, supporting by biochemical assays and imaging techniques. Based on our data, in 2D cell culture conditions, the ZOL treatment of PCSCs isolated according to both C133 and CD44 cell surface properties induced early/late apoptosis and suppressed migration ability. The CD133 gene expression and protein levels were altered, depending on culture systems. CD133 expression was significantly reduced in 2D cells upon ZOL treatment. FT-IR data revealed that the integrity, fluidity, and ordering/disordering states of the cell membrane and nucleic acid content were altered in both 2D and 3D cells after ZOL treatment. Regular protein structures decrease in 2D cells while glycogen and protein contents increase in 3D cells, indicating a more pronounced cytotoxic effect of ZOL for 2D cells. Untreated 3D PCSCs exhibited an even different spectral profile associated with IR signals of lipids, proteins, nucleic acids, and glycogen in comparison to untreated 2D cells. Our study revealed significant differences in the drug response and cellular constituents between 2D and 3D cells. Exploring molecular targets and/or drug-action mechanisms is significant in cancer treatment approaches; thus, FT-IR spectroscopy can be successfully applied as a novel drug-screening method in clinical research.
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Affiliation(s)
- Günnur Güler
- Biophysics Laboratory, Department of Physics, Izmir Institute of Technology, Urla, 35433, Izmir, Turkey.
| | - Eda Acikgoz
- Department of Histology and Embryology, Faculty of Medicine, Van Yuzuncu Yil University, 65080, Van, Turkey.
| | - Günel Mukhtarova
- Department of Basic Oncology, Faculty of Medicine, Ege University, 35550, Izmir, Turkey
| | - Gulperi Oktem
- Department of Histology and Embryology, Faculty of Medicine, Ege University, 35100, Izmir, Turkey
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42
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Guerrero-Ochoa P, Rodríguez-Zapater S, Anel A, Esteban LM, Camón-Fernández A, Espilez-Ortiz R, Gil-Sanz MJ, Borque-Fernando Á. Prostate Cancer and the Mevalonate Pathway. Int J Mol Sci 2024; 25:2152. [PMID: 38396837 PMCID: PMC10888820 DOI: 10.3390/ijms25042152] [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: 01/10/2024] [Revised: 02/04/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
Antineoplastic therapies for prostate cancer (PCa) have traditionally centered around the androgen receptor (AR) pathway, which has demonstrated a significant role in oncogenesis. Nevertheless, it is becoming progressively apparent that therapeutic strategies must diversify their focus due to the emergence of resistance mechanisms that the tumor employs when subjected to monomolecular treatments. This review illustrates how the dysregulation of the lipid metabolic pathway constitutes a survival strategy adopted by tumors to evade eradication efforts. Integrating this aspect into oncological management could prove valuable in combating PCa.
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Affiliation(s)
- Patricia Guerrero-Ochoa
- Health Research Institute of Aragon Foundation, 50009 Zaragoza, Spain; (P.G.-O.); (A.C.-F.); (R.E.-O.); (M.J.G.-S.)
| | - Sergio Rodríguez-Zapater
- Minimally Invasive Research Group (GITMI), Faculty of Veterinary Medicine, University of Zaragoza, 50009 Zaragoza, Spain;
| | - Alberto Anel
- Department of Biochemistry and Molecular and Cellular Biology, Faculty of Sciences, University of Zaragoza, 50009 Zaragoza, Spain;
| | - Luis Mariano Esteban
- Department of Applied Mathematics, Escuela Universitaria Politécnica de La Almunia, Institute for Biocomputation and Physic of Complex Systems, Universidad de Zaragoza, 50100 La Almunia de Doña Godina, Spain
| | - Alejandro Camón-Fernández
- Health Research Institute of Aragon Foundation, 50009 Zaragoza, Spain; (P.G.-O.); (A.C.-F.); (R.E.-O.); (M.J.G.-S.)
| | - Raquel Espilez-Ortiz
- Health Research Institute of Aragon Foundation, 50009 Zaragoza, Spain; (P.G.-O.); (A.C.-F.); (R.E.-O.); (M.J.G.-S.)
- Department of Urology, Miguel Servet University Hospital, 50009 Zaragoza, Spain
- Area of Urology, Department of Surgery, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - María Jesús Gil-Sanz
- Health Research Institute of Aragon Foundation, 50009 Zaragoza, Spain; (P.G.-O.); (A.C.-F.); (R.E.-O.); (M.J.G.-S.)
