Cancer stem cells (CSCs), first identified in blood cancers, are increasingly recognized as significant biomarkers and targets in tumor therapy due to their metastatic potential and role in cancer recurrence. Recent research has demonstrated the dedication of scientists in targeting CSCs to explore novel therapeutic strategies. Many types of cancer exhibit metastasis, heterogeneity, and resistance to treatment, all of which are influenced by CSCs. These cells utilize various transcription factors and signaling pathways to carry out these functions. By identifying and understanding these pathways, new therapeutic breakthroughs can be achieved. Thus, targeting cancer stem cells holds great potential and importance in cancer treatment. Moreover, CSCs offer promising avenues for treating otherwise incurable diseases. However, targeting CSCs presents challenges such as immunological rejection and disease recurrence. Advancing research into CSCs may reveal new insights in the fight against cancer and ultimately improve human health. This review explores the roles of CSCs in cancer development and treatment, aiming to uncover new therapeutic approaches.
Eid RA, Alaa Edeen M, Shedid EM, et al., 2023, Targeting Cancer Stem Cells as the Key Driver of Carcinogenesis and Therapeutic Resistance. Int J Mol Sci, 24(2): 1786. https://doi.org/10.3390/ijms24021786
Mori L, Ben Amar M, 2023, Stochasticity and Drug Effects in Dynamical Model for Cancer Stem Cells. Cancers (Basel), 15(3): 677. https://doi.org/10.3390/cancers15030677
Yang Y, Li X, Wang T, et al., 2020, Emerging Agents that Target Signaling Pathways in Cancer Stem Cells. J Hematol Oncol, 13: 60. https://doi.org/10.1186/s13045-020-00901-6
Zhu M, Li S, Cao X, et al., 2023, The STAT Family: Key Transcription Factors Mediating Crosstalk Between Cancer Stem Cells and Tumor Immune Microenvironment. Semin Cancer Biol, 88: 18–31. https://doi.org/10.1016/j.semcancer.2022.11.011
Lo UG, Chen YA, Cen J, et al., 2022, The Driver Role of JAK-STAT Signalling in Cancer Stemness Capabilities Leading to New Therapeutic Strategies for Therapy- and Castration-Resistant Prostate Cancer. Clin Transl Med, 12(8): e978. https://doi.org/10.1002/ctm2.978
Thomas A, Pathak N, Moses L, et al., 2024, Chapter 32 – Components of Cancer Stem Cells Microenvironment: Influence on the Tumorigenic Property and Stemness in Cancer Stem Cells, in Pathak S, Banerjee A (eds) Cancer Stem Cells and Signaling Pathways. Academic Press, Cambridge (MA), 549–579. https://doi.org/10.1016/B978-0-443-13212-4.00002-7
Pandey PK, 2024, Chapter 22 – Clinical Limitation in Stem Cell Therapy, in Verma YK, Satija NK, Raghav PK, et al., (eds) Stem Cells: An Alternative Therapy for COVID-19 and Cytokine Storm. Academic Press, Cambridge (MA), 363–368. https://doi.org/10.1016/B978-0-323-95545-4.00014-1
Carvalho J, 2020, Cell Reversal From a Differentiated to a Stem-Like State at Cancer Initiation. Front Oncol, 10: 541. https://doi.org/10.3389/fonc.2020.00541
Lasorsa F, Rutigliano M, Milella M, et al., 2023, Cancer Stem Cells in Renal Cell Carcinoma: Origins and Biomarkers. Int J Mol Sci, 24(17): 13179. https://doi.org/10.3390/ijms241713179
Lee TK, Guan XY, Ma S, 2022, Cancer Stem Cells in Hepatocellular Carcinoma – From Origin to Clinical Implications. Nat Rev Gastroenterol Hepatol, 19(1): 26–44. https://doi.org/10.1038/s41575-021-00508-3
Abubakar M, Khatoon N, Saddique A, et al., 2024, Skin Cancer and Human Papillomavirus. Journal of Population Therapeutics and Clinical Pharmacology, 31(2): 790–816.
