Endoreplication: The Good, the Bad, and the Ugly

To battle adverse internal and external conditions and maintain homeostasis, diploid organisms employ various cellular processes, such as proliferation and apoptosis. In some tissues, an alternative mechanism, endoreplication, is employed toward similar goals. Endoreplication is an evolutionarily conserved cell cycle program during which cells replicate their genomes without division, resulting in polyploid cells. Importantly, endoreplication is reported to be indispensable for normal development and organ formation across various organisms, from fungi to humans. In recent years, more attention has been drawn to delineating its connections to wound healing and tumorigenesis. In this Review, we discuss mechanisms of endoreplication and polyploidization, their essential and positive roles in normal development and tissue homeostasis, and the relationship between polyploidy and cancer. As an alternative cell cycle program, endoreplication is crucial during development. Polyploid cells assume various pivotal functions in metazoans. Besides its significant role in development, endoreplication is induced by various signaling pathways to maintain homeostasis and tissue integrity, and to assist the wound healing and tissue repair processes. Polyploidy and aneuploidy are widespread across different types of cancer, contributing to cancer progression, surveillance escape, and relapse. Polyploid giant cancer cells (PGCCs) possess stem cell characteristics, and can differentiate into three germ layers in vitro. PGCCs can form tumors through asymmetric budding or bursting.