- Department of Urology, Miguel Servet University Hospital, 50009 Zaragoza, Spain
| | - Ángel Borque-Fernando
- Health Research Institute of Aragon Foundation, 50009 Zaragoza, Spain; (P.G.-O.); (A.C.-F.); (R.E.-O.); (M.J.G.-S.)
- Department of Applied Mathematics, Escuela Universitaria Politécnica de La Almunia, Institute for Biocomputation and Physic of Complex Systems, Universidad de Zaragoza, 50100 La Almunia de Doña Godina, Spain
- Department of Urology, Miguel Servet University Hospital, 50009 Zaragoza, Spain
- Area of Urology, Department of Surgery, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
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43
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Ambrosini G, Cordani M, Zarrabi A, Alcon-Rodriguez S, Sainz RM, Velasco G, Gonzalez-Menendez P, Dando I. Transcending frontiers in prostate cancer: the role of oncometabolites on epigenetic regulation, CSCs, and tumor microenvironment to identify new therapeutic strategies. Cell Commun Signal 2024; 22:36. [PMID: 38216942 PMCID: PMC10790277 DOI: 10.1186/s12964-023-01462-0] [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: 10/05/2023] [Accepted: 12/27/2023] [Indexed: 01/14/2024] Open
Abstract
Prostate cancer, as one of the most prevalent malignancies in males, exhibits an approximate 5-year survival rate of 95% in advanced stages. A myriad of molecular events and mutations, including the accumulation of oncometabolites, underpin the genesis and progression of this cancer type. Despite growing research demonstrating the pivotal role of oncometabolites in supporting various cancers, including prostate cancer, the root causes of their accumulation, especially in the absence of enzymatic mutations, remain elusive. Consequently, identifying a tangible therapeutic target poses a formidable challenge. In this review, we aim to delve deeper into the implications of oncometabolite accumulation in prostate cancer. We center our focus on the consequential epigenetic alterations and impacts on cancer stem cells, with the ultimate goal of outlining novel therapeutic strategies.
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Affiliation(s)
- Giulia Ambrosini
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, 37134, Verona, Italy
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biology, Complutense University, 28040, Madrid, Spain.
- Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040, Madrid, Spain.
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering & Natural Sciences, Istinye University, Istanbul, 34396, Turkey
- Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600 077, India
| | - Sergio Alcon-Rodriguez
- Departamento de Morfología y Biología Celular, School of Medicine, Julián Claveria 6, 33006, Oviedo, Spain
- Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, 33006, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias (HUCA), 33011, Oviedo, Spain
| | - Rosa M Sainz
- Departamento de Morfología y Biología Celular, School of Medicine, Julián Claveria 6, 33006, Oviedo, Spain
- Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, 33006, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias (HUCA), 33011, Oviedo, Spain
| | - Guillermo Velasco
- Department of Biochemistry and Molecular Biology, Faculty of Biology, Complutense University, 28040, Madrid, Spain
- Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040, Madrid, Spain
| | - Pedro Gonzalez-Menendez
- Departamento de Morfología y Biología Celular, School of Medicine, Julián Claveria 6, 33006, Oviedo, Spain.
- Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, 33006, Oviedo, Spain.
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias (HUCA), 33011, Oviedo, Spain.
| | - Ilaria Dando
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, 37134, Verona, Italy.
