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  • Genomic Instability and Cancer Stem Cells: Implications for Cancer Progression and Therapeutic Resistance

  • Shima Hasani,1,*
    1. Department of Animal Biology, Faculty of Natural Sciences, The University of Tabriz, Tabriz, Iran.


  • Introduction: Genomic instability, characterized by an increased frequency of mutations, chromosomal aberrations, and DNA damage, is a hallmark of cancer. Cancer stem cells (CSCs), a subpopulation within tumors with self-renewal and differentiation capabilities, have been implicated in tumor initiation, progression, and resistance to conventional therapies. The interplay between genomic instability and CSCs is emerging as a critical factor in driving cancer heterogeneity, metastasis, and treatment failure. This review aims to provide a comprehensive analysis of the role of genomic instability in the maintenance and function of CSCs, highlighting the underlying molecular mechanisms. We will explore how genomic instability contributes to the emergence and evolution of CSCs and discuss the therapeutic challenges posed by this relationship.
  • Methods: A systematic literature review was conducted, focusing on studies investigating the relationship between genomic instability and CSCs across various cancer types. Key findings were synthesized to identify common pathways and potential therapeutic targets.
  • Results: Genomic instability in CSCs arises from a variety of genetic and epigenetic alterations that disrupt critical cellular processes, such as DNA repair, cell cycle regulation, and chromosomal segregation. These disruptions not only contribute to the maintenance and survival of CSCs but also endow them with adaptive capabilities that promote tumor progression and therapeutic resistance.Key Findings:Defective DNA Damage Response (DDR) Pathways: CSCs frequently exhibit deficiencies in DNA damage response (DDR) pathways, including homologous recombination (HR) and non-homologous end joining (NHEJ). For instance, mutations in BRCA1/2 genes, which are commonly associated with breast and ovarian cancers, lead to defective HR repair, resulting in the accumulation of DNA double-strand breaks. In response to these deficiencies, CSCs often activate alternative repair mechanisms, such as error-prone NHEJ, which increases genomic instability. This ongoing accumulation of genetic damage generates a diverse pool of CSCs with varying resistance profiles, enabling the selection of subclones that can survive and proliferate under therapeutic pressures. Such genetic diversity within CSCs is a key factor driving relapse and metastasis in cancer patients.Chromosomal Instability (CIN) and Aneuploidy: Chromosomal instability (CIN), characterized by frequent gains and losses of whole chromosomes or large chromosomal regions, is another hallmark of CSCs. This form of genomic instability is particularly prominent in colorectal cancer, where CSCs have been shown to exhibit high levels of CIN. The resulting aneuploidy, or abnormal number of chromosomes, leads to the dysregulation of oncogenes and tumor suppressor genes, further enhancing tumor heterogeneity. This chromosomal missegregation not only allows CSCs to adapt to changing microenvironments but also enables them to evade immune surveillance. Importantly, the ongoing chromosomal reshuffling in CSCs generates novel karyotypes that can confer resistance to targeted therapies, posing a significant challenge to effective cancer treatment.Epigenetic Modifications: Epigenetic alterations, such as DNA methylation and histone modifications, play a crucial role in regulating gene expression in CSCs. Aberrant methylation of tumor suppressor genes, like CDKN2A, has been observed in glioblastoma stem cells, leading to their silencing and promoting unchecked cell cycle progression. These epigenetic changes can induce genomic instability by altering the expression of key genes involved in DNA repair and chromosome stability. Furthermore, the reversible nature of epigenetic modifications allows CSCs to dynamically respond to therapeutic interventions, switching between different states that confer survival advantages under stress.Telomere Dysfunction: Telomere maintenance is another critical factor contributing to the genomic instability of CSCs. CSCs often display altered telomerase activity, leading to telomere shortening or elongation. In pancreatic cancer, CSCs with critically short telomeres undergo telomere crisis, resulting in chromosomal fusions and breakage-fusion-bridge cycles. These cycles generate extensive genomic rearrangements, creating a population of CSCs with enhanced metastatic potential and resistance to therapy. Conversely, some CSCs upregulate telomerase to maintain telomere length, thereby sustaining their immortality and promoting tumor growth.Microenvironment-Induced Instability: The tumor microenvironment (TME) plays a pivotal role in inducing genomic instability in CSCs. Hypoxia, a common feature of the TME, has been shown to downregulate key DNA repair genes in CSCs, such as RAD51 and MRE11, leading to the accumulation of DNA damage. Additionally, interactions between CSCs and stromal cells can trigger the secretion of reactive oxygen species (ROS), further promoting genomic instability. This dynamic crosstalk between CSCs and the TME not only enhances the adaptability of CSCs but also drives their evolution towards more aggressive phenotypes.
  • Conclusion: Genomic instability plays a pivotal role in the biology of CSCs, contributing to their maintenance, evolution, and resistance to treatment. Understanding the molecular mechanisms linking genomic instability and CSCs is crucial for the development of targeted therapies that can effectively eliminate these cells and improve patient outcomes. Future research should focus on identifying novel biomarkers and therapeutic targets within this context to overcome the challenges posed by CSC-driven tumor heterogeneity and resistance. The integration of advanced genomic technologies and epigenetic therapies holds promise in unraveling the complexities of CSCs, offering hope for more effective and lasting cancer treatments.
  • Keywords: Genomic Instability, Cancer Stem Cells, Therapeutic Resistance, Tumor Heterogeneity, DNA Damage.

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