Liao J, Chen B, Zhu Z, et al., 2023, Long Noncoding RNA (lncRNA) H19: An Essential Developmental Regulator with Expanding Roles in Cancer, Stem Cell Differentiation, and Metabolic Diseases. Genes Dis, 10(4): 1351–1366. https://doi.org/10.1016/j.gendis.2023.02.008
Borlongan MC, Saha D, Wang H, 2024, Tumor Microenvironment: A Niche for Cancer Stem Cell Immunotherapy. Stem Cell Rev Rep, 20(1): 3–24. https://doi.org/10.1007/s12015-023-10639-6
Cazzola A, Calzon Lozano D, Menne DH, et al., 2023, Lymph Vessels Associate with Cancer Stem Cells from Initiation to Malignant Stages of Squamous Cell Carcinoma. Int J Mol Sci, 24(17): 13615. https://doi.org/10.3390/ijms241713615
Salama DEA, Hasan A, Balbola GA, et al., 2024, Immunohistochemical Comparison of CD44 and Hypoxia Inducible Factor-1 Alpha (HIF-1Alpha) in Oral Squamous Cell Carcinoma and Oral Epithelial Dysplasia: A Comparative Study. J Med Chem Sci, 7(1): 9–23. https://doi.org/10.26655/JMCHEMSCI.2024.1.2
Costoya JA, Arce VM, 2023, Cancer Cells Escape the Immune System by Increasing Stemness Through Epigenetic Reprogramming. Cell Mol Immunol, 20(1): 6–7. https://doi.org/10.1038/s41423-022-00953-3
Zou W, Zhao J, Li Y, et al., 2020, Rat Bone Marrow-Derived Mesenchymal Stem Cells Promote the Migration and Invasion of Colorectal Cancer Stem Cells. Onco Targets Ther, 13: 6617–6628. https://doi.org/10.2147/OTT.S249353
Chaudhary A, Raza SS, Haque R, 2023, Transcriptional Factors Targeting in Cancer Stem Cells for Tumor Modulation. Semin Cancer Biol, 88: 123–137. https://doi.org/10.1016/j.semcancer.2022.12.010
Yang L, Shi P, Zhao G, et al., 2020, Targeting Cancer Stem Cell Pathways for Cancer Therapy. Signal Transduct Target Ther, 5(1): 8. https://doi.org/10.1038/s41392-020-0110-5
Lam KH, Ma S, 2023, Noncellular Components in the Liver Cancer Stem Cell Niche: Biology and Potential Clinical Implications. Hepatology, 78(3): 991–1005. https://doi.org/10.1002/hep.32629
Mazurakova A, Koklesova L, Vybohova D, et al., 2023, Therapy-Resistant Breast Cancer in Focus: Clinically Relevant Mitigation by Flavonoids Targeting Cancer Stem Cells. Front Pharmacol, 14: 1160068. https://doi.org/10.3389/fphar.2023.1160068
Meyer F, Engel AM, Krause AK, et al., 2022, Efficient DNA Repair Mitigates Replication Stress Resulting in Less Immunogenic Cytosolic DNA in Radioresistant Breast Cancer Stem Cells. Front Immunol, 13: 765284. https://doi.org/10.3389/fimmu.2022.765284
Smadja DM, 2024, Hyperthermia for Targeting Cancer and Cancer Stem Cells: Insights from Novel Cellular and Clinical Approaches. Stem Cell Rev Rep, 20(6): 1532–1539. https://doi.org/10.1007/s12015-024-10736-0
Tiwari M, Srivastava P, Abbas S, et al., 2024, Emerging Role of Autophagy in Governing Cellular Dormancy, Metabolic Functions, and Therapeutic Responses of Cancer Stem Cells. Cells, 13(5): 447. https://doi.org/10.3390/cells13050447
Ebrahimi N, Afshinpour M, Fakhr SS, et al., 2023, Cancer Stem Cells in colorectal cancer: Signaling Pathways Involved in Stemness and Therapy Resistance. Crit Rev Oncol Hematol, 182: 103920. https://doi.org/10.1016/j.critrevonc.2023.103920