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44
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Maleki EH, Bahrami AR, Matin MM. Cancer cell cycle heterogeneity as a critical determinant of therapeutic resistance. Genes Dis 2024; 11:189-204. [PMID: 37588236 PMCID: PMC10425754 DOI: 10.1016/j.gendis.2022.11.025] [Citation(s) in RCA: 37] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 10/20/2022] [Accepted: 11/16/2022] [Indexed: 01/15/2023] Open
Abstract
Intra-tumor heterogeneity is now arguably one of the most-studied topics in tumor biology, as it represents a major obstacle to effective cancer treatment. Since tumor cells are highly diverse at genetic, epigenetic, and phenotypic levels, intra-tumor heterogeneity can be assumed as an important contributing factor to the nullification of chemotherapeutic effects, and recurrence of the tumor. Based on the role of heterogeneous subpopulations of cancer cells with varying cell-cycle dynamics and behavior during cancer progression and treatment; herein, we aim to establish a comprehensive definition for adaptation of neoplastic cells against therapy. We discuss two parallel and yet distinct subpopulations of tumor cells that play pivotal roles in reducing the effects of chemotherapy: "resistant" and "tolerant" populations. Furthermore, this review also highlights the impact of the quiescent phase of the cell cycle as a survival mechanism for cancer cells. Beyond understanding the mechanisms underlying the quiescence, it provides an insightful perspective on cancer stem cells (CSCs) and their dual and intertwined functions based on their cell cycle state in response to treatment. Moreover, CSCs, epithelial-mesenchymal transformed cells, circulating tumor cells (CTCs), and disseminated tumor cells (DTCs), which are mostly in a quiescent state of the cell cycle are proved to have multiple biological links and can be implicated in our viewpoint of cell cycle heterogeneity in tumors. Overall, increasing our knowledge of cell cycle heterogeneity is a key to identifying new therapeutic solutions, and this emerging concept may provide us with new opportunities to prevent the dreadful cancer recurrence.
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Affiliation(s)
- Ebrahim H. Maleki
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, 9177948974 Mashhad, Iran
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 31-007 Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, 30-348 Krakow, Poland
| | - Ahmad Reza Bahrami
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, 9177948974 Mashhad, Iran
- Industrial Biotechnology Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, 9177948974 Mashhad, Iran
| | - Maryam M. Matin
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, 9177948974 Mashhad, Iran
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, 9177948974 Mashhad, Iran
- Stem Cell and Regenerative Medicine Research Group, Iranian Academic Center for Education, Culture and Research (ACECR), Khorasan Razavi Branch, 917751376 Mashhad, Iran
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45
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Bharti S, Kumar A. Synergies in stem cell research: Integrating technologies, strategies, and bionanomaterial innovations. Acta Histochem 2024; 126:152119. [PMID: 38041895 DOI: 10.1016/j.acthis.2023.152119] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 11/19/2023] [Accepted: 11/19/2023] [Indexed: 12/04/2023]
Abstract
Since the 1960 s, there has been a substantial amount of research directed towards investigating the biology of several types of stem cells, including embryonic stem cells, brain cells, and mesenchymal stem cells. In contemporary times, a wide array of stem cells has been utilized to treat several disorders, including bone marrow transplantation. In recent years, stem cell treatment has developed as a very promising and advanced field of scientific research. The progress of therapeutic methodologies has resulted in significant amounts of anticipation and expectation. Recently, there has been a notable proliferation of experimental methodologies aimed at isolating and developing stem cells, which have emerged concurrently. Stem cells possess significant vitality and exhibit vigorous proliferation, making them suitable candidates for in vitro modification. This article examines the progress made in stem cell isolation and explores several methodologies employed to promote the differentiation of stem cells. This study also explores the method of isolating bio-nanomaterials and discusses their viewpoint in the context of stem cell research. It also covers the potential for investigating stem cell applications in bioprinting and the usage of bionanomaterial in stem cell-related technologies and research. In conclusion, the review article concludes by highlighting the importance of incorporating state-of-the-art methods and technological breakthroughs into the future of stem cell research. Putting such an emphasis on constant innovation highlights the ever-changing character of science and the never-ending drive toward unlocking the maximum therapeutic potential of stem cells. This review would be a useful resource for researchers, clinicians, and policymakers in the stem cell research area, guiding the next steps in this fast-developing scientific concern.
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Affiliation(s)
- Sharda Bharti
- Department of Biotechnology, National Institute of Technology, Raipur, CG, India
| | - Awanish Kumar
- Department of Biotechnology, National Institute of Technology, Raipur, CG, India.
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46
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Rehman A, Panda SK, Tirino V, Del Vecchio V. Cancer Stem Cells: Detection and Characterization from Solid Tumors. Methods Mol Biol 2024; 2835:215-228. [PMID: 39105918 DOI: 10.1007/978-1-0716-3995-5_18] [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] [Indexed: 08/07/2024]
Abstract
Cancer stem cells (CSCs) have emerged as an attractive research interest due to their prominent role in development of the tumors. CSCs are rare dormant cells that can self-renew and maintain tumor development and heterogeneity. A better understanding of CSCs can improve tumor classification and contribute toward the development of novel therapeutic approaches to fight cancer. Hence, it is of immense importance to comprehend the basic function of CSCs in tumor formation, which can only be possible by devising perfected methodologies to isolate, detect, and characterize them. In this chapter, we outline the key protocols to culture, identify, and isolate CSCs from solid tumors to further advance basic and clinical investigation related to CSCs and their role in tumor biology.
