British journal of cancer · 2025
Effects of mitotically active polyploid giant cancer cells on chemoresistance through interaction with cancer-associated fibroblasts.
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Itoh Go, Fukushi Yuma, Takagane Kurara, Kanetaka Keisuke, Suzuki Hitomi, Kawasaki Yohei, Kuriyama Sei, Iemura Kenji, Tanaka Kozo, Goto Akiteru, Tanaka Masamitsu
Аннотация
BACKGROUND: Polyploid giant cancer cells (PGCCs), characterized by enlarged or multiple nuclei, have long been considered non-proliferative and hallmarks of high malignancy. However, their functional contribution to tumor progression remains unclear.
METHODS: We identified and characterized a subset of mitotically active (MA)-PGCCs in human oral squamous cell carcinoma specimens and cell lines. Mitotic activity and cell cycle was assessed using immunofluorescence, time-lapse microscopy and FUCCI. We evaluated the interactions between MA-PGCCs and cancer-associated fibroblasts (CAFs), focusing on transforming growth factor-beta (TGF-β) signaling. Chemoresistance to 5-fluorouracil (5-FU) was analyzed using cell viability assays.
RESULTS: MA-PGCCs exhibited both bipolar and multipolar mitosis, generating heterogeneous progeny that contributed to genomic instability. These cells increased the number of CAFs with elevated TGF-β expression, promoting epithelial-mesenchymal transition (EMT) and enhancing resistance to 5-FU. Mechanistically, enhanced reactive oxygen species in MA-PGCCs upregulated urokinase-type plasminogen activator (uPA) and its receptor uPAR, promoting plasmin-mediated activation of TGF-β secreted from adjacent CAFs. Upregulation of TGF-β receptors in MA-PGCCs further amplified TGF-β signaling, accelerating EMT.
CONCLUSIONS: Our findings identify MA-PGCCs as a proliferative subpopulation that promotes EMT and chemoresistance through a TGF-β-uPA/uPAR feedback loop. Targeting this pathway may offer a novel therapeutic strategy for the treatment of aggressive tumors enriched in MA-PGCCs.
METHODS: We identified and characterized a subset of mitotically active (MA)-PGCCs in human oral squamous cell carcinoma specimens and cell lines. Mitotic activity and cell cycle was assessed using immunofluorescence, time-lapse microscopy and FUCCI. We evaluated the interactions between MA-PGCCs and cancer-associated fibroblasts (CAFs), focusing on transforming growth factor-beta (TGF-β) signaling. Chemoresistance to 5-fluorouracil (5-FU) was analyzed using cell viability assays.
RESULTS: MA-PGCCs exhibited both bipolar and multipolar mitosis, generating heterogeneous progeny that contributed to genomic instability. These cells increased the number of CAFs with elevated TGF-β expression, promoting epithelial-mesenchymal transition (EMT) and enhancing resistance to 5-FU. Mechanistically, enhanced reactive oxygen species in MA-PGCCs upregulated urokinase-type plasminogen activator (uPA) and its receptor uPAR, promoting plasmin-mediated activation of TGF-β secreted from adjacent CAFs. Upregulation of TGF-β receptors in MA-PGCCs further amplified TGF-β signaling, accelerating EMT.
CONCLUSIONS: Our findings identify MA-PGCCs as a proliferative subpopulation that promotes EMT and chemoresistance through a TGF-β-uPA/uPAR feedback loop. Targeting this pathway may offer a novel therapeutic strategy for the treatment of aggressive tumors enriched in MA-PGCCs.