Abstract
BackgroundProstate cancer recurrence involves increased growth of cancer epithelial cells, as androgen dependent prostate cancer progresses to castrate resistant prostate cancer (CRPC) following initial therapy. Understanding CRPC prostate regrowth will provide opportunities for new cancer therapies to treat advanced disease.Methodology/Principal FindingsElevated chemokine expression in the prostate stroma of a castrate resistant mouse model, Tgfbr2fspKO, prompted us to look at the involvement of bone marrow derived cells (BMDCs) in prostate regrowth. We identified bone marrow cells recruited to the prostate in GFP-chimeric mice. A dramatic increase in BMDC recruitment for prostate regrowth occurred three days after exogenous testosterone implantation. Recruitment led to incorporation of BMDCs within the prostate epithelia. Immunofluorescence staining suggested BMDCs in the prostate coexpressed androgen receptor; p63, a basal epithelial marker; and cytokeratin 8, a luminal epithelial marker. A subset of the BMDC population, mesenchymal stem cells (MSCs), were specifically found to be incorporated in the prostate at its greatest time of remodeling. Rosa26 expressing MSCs injected into GFP mice supported MSC fusion with resident prostate epithelial cells through co-localization of β-galactosidase and GFP during regrowth. In a human C4-2B xenograft model of CRPC, MSCs were specifically recruited. Injection of GFP-labeled MSCs supported C4-2B tumor progression by potentiating canonical Wnt signaling. The use of MSCs as a targeted delivery vector for the exogenously expressed Wnt antagonist, secreted frizzled related protein-2 (SFRP2), reduced tumor growth, increased apoptosis and potentiated tumor necrosis.Conclusions/SignificanceMesenchymal stem cells fuse with prostate epithelia during the process of prostate regrowth. MSCs recruited to the regrowing prostate can be used as a vehicle for transporting genetic information with potential therapeutic effects on castrate resistant prostate cancer, for instance by antagonizing Wnt signaling through SFRP2.
Highlights
Prostate cancer mortality continues to rise as the aging population expands
The mechanism for the castrate resistant phenotype was associated with stromal fibroblastic expression of Wnt ligands, that in turn activated canonical Wnt signaling in the epithelia [5,6]
Previous studies with the Tgfbr2fspKO mouse model showed that the conditional stromal knockout of TGF-b signaling led to castrate resistant prostate cancer (CRPC) [5]
Summary
Radiation, and androgen ablation therapy, cancer recurrence is androgenindependent and is termed castrate resistant prostate cancer (CRPC). We used transgenic mouse models to help understand the involvement of recruited cells in prostate regrowth. Prostatic epithelial Wnt signaling was identified in transgenic mouse models of CRPC. One such model we developed had a conditional stromal knockout of the TGF-b type II receptor, termed Tgfbr2fspKO, [3]. Systemic SFRP2-adenovirus treatment in Tgfbr2fspKO mice was associated with morbidity Another model with prostatic epithelial expression of constitutively activated b-catenin developed HGPIN and sustained growth following castration [7]. Prostate cancer recurrence involves increased growth of cancer epithelial cells, as androgen dependent prostate cancer progresses to castrate resistant prostate cancer (CRPC) following initial therapy. Understanding CRPC prostate regrowth will provide opportunities for new cancer therapies to treat advanced disease
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