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Affiliation(s)
- A Rehman
- Department of Experimental Medicine, Histology and Embryology Section, University of Campania "L. Vanvitelli", Naples, Italy
| | - S Kumar Panda
- Department of Experimental Medicine, Histology and Embryology Section, University of Campania "L. Vanvitelli", Naples, Italy
| | - V Tirino
- Department of Experimental Medicine, Histology and Embryology Section, University of Campania "L. Vanvitelli", Naples, Italy
| | - V Del Vecchio
- Department of Experimental Medicine, Histology and Embryology Section, University of Campania "L. Vanvitelli", Naples, Italy.
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47
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Pronoy TUH, Islam F, Gopalan V, Lam AKY. Surface Markers for the Identification of Cancer Stem Cells. Methods Mol Biol 2024; 2777:51-69. [PMID: 38478335 DOI: 10.1007/978-1-0716-3730-2_4] [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] [Indexed: 03/26/2024]
Abstract
Cancer stem cells have genetic and functional characteristics which can turn them resistant to standard cancer therapeutic targets. Identification of these cells is challenging and is done mainly by detecting the expression of antigens specific to stem cells. Currently, there is a significant number of surface markers available which can detect cancer stem cells by directly targeting the specific antigens present in cells. These markers possess differential expression patterns and sub-localizations in cancer stem cells compared to nonneoplastic and somatic cells. In addition to these biomarkers, multiple analytical methods and techniques, including functional assays, cell sorting, filtration approaches, and xenotransplantation methods, are used to identify cancer stem cells. This chapter will overview the functional significance of cancer stem cells, their biological correlations, specific markers, and detection methods.
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Affiliation(s)
- Tasfik Ul Haque Pronoy
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh
| | - Farhadul Islam
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh
| | - Vinod Gopalan
- Cancer Molecular Pathology, School of Medicine and Dentistry, Griffith University, Gold Coast, QLD, Australia
| | - Alfred King-Yin Lam
- Cancer Molecular Pathology, School of Medicine and Dentistry, Griffith University, Gold Coast, QLD, Australia.
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48
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Hasanzadeh A, Ebadati A, Dastanpour L, Aref AR, Sahandi Zangabad P, Kalbasi A, Dai X, Mehta G, Ghasemi A, Fatahi Y, Joshi S, Hamblin MR, Karimi M. Applications of Innovation Technologies for Personalized Cancer Medicine: Stem Cells and Gene-Editing Tools. ACS Pharmacol Transl Sci 2023; 6:1758-1779. [PMID: 38093832 PMCID: PMC10714436 DOI: 10.1021/acsptsci.3c00102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 10/19/2023] [Accepted: 10/23/2023] [Indexed: 02/16/2024]
Abstract
Personalized medicine is a new approach toward safer and even cheaper treatments with minimal side effects and toxicity. Planning a therapy based on individual properties causes an effective result in a patient's treatment, especially in a complex disease such as cancer. The benefits of personalized medicine include not only early diagnosis with high accuracy but also a more appropriate and effective therapeutic approach based on the unique clinical, genetic, and epigenetic features and biomarker profiles of a specific patient's disease. In order to achieve personalized cancer therapy, understanding cancer biology plays an important role. One of the crucial applications of personalized medicine that has gained consideration more recently due to its capability in developing disease therapy is related to the field of stem cells. We review various applications of pluripotent, somatic, and cancer stem cells in personalized medicine, including targeted cancer therapy, cancer modeling, diagnostics, and drug screening. CRISPR-Cas gene-editing technology is then discussed as a state-of-the-art biotechnological advance with substantial impacts on medical and therapeutic applications. As part of this section, the role of CRISPR-Cas genome editing in recent cancer studies is reviewed as a further example of personalized medicine application.
