Polyploid giant cancer cells: the hidden players in ovarian cancer progression and prognosis

Polyploid giant cancer cells (PGCCs) showcase a unique and often undervalued subpopulation within tumors that performs a major role in promoting the aggressiveness and therapy resistance of ovarian cancer that is one of the deadliest cancers. These unusually large numbers of cells, which may be multinucleated or single-nucleated, typically arise when cancer cells are exposed to different stress conditions. Their formation begins through mechanisms like endoreplication, failed cytokinesis, or disrupted cell fusion. Functionally, in ovarian cancer, these PGCCs act as "mother" cells, generating heterogeneous sets of smaller, more resilient daughter cells through depolyploidization or meiosis. This unusual and unique capability induces a significant tumor relapse and reemergence. Moreover, they drive epithelial-to-mesenchymal transition (EMT), increasing invasiveness, metastatic ability, and ovarian tumor embolization. Their identification within circulating tumor cells (CTCs) is being examined as a biomarker for worse prognosis and disease progression. Importantly, ovarian PGCCs are inherently multidrug-resistant as they escape apoptosis, re-regulate metabolic activities, and actively efflux chemotherapeutic agents into the extracellular environment. These characteristics make them notably challenging to fully eliminate with conventional therapeutic strategies. Targeting PGCCs might offer a game-changing way to overcome therapeutic resistance and improve patient outcomes in advanced ovarian cancer.