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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p> <p></p>

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Effects of mitotically active polyploid giant cancer cells on chemoresistance through interaction with cancer-associated fibroblasts

  • 期刊论文

  • 发表日期：

    2025年12月21日

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  • Go Itoh,
  • Yuma Fukushi,
  • Kurara Takagane,
  • Keisuke Kanetaka,
  • Hitomi Suzuki,
  • Yohei Kawasaki,
  • Sei Kuriyama,
  • Kenji Iemura,
  • Kozo Tanaka,
  • Akiteru Goto,
  • Masamitsu Tanaka

摘要

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.