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The establishment of metastatic prostate cancer (CaP) in bone and its tendency to elicit an osteoblastic bone response occurs via mechanisms not yet fully understood. Factors primarily or exclusively produced by CaP cells have been implicated in the bone osteoblastic response. Among these secreted factors are the human kallikrein proteins, including PSA. The objective of this study was to examine the potential roles of PSA in the development of the osteoblastic bone response elicited by metastatic CaP. Chinese hamster ovary cells were transfected to express PSA using the TET-on system (CHO/PSA). CHO/PSA cells treated with tetracycline had up to six-fold higher PSA levels compared to LNCaP cells (161.97±6.67 vs. 26.75±0.825 ng/ml/105 cells, P=0.0025). PSA expression did not alter the proliferation of CHO/PSA cells. PSA expression decreased osteoclast formation from RAW264.7 cells in co-culture experiments. Studies on the effects of PSA on osteoblast proliferation and differentiation are currently underway. To examine the effects of PSA expression in vivo,CHO/PSA cells were injected subcutaneously into intact male SCID mice and PSA expression was induced by the administration of doxycycline (Dox). High serum PSA levels were detected in the Dox induced animals. Four weeks post-injection, approximately half of the total serum PSA consisted of fPSA (fPSA=999±363 ng/ml, tPSA=1545±368 ng/ml), suggesting that the remainder of the total PSA consisted of enzymatically active PSA. PSA expression did not affect tumor growth in this model system. To evaluate the effects of PSA expression on bone, intact male SCID mice were intratibially injected with CHO/PSA cells. PSA expression was induced by the administration of Dox. High levels of serum PSA (1083±159 ng/ml) were measured in the Dox induced animals three weeks post-cell injection. Also, approximately half of the total serum PSA consisted of fPSA (fPSA=601±95 ng/ml), suggesting that the remainder of the total PSA was enzymatically active. Micro CT analysis of tumored tibiae showed that the periosteal and cortical bone volumes were decreased in the Dox- induced mice. Interestingly, endosteal bone volumes were also significantly decreased in comparison to untreated animals (0.48±0.03 vs. 0.67±0.08, P=0.05). In conclusion, our results suggest that PSA alone does not elicit an osteoblastic bone response. We are currently conducting bone histomorphometric analysis and additional animal studies to more clearly determine the role of PSA in the significant bone changes observed in vivo.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]