The two sides of chromosomal instability:drivers and brakes in cancer

Chromosomal instability(CIN)is a hallmark of cancer and is associated with tumor cell malignancy.CIN triggers a chain reaction in cells leading to chromosomal abnormalities,including deviations from the normal chromosome number or structural changes in chromosomes.CIN arises from errors in DNA replication and chromosome segregation during cell division,leading to the formation of cells with abnormal number and/or structure of chromosomes.Errors in DNA replication result from abnormal replication licensing as well as replication stress,such as double-strand breaks and stalled replication forks;meanwhile,errors in chromosome segregation stem from defects in chromosome segregation machinery,including centrosome amplification,erroneous microtubule-kinetochore attachments,spindle assembly checkpoint,or defective sister chromatids cohesion.In normal cells,CiN is deleterious and is associated with DNA damage,proteotoxic stress,metabolic alteration,cell cycle arrest,and senescence.Paradoxically,despite these negative consequences,CiN is one of the hallmarks of cancer found in over 90%of solid tumors and in blood cancers.Furthermore,CiN could endow tumors with enhanced adaptation capabilities due to increased intratumor heterogeneity,thereby facilitating adaptive resistance to therapies;however,excessive CiN could induce tumor cells death,leading to the"just-right"model for CIN in tumors.Elucidating the complex nature of CIN is crucial for understanding the dynamics of tumorigenesis and for developing effective anti-tumor treatments.This review provides an overview of causes and consequences of CIN,as well as the paradox of CIN,a phenomenon that continues to perplex researchers.Finally,this review explores the potential of CIN-based anti-tumor therapy.