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Affiliation(s)
- Akbar Hasanzadeh
- Cellular
and Molecular Research Center, Iran University
of Medical Sciences, Tehran 14535, Iran
- Department
of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 14535, Iran
- Advances
Nanobiotechnology and Nanomedicine Research Group (ANNRG), Iran University of Medical Sciences, Tehran 14535, Iran
| | - Arefeh Ebadati
- Cellular
and Molecular Research Center, Iran University
of Medical Sciences, Tehran 14535, Iran
- Department
of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 14535, Iran
- Advances
Nanobiotechnology and Nanomedicine Research Group (ANNRG), Iran University of Medical Sciences, Tehran 14535, Iran
| | - Lida Dastanpour
- Cellular
and Molecular Research Center, Iran University
of Medical Sciences, Tehran 14535, Iran
- Department
of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 14535, Iran
- Advances
Nanobiotechnology and Nanomedicine Research Group (ANNRG), Iran University of Medical Sciences, Tehran 14535, Iran
| | - Amir R. Aref
- Department
of Medical Oncology and Belfer Center for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts 02115, United States
| | - Parham Sahandi Zangabad
- Monash
Institute of Pharmaceutical Sciences, Department of Pharmacy and Pharmaceutical
Sciences, Monash University, Parkville, Melbourne, Victoria 3052, Australia
| | - Alireza Kalbasi
- Department
of Medical Oncology, Dana-Farber Cancer
Institute, Boston, Massachusetts 02115, United States
| | - Xiaofeng Dai
- School of
Biotechnology, Jiangnan University, Wuxi 214122, China
- National
Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi 214122, China
- Jiangsu Provincial
Research Center for Bioactive Product Processing Technology, Jiangnan University, Wuxi 214122, China
| | - Geeta Mehta
- Department
of Biomedical Engineering, University of
Michigan, Ann Arbor, Michigan 48109, United States
- Department
of Materials Science and Engineering, University
of Michigan, Ann Arbor, Michigan 48109, United States
- Macromolecular
Science and Engineering, University of Michigan, Ann Arbor, Michigan 48109, United States
- Rogel Cancer
Center, University of Michigan, Ann Arbor, Michigan 48109, United States
- Precision
Health, University of Michigan, Ann Arbor, Michigan 48105, United States
| | - Amir Ghasemi
- Department
of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 14535, Iran
- Department
of Materials Science and Engineering, Sharif
University of Technology, Tehran 14588, Iran
| | - Yousef Fatahi
- Nanotechnology
Research Centre, Faculty of Pharmacy, Tehran
University of Medical Sciences, Tehran 14166, Iran
- Department
of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 14166, Iran
- Universal
Scientific Education and Research Network (USERN), Tehran 14166, Iran
| | - Suhasini Joshi
- Chemical
Biology Program, Memorial Sloan Kettering
Cancer Center, New York, New York 10065, United States
| | - Michael R. Hamblin
- Laser Research
Centre, Faculty of Health Science, University
of Johannesburg, Doornfontein 2028, South Africa
- Radiation
Biology Research Center, Iran University
of Medical Sciences, Tehran 14535, Iran
| | - Mahdi Karimi
- Cellular
and Molecular Research Center, Iran University
of Medical Sciences, Tehran 14535, Iran
- Department
of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 14535, Iran
- Oncopathology
Research Center, Iran University of Medical
Sciences, Tehran 14535, Iran
- Research
Center for Science and Technology in Medicine, Tehran University of Medical Sciences, Tehran 14166, Iran
- Applied
Biotechnology Research Centre, Tehran Medical Science, Islamic Azad University, Tehran 14166, Iran
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49
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Louati K, Maalej A, Kolsi F, Kallel R, Gdoura Y, Borni M, Hakim LS, Zribi R, Choura S, Sayadi S, Chamkha M, Mnif B, Khemakhem Z, Boudawara TS, Boudawara MZ, Safta F. Shotgun Proteomic-Based Approach with a Q-Exactive Hybrid Quadrupole-Orbitrap High-Resolution Mass Spectrometer for Protein Adductomics on a 3D Human Brain Tumor Neurospheroid Culture Model: The Identification of Adduct Formation in Calmodulin-Dependent Protein Kinase-2 and Annexin-A1 Induced by Pesticide Mixture. J Proteome Res 2023; 22:3811-3832. [PMID: 37906427 PMCID: PMC10696604 DOI: 10.1021/acs.jproteome.3c00484] [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: 08/03/2023] [Revised: 09/27/2023] [Accepted: 10/16/2023] [Indexed: 11/02/2023]
