Per and polyfluoroalkyl substances (PFAS) promote proliferation and migration in genetically distinct kidney cancer cell lines

Introduction and Objectives: Per- and polyfluoroalkyl substances (PFAS) such as GenX, PFOA, and PFOS are persistent environmental pollutants increasingly associated with renal carcinogenesis. Their direct effects on kidney cancer progression remain unclear. This study investigated whether PFAS exposure enhances proliferation and migration in two genetically distinct kidney cancer models-human RCC-ER (VHL-mutant) and murine Renca (VHL-wild type). Methods: RCC-ER and Renca cells were treated with GenX, PFOA, or PFOS at physiologically relevant concentrations (0.5-40 nM). Proliferation was monitored over 72 h using the IncuCyte S3 system. Migration was assessed in ImageLock plates, where wounds were created after 24 h and imaged every 1.5 h for 72 h. Wound closure was quantified by percentage wound closure (WC) and relative wound density (RWD) using IncuCyte software. All experiments were performed in triplicate to assess dose dependency and statistical significance. Results: PFAS exposure significantly enhanced both proliferation and migration in kidney cancer cells, with compound- and cell line-specific variations. RenCa cells exhibited strong proliferative responses to GenX and PFOS from 0.5-20 nM, peaking at 5 nM respectively, while PFOA showed cytotoxic effects at these doses. In contrast, RCC-ER cells demonstrated increased proliferation in response to PFOA (max at 40 nM) and PFOS (max at 5 nM), whereas GenX had minimal effect on proliferation at low doses. All three PFAS markedly accelerated wound closure and relative wound density in both cell lines, indicating enhanced migratory potential. Collectively, these data reveal that PFAS compounds augment pro-oncogenic behaviors across human and murine kidney cancer models. Conclusion: PFAS compounds promote proliferative and migratory phenotypes in both murine and human kidney cancer models through distinct but convergent metabolic mechanisms. The conserved effects across VHL-wild-type and VHL-mutant systems underscore PFAS as a potential environmental accelerator of renal tumor progression and justify further mechanistic and translational studies.