In a new study done by Lee et al., p63-CreERT2; Rosa-LoxP-STOP-LoxP-tdRFP; TRAMP mice were generated for tracing the fate of p63-expressing BCs during PC development in TRAMP mice. TRAMP mice are prone to development of both NEPC and adenocarcinoma. After transiently treated with tamoxifen to activate CreERT2 in the p63-expressing BCs, most BCs were labeled with tdRFP expression at 4 weeks of age. By 20 weeks of age, all mice developed extensive NEPC and adenocarcinoma cells with tdRFP expression, indicating that both NEPC and adenocarcinoma cells can originate from the p63-expressing BCs. K8-CreERT2; Rosa-LoxP-STOP-LoxP-tdRFP; TRAMP mice were also generated for tracing the fate of luminal epithelial cells during PC development in TRAMP mice. Tamoxifen treatment resulted in tdRFP expression in more than 50% of the luminal epithelial cells in the prostates of these mice at 4 weeks of age. Interestingly, only tdRFP-expressing adenocarcinoma cells but no tdRFP-expressing NEPC cells were present in the prostates of these mice when examined at 20 weeks of age. Activation of tdGFP expression in cytokeratin 8 (K8)-expressing luminal epithelial tumor cells at later stages in these mice also did not produce any tdRFP-expressing NEPC cells. These results demonstrated that NEPC cells did not originate from K8-expressing luminal epithelial cells or pre-existing adenocarcinoma cells in TRAMP mice. Furthermore, this study also demonstrated that expression of SV40 T/t antigens that inhibit p53, RB and PP2A induced rat prostatic progenitor cell differentiation into NEPC cells in vitro and in vivo, which suggests that NEPC cells can directly originate from epithelial progenitor cells. Together, these findings indicate that NEPC can arise independently from basal progenitor cells without trans-differentiation from the pre-existing adenocarcinoma, and thereby should be diagnosed and treated as early as possible instead of waiting for the completion of endocrine therapy or chemotherapy.
Dong-Kee Lee, Ph.D., Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
Jianming Xu, Ph.D., Professor, Department of Molecular and Cellular Biology, Director, Genetically Engineered Mouse Core, Baylor College of Medicine, Houston, Texas
1. Dong-Kee Lee et al.https://doi.org/10.1038/s41422-019-0149-4