Clara JA, Monge C, Yang Y, et al., 2020, Targeting Signalling Pathways and the Immune Microenvironment of Cancer Stem Cells – A Clinical Update. Nat Rev Clin Oncol, 17(4): 204–232. https://doi.org/10.1038/s41571-019-0293-2
Li YR, Fang Y, Lyu Z, et al., 2023, Exploring the Dynamic Interplay Between Cancer Stem Cells and the Tumor Microenvironment: Implications for Novel Therapeutic Strategies. J Transl Med, 21(1): 686. https://doi.org/10.1186/s12967-023-04575-9
Stouras I, Vasileiou M, Kanatas PF, et al., 2023, Metabolic Profiles of Cancer Stem Cells and Normal Stem Cells and Their Therapeutic Significance. Cells, 12(23): 2686. https://doi.org/10.3390/cells12232686
Liu Y, Wang H, 2024, Biomarkers and Targeted Therapy for Cancer Stem Cells. Trends in Pharmacological Sciences, 45(1): 56–66. https://doi.org/10.1016/j.tips.2023.11.006
Lim JR, Mouawad J, Gorton OK, et al., 2021, Cancer Stem Cell Characteristics and Their Potential as Therapeutic Targets. Med Oncol, 38(7): 76. https://doi.org/10.1007/s12032-021-01524-8
Hoque S, Dhar R, Kar R, et al., 2023, Cancer Stem Cells (CSCs): Key Player of Radiotherapy Resistance and Its Clinical Significance. Biomarkers, 28(2): 139–151. https://doi.org/10.1080/1354750X.2022.2157875
Gonzalez-Callejo P, Garcia-Astrain C, Herrero-Ruiz A, et al., 2024, 3D Bioprinted Tumor-Stroma Models of Triple-Negative Breast Cancer Stem Cells for Preclinical Targeted Therapy Evaluation. ACS Appl Mater Interfaces, 16(21): 27151–27163. https://doi.org/10.1021/acsami.4c04135
Souto EP, Dobrolecki LE, Villanueva H, et al., 2022, In Vivo Modeling of Human Breast Cancer Using Cell Line and Patient-Derived Xenografts. J Mammary Gland Biol Neoplasia, 27(2): 211–230. https://doi.org/10.1007/s10911-022-09520-y. Erratum in J Mammary Gland Biol Neoplasia, 27(2): 231. https://doi.org/10.1007/s10911-022-09524-8
Hasanzadeh A, Ebadai A, Dastanpour L, et al., 2023, Applications of Innovation Technologies for Personalized Cancer Medicine: Stem Cells and Gene-Editing Tools. ACS Pharmacol Transl Sci, 6(12): 1758–1779. https://doi.org/10.1021/acsptsci.3c00102
Erdem M, Lee KH, Hardt M, et al., 2024, MACC1 Regulates LGR5 to Promote Cancer Stem Cell Properties in Colorectal Cancer. Cancers (Basel), 16(3): 604. https://doi.org/10.3390/cancers16030604
Warrier NM, Kelkar N, Johnson CT, et al., 2023, Understanding cancer stem cells and plasticity: Towards better therapeutics. Eur J Cell Biol, 102(2): 151321. https://doi.org/10.1016/j.ejcb.2023.151321
Kyriakopoulou K, Koutsakis C, Piperigkou Z, et al., 2023, Recreating the Extracellular Matrix: Novel 3D Cell Culture Platforms in Cancer Research. FEBS J, 290(22): 5238–5247. https://doi.org/10.1111/febs.16778
Huang YH, Wang WL, Wang PH, et al., 2024, EXOSC5 Maintains Cancer Stem Cell Activity in Endometrial Cancer by Regulating the NTN4/Integrin Beta1 Signalling Axis. Int J Biol Sci, 20(1): 265–279. https://doi.org/10.7150/ijbs.86275
Ling L, Wen Y, Xiong Y, et al., 2024, Anisomycin Inhibits the Activity of Human Ovarian Cancer Stem Cells via Regulating Antisense RNA NCBP2-AS2/MEK/ERK/STAT3 Signaling. J Gene Med, 26(1): e3571. https://doi.org/10.1002/jgm.3571
