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Normal human prostate (NHP) epithelial cells undergo senescencein vitroandin vivobut the potential role of senescent NHP cells in prostate tumorigenesis remain unclear. Here we show that senescent NHP cells enhance thein vivotumorigenicity of low-tumorigenic LNCaP prostate cancer and low/non-tumorigenic subset of cells (called L cells) isolated from multiple bulk-cultured prostate (and other) cancer cell lines. Subsequent studies suggest cell–cell fusion as a potential mechanism for senescent NHP cell-enhanced tumor development. Using fluorescently tagged tumor cells and/or NHP cells, we find that NHP cells, like fibroblasts, can undergo fusion with unfractionated tumor cells or the L cells. Using 293T-L cells as the model cell system, we verify NHP and 293T-L cell fusion by using differential RT-PCR, karyotyping, and gene expression analyses. Further experiments demonstrate that senescent NHP cells that have lost progenitor markers, accumulated p16INK4a (p16) protein expression, and acquired the AR mRNA expression, appear to be the preferential fusion targets. Strikingly, the tumorigenicity of the NHP/293T-L hybrid cells was inhibited by exogenous p16 as well as hTERT. Chromosomal analyses revealed that hTERT probably inhibited thein vivotumorigenicity by maintaining genomic stability. These results suggest that senescent NHP cells, like senescent fibroblasts, may promote tumor development and that one of the mechanisms underlying the senescent NHP cell-enhanced tumorigenicity could be through cell fusion.