Abstract
Pesticides are increasingly used in combinations in crop protection, resulting in enhanced toxicities for various organisms. Although protein adductomics is challenging, it remains a powerful bioanalytical tool to check environmental exposure and characterize xenobiotic adducts as putative toxicity biomarkers with high accuracy, facilitated by recent advances in proteomic methodologies and a mass spectrometry high-throughput technique. The present study aims to predict the potential neurotoxicity effect of imidacloprid and λ-cyhalothrin insecticides on human neural cells. Our protocol consisted first of 3D in vitro developing neurospheroids derived from human brain tumors and then treatment by pesticide mixture. Furthermore, we adopted a bottom-up proteomic-based approach using nanoflow ultraperformance liquid chromatography coupled with a high-resolution mass spectrometer for protein-adduct analysis with prediction of altered sites. Two proteins were selected, namely, calcium-calmodulin-dependent protein kinase-II (CaMK2) and annexin-A1 (ANXA1), as key targets endowed with primordial roles. De novo sequencing revealed several adduct formations in the active site of 82-ANXA1 and 228-CaMK2 as a result of neurotoxicity, predicted by the added mass shifts for the structure of electrophilic precursors. To the best of our knowledge, our study is the first to adopt a proteomic-based approach to investigate in depth pesticide molecular interactions and their potential to adduct proteins which play a crucial role in the neurotoxicity mechanism.
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Affiliation(s)
- Kaouthar Louati
- Faculty
of Pharmacy, Laboratory of Pharmacology, Analytics & Galenic Drug
Development-LR12ES09, University of Monastir, Road Avicenne, Monastir 5000, Tunisia
| | - Amina Maalej
- Laboratory
of Environmental Bioprocesses, Centre of
Biotechnology of Sfax, Road of Sidi-Mansour, P.O. Box 1177, Sfax 3018, Tunisia
| | - Fatma Kolsi
- Department
of Neurosurgery, Habib Bourguiba University
Hospital, Road El Ain
km 1.5, Avenue of Ferdaous, Sfax 3089, Tunisia
- Faculty
of Medicine, Avenue of Majida Boulila, University
of sfax, Sfax 3029, Tunisia
| | - Rim Kallel
- Laboratory
of Pathological Anatomy and Cytology, Habib
Bourguiba University Hospital, Road El Ain km 1.5, Avenue of Ferdaous, Sfax 3089, Tunisia
- Faculty
of Medicine, Avenue of Majida Boulila, University
of sfax, Sfax 3029, Tunisia
| | - Yassine Gdoura
- Department
of Neurosurgery, Habib Bourguiba University
Hospital, Road El Ain
km 1.5, Avenue of Ferdaous, Sfax 3089, Tunisia
- Faculty
of Medicine, Avenue of Majida Boulila, University
of sfax, Sfax 3029, Tunisia
| | - Mahdi Borni
- Department
of Neurosurgery, Habib Bourguiba University
Hospital, Road El Ain
km 1.5, Avenue of Ferdaous, Sfax 3089, Tunisia
- Faculty
of Medicine, Avenue of Majida Boulila, University
of sfax, Sfax 3029, Tunisia
| | - Leila Sellami Hakim
- Laboratory
of Pathological Anatomy and Cytology, Habib
Bourguiba University Hospital, Road El Ain km 1.5, Avenue of Ferdaous, Sfax 3089, Tunisia
| | - Rania Zribi
- Higher
Institute of Applied Studies to Humanities of Tunis (ISEAHT), University of Tunis, 11 Road of Jebel Lakdhar, Tunis 1005, Tunisia
| | - Sirine Choura
- Laboratory
of Environmental Bioprocesses, Centre of
Biotechnology of Sfax, Road of Sidi-Mansour, P.O. Box 1177, Sfax 3018, Tunisia
| | - Sami Sayadi
- Biotechnology
Program, Center for Sustainable Development, College of Arts and Sciences, Qatar University, Doha 2713, Qatar
| | - Mohamed Chamkha
- Laboratory
of Environmental Bioprocesses, Centre of
Biotechnology of Sfax, Road of Sidi-Mansour, P.O. Box 1177, Sfax 3018, Tunisia
| | - Basma Mnif
- Department
of Bacteriology, Habib Bourguiba University