Engel RM, Chan WH, Nickless D, et al., 2020, Patient-Derived Colorectal Cancer Organoids Upregulate Revival Stem Cell Marker Genes following Chemotherapeutic Treatment. J Clin Med, 9(1): 128. https://doi.org/10.3390/jcm9010128
Zhou B, Feng Z, Xu J, et al., 2023, Organoids: Approaches and Utility in Cancer Research. Chin Med J (Engl), 136(15): 1783–1793. https://doi.org/10.1097/CM9.0000000000002477
Dogan E, Kisim A, Bati-Ayaz G, et al., 2021, Cancer Stem Cells in Tumor Modeling: Challenges and Future Directions. Adv Nanobiomed Res, 1(11): 2100017. https://doi.org/10.1002/anbr.202100017
Hassan M, Nasr SM, Amin NA, et al., 2022, Circulating Liver Cancer Stem Cells and Their Stemness-Associated MicroRNAs as Diagnostic and Prognostic Biomarkers for Viral Hepatitis-Induced Liver Cirrhosis and Hepatocellular Carcinoma. Noncoding RNA Res, 8(2): 155–163. https://doi.org/10.1016/j.ncrna.2022.12.006
Yu SS, Cirillo N, 2020, The Molecular Markers of Cancer Stem Cells in Head and Neck Tumors. J Cell Physiol, 235(1): 65–73. https://doi.org/10.1002/jcp.28963
Jones CL, Inguva A, Jordan CT, 2021, Targeting Energy Metabolism in Cancer Stem Cells: Progress and Challenges in Leukemia and Solid Tumors. Cell Stem Cell, 28(3): 378–393. https://doi.org/10.1016/j.stem.2021.02.013
Zeng Z, Fu M, Hu Y, et al., 2023, Regulation and Signaling Pathways in Cancer Stem Cells: Implications for Targeted Therapy for Cancer. Mol Cancer, 22(1): 172. https://doi.org/10.1186/s12943-023-01877-w
Valent P, Sadovnik I, Peter B, et al., 2023, Vienna Cancer Stem Cell Club (VCSCC): 20 Year Jubilee and Future Perspectives. Expert Rev Hematol, 16(9): 659–670. https://doi.org/10.1080/17474086.2023.2232545
Zhang Q, Han Z, Zhu Y, et al., 2020, The Role and Specific Mechanism of OCT4 in Cancer Stem Cells: A Review. Int J Stem Cells, 13(3): 312–325. https://doi.org/10.15283/ijsc20097
Ding J, Li HY, Zhang L, et al., 2021, Hedgehog Signaling, a Critical Pathway Governing the Development and Progression of Hepatocellular Carcinoma. Cells, 10(1): 123. https://doi.org/10.3390/cells10010123
Fang Z, Meng Q, Xu J, et al., 2023, Signaling Pathways in Cancer-Associated Fibroblasts: Recent Advances and Future Perspectives. Cancer Commun (Lond), 43(1): 3–41. https://doi.org/10.1002/cac2.12392
Moreno-Londono AP, Robles-Flores M, 2024, Functional Roles of CD133: More than Stemness Associated Factor Regulated by the Microenvironment. Stem Cell Rev Rep, 20(1): 25–51. https://doi.org/10.1007/s12015-023-10647-6
Filipek-Gorzala J, Kwiecinska P, Szade A, et al., 2024, The Dark Side of Stemness – The Role of Hematopoietic Stem Cells in Development of Blood Malignancies. Front Oncol, 14: 1308709. https://doi.org/10.3389/fonc.2024.1308709
Ferrer AI, Trinidad JR, Sandiford O, et al., 2020, Epigenetic Dynamics in Cancer Stem Cell Dormancy. Cancer Metastasis Rev, 39(3): 721–738. https://doi.org/10.1007/s10555-020-09882-x
Atashzar MR, Baharlou R, Karami J, et al., 2020, Cancer Stem Cells: A Review from Origin to Therapeutic Implications. J Cell Physiol, 235(2): 790–803. https://doi.org/10.1002/jcp.29044
