Neuroendocrine Prostate Cancer Cells Originate from the p63-Expressing Basal Cells but Not the Pre-Existing Adenocarcinoma Cells in Mice

Neuroendocrine prostate cancer (NEPC) was previously thought rare, making it an understudied field. Recent studies revealed that ~30% of the advanced prostate cancers (PCs), especially after androgen deprivation therapy (ADT), contain focal NEPC cells. NEPC is highly metastatic and counts for a big proportion of PC death. One important question for understanding NEPC is where these NEPC cells come from. Previous studies suggested that NEPCs might originate from neuroendocrine cells, cancer stem cells, or pre-existing adenocarcinoma cells via trans-differentiation. Recently, Zou et al. demonstrated that NEPC cells could originate from luminal epithelial tumor cells by tracing the Nkx3.1-expressing luminal epithelial tumor cells in a double TP53 and Pten knockout-induced PC mouse model (Cancer Discovery 7, 736-749, 2017). This finding supports the previously proposed trans-differentiation model. Park et al. showed that ablation of p53 and RB1 and overexpression of c-Myc and active AKT1 in the human prostate basal cells (BCs) could induce NEPC cells (Science 362, 91-95, 2018). However, it was unclear whether BCs were directly reprogrammed to NEPC cells, or to adenocarcinoma cells first and then NEPC cells via a trans-differentiation process.

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.

Written by:
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

Abstract Reference:
1. Dong-Kee Lee et al. Cell Research. Neuroendocrine prostate carcinoma cells originate from the p63-expressing basal cells but not the pre-existing adenocarcinoma cells in mice (February 2019) DOI https://doi.org/10.1038/s41422-019-0149-4

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