Dysregulation of the Cyclin D/E2F activity as a core mechanism driving cancer stem cell plasticity and cell cycle...

Cancer stem cells (CSCs) represent a highly specialized intratumoral compartment responsible for tumor initiation, metastatic dissemination, therapeutic resistance, and disease recurrence. A central conceptual challenge in CSC biology is their capacity to oscillate between a quiescent G₀ state and a proliferative, stem-like phenotype, reflecting a high degree of phenotypic plasticity. Although dysregulation of the G1/S checkpoint is a hallmark of malignant transformation, its mechanistic contribution to CSC identity and plastic behavior remains poorly defined.This review outlines a conceptual model that integrates aberrant G1/S control with CSC state transitions. We propose that defective checkpoint regulation accelerates CSC proliferation, leading to the progressive intracellular accumulation of Cyclin D, which in turn drives a self-reinforcing, rapid G1 progression through phosphorylation-dependent pathways that operate independently of the slower, transcription-driven Cyclin D-Rb-E2F regulatory axis. With continued cycling, depletion of key E2F-regulated DNA replication factors ensues, eventually forcing CSCs into a quiescent, biosynthetic restoration phase. During this interval, essential genomic replication and cell cycle machinery are replenished until microenvironmental or intracellular cues trigger reentry into the proliferative cycle, giving rise to another burst of accelerated division.Through these cyclical perturbations in the Cyclin D/E2F balance, CSCs undergo temporally governed shifts between quiescent and proliferative states, thereby sustaining plasticity, intratumoral heterogeneity, and treatment-resistant phenotypes. This model also identifies potential therapeutic strategies, such as leveraging stimuli-responsive delivery systems that exploit cyclic CSC vulnerabilities.