Impact of G1 phase kinetics on the acquisition of stemness in cancer cells: the critical role of cyclin D.

Abstract

Cancer stem cells (CSCs) represent a unique subpopulation of cells with the ability to self-renew and differentiate, thereby sustaining tumor growth and contributing to disease recurrence. Although CSCs predominantly reside in the G₀ phase, their stem-like properties, such as the expression of specific CD markers, self-renewal, differentiation potential, tumor initiation, drug resistance, and increased invasive and metastatic potential, manifest during their active proliferative phase. Rapidly dividing cells exhibit alterations in their cell cycle, often characterized by shortened or bypassed G₁ phases, a phenomenon observed in both embryonic stem cells and cancerous cells. Dysregulation of cell cycle control is a hallmark of cancer, leading to uncontrolled cellular proliferation and tumorigenesis. Disruption in key regulatory proteins, signaling pathways, and cell cycle checkpoints-particularly during the G₁ phase-enables cancer cells to escape normal proliferation restrictions. The rapid cell-cycle progression can impair the timely degradation of proteins critical for cell cycle regulation, particularly cyclin D, thereby compromising proper cell cycle control. Therefore these proteins may be passed to daughter cells, promoting further rounds of rapid cycles. Additionally, cyclin D is often overexpressed in cancer cells, further exacerbating uncontrolled proliferation. These mechanisms may underpin key properties of CSCs, including rapid proliferation and their stem-like traits. This review examines the relationship between G₁ phase kinetics and the acquisition of stem-like characteristics, emphasizing how rapid G₁ phase progression and transitions between dormancy and active proliferation contribute to the emergence of CSC traits.