Shu X, Chen M, Liu SY, et al., 2023, Palladin Promotes Cancer Stem Cell-Like Properties in Lung Cancer by Activating Wnt/B-Catenin Signaling. Cancer Med, 12(4): 4510–4520. https://doi.org/10.1002/cam4.5192
Masoumi J, Jafarzadeh A, Abdolalizadeh J, et al., 2021, Cancer Stem Cell-Targeted Chimeric Antigen Receptor (CAR)-T Cell Therapy: Challenges and Prospects. Acta Pharm Sin B, 11(7): 1721–1739. https://doi.org/10.1016/j.apsb.2020.12.015
Lathia J, Liu H, Matei D, 2020, The Clinical Impact of Cancer Stem Cells. Oncologist, 25(2): 123–131. https://doi.org/10.1634/theoncologist.2019-0517
Pan Y, Yu L, Liu L, et al., 2024, Genetically Engineered Nanomodulators Elicit Potent Immunity Against Cancer Stem Cells by Checkpoint Blockade and Hypoxia Relief. Bioact Mater, 38: 31–44. https://doi.org/10.1016/j.bioactmat.2024.04.008
Wu B, Shi X, Jiang M, et al., 2023, Cross-Talk Between Cancer Stem Cells and Immune Cells: Potential Therapeutic Targets in the Tumor Immune Microenvironment. Mol Cancer, 22(1): 38. https://doi.org/10.1186/s12943-023-01748-4
Montazersaheb P, Pishgahzadeh E, Jahani VB, et al., 2023, Magnetic Nanoparticle-Based Hyperthermia: A Prospect in Cancer Stem Cell Tracking and Therapy. Life Sci, 323: 121714. https://doi.org/10.1016/j.lfs.2023.121714
Xiong JX, Li YT, Tan XY, et al., 2024, Targeting PRSS23 with Tipranavir Induces Gastric Cancer Stem Cell Apoptosis and Inhibits Growth of Gastric Cancer via the MKK3/p38 MAPK-IL24 Pathway. Acta Pharmacol Sin, 45(2): 405–421. https://doi.org/10.1038/s41401-023-01165-9
Shi M, Huang K, Wei J, et al., 2024, Identification and Validation of a Prognostic Signature Derived from the Cancer Stem Cells for Oral Squamous Cell Carcinoma. Int J Mol Sci, 25(2): 1031. https://doi.org/10.3390/ijms25021031
Tuncer Z, Kurar E, Duran T, 2024, Investigation of the Effect of Belinostat on MCF-7 Breast Cancer Stem Cells via the Wnt, Notch, and Hedgehog Signaling Pathway. Saudi Med J, 45(2): 121–127. https://doi.org/10.15537/smj.2024.45.2.20230478
Wu B, Shi X, Jiang M, et al., 2023, Cross-Talk Between Cancer Stem Cells and Immune Cells: Potential Therapeutic Targets in the Tumor Immune Microenvironment. Mol Cancer, 22(1): 38. https://doi.org/10.1186/s12943-023-01748-4
Gaggianesi M, Di Franco S, Pantina VD, et al., 2021, Messing Up the Cancer Stem Cell Chemoresistance Mechanisms Supported by Tumor Microenvironment. Front Oncol, 11: 702642. https://doi.org/10.3389/fonc.2021.702642
Jain H, Dhawan P, Rao S, et al., 2023, The Impediments of Cancer Stem Cells and An Exploration into the Nanomedical Solutions for Glioblastoma. Anticancer Agents Med Chem, 23(4): 368–382. https://doi.org/10.2174/1871520622666220901101204
Chhetri D, Munuswamy-Ramanujam G, Kumar RCS, et al., 2024, Chapter 23 – Epigenetic Signaling: Regulation of Cancer Stem Cells in Colorectal Cancer, in Pathak S, Banerjee A (eds) Cancer Stem Cells and Signaling Pathways. Academic Press, Cambridge (MA), 395–408. https://doi.org/10.1016/B978-0-443-13212-4.00004-0