Hospital, Road El Ain
km 1.5, Avenue of Ferdaous, Sfax 3089, Tunisia
- Faculty
of Medicine, Avenue of Majida Boulila, University
of sfax, Sfax 3029, Tunisia
| | - Zouheir Khemakhem
- Legal Medicine
Department, Habib Bourguiba University Hospital, Road El Ain km 1.5, Avenue of Ferdaous, Sfax 3089, Tunisia
- Faculty
of Medicine, Avenue of Majida Boulila, University
of sfax, Sfax 3029, Tunisia
| | - Tahya Sellami Boudawara
- Laboratory
of Pathological Anatomy and Cytology, Habib
Bourguiba University Hospital, Road El Ain km 1.5, Avenue of Ferdaous, Sfax 3089, Tunisia
- Faculty
of Medicine, Avenue of Majida Boulila, University
of sfax, Sfax 3029, Tunisia
| | - Mohamed Zaher Boudawara
- Department
of Neurosurgery, Habib Bourguiba University
Hospital, Road El Ain
km 1.5, Avenue of Ferdaous, Sfax 3089, Tunisia
- Faculty
of Medicine, Avenue of Majida Boulila, University
of sfax, Sfax 3029, Tunisia
| | - Fathi Safta
- Faculty
of Pharmacy, Laboratory of Pharmacology, Analytics & Galenic Drug
Development-LR12ES09, University of Monastir, Road Avicenne, Monastir 5000, Tunisia
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Tatar C, Avci CB, Acikgoz E, Oktem G. Doxorubicin-induced senescence promotes resistance to cell death by modulating genes associated with apoptotic and necrotic pathways in prostate cancer DU145 CD133 +/CD44 + cells. Biochem Biophys Res Commun 2023; 680:194-210. [PMID: 37748252 DOI: 10.1016/j.bbrc.2023.09.032] [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: 06/16/2023] [Revised: 08/30/2023] [Accepted: 09/14/2023] [Indexed: 09/27/2023]
Abstract
Cancer stem cells (CSCs) are the most important cause of cancer treatment failure. Traditional cancer treatments, such as chemotherapy and radiotherapy, damage healthy cells alongside malignant cells, leading to severe adverse effects. Therefore, inducing cellular senescence without triggering apoptosis, which further damages healthy cells, may be an alternative strategy. However, there is insufficient knowledge regarding senescence induction in CSCs that show resistance to treatment and stemness properties. The present study aims to elucidate the effects of senescence induction on proliferation, cell cycle, and apoptosis in prostate CSCs and non-CSCs. Prostate CSCs were isolated from DU145 cancer cells using the FACS method. Subsequently, senescence induction was performed in RWPE-1, DU145, prostate CSCs, and non-CSCs by using different concentrations of Doxorubicin (DOX). Cellular senescence was detected using the senescence markers SA-β-gal, Ki67, and senescence-associated heterochromatin foci (SAHF). The effects of senescence on cell cycle and apoptosis were evaluated using the Muse Cell Analyzer, and genes in signaling pathways associated with the apoptotic/necrotic pathway were analyzed by real-time PCR. Prostate CSCs were isolated with 95.6 ± 1.4% purity according to CD133+/CD44+ characteristics, and spheroid formation belonging to stem cells was observed. After DOX-induced senescence, we observed morphological changes, SA-β-gal positivity, SAHF, and the lack of Ki67 in senescent cells. Furthermore; we detected G2/M cell cycle arrest and downregulation of various apoptosis-related genes in senescent prostate CSCs. Our results showed that DOX is a potent inducer of senescence for prostate CSCs, inhibits proliferation by arresting the cell cycle, and senescent prostate CSCs develop resistance to apoptosis.
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Affiliation(s)
- Cansu Tatar
- Department of Stem Cell, Institute of Health Science, Ege University, 35100, Izmir, Turkey.
| | - Cigir Biray Avci
- Department of Medical Biology, Faculty of Medicine, Ege University, 35100, Izmir, Turkey.
| | - Eda Acikgoz
- Department of Histology and Embryology, Faculty of Medicine, Van Yuzuncu Yil University, Van, 65080, Turkey.
| | - Gulperi Oktem
- Department of Stem Cell, Institute of Health Science, Ege University, 35100, Izmir, Turkey; Department of Histology and Embryology, Faculty of Medicine, Ege University, 35100, Izmir, Turkey.
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