PSA affects prostate cancer cell invasion in vitro and induces an osteoblastic phenotype in bone in vivo

Background:Patients with advanced prostate cancer frequently have a poor prognosis as a result of metastasis and present with high serum PSA levels. There is evidence suggesting that the serine protease activity of PSA could be involved in the invasion and metastasis of prostate cancer. In this study, we determined the effects of PSA and its precursor, pro-PSA, on invasion and the type of bone metastasis.Methods:We stably transfected prostate adenocarcinoma cells, human DU-145 and rat MatLyLu, with either the full-length prepro-PSA sequence or pre-PSA DNA, to generate subclones of cells that secrete pro-PSA or free PSA, respectively. Secretion of PSA was measured by western blot analysis and enzyme-linked immunosorbent assay (ELISA). The invasive and migratory properties of the cells were determined using a basement membrane extract and were compared with corresponding empty vector control cells. Twelve days after injection of PSA-secreting MatLyLu cells into the femora of nude mice, bone tumor burden and histomorphometry were determined using a stereological technique.Results:The transfected cells secreted 0.15–2.23 ng PSA/106 cells/day. Pro-PSA-secreting subclones increased invasion and migration by 24–263%. Conversely, the PSA-secreting subclones significantly reduced both invasion and migration by 59–70%. The divergent effects on invasion and migration observed in pro-PSA- and PSA-secreting subclones indicate that different forms of PSA may have different functions. Intrafemoral injections with PSA-secreting MatLyLu cells resulted in an increase in osteoblastic parameters when compared with non-PSA-secreting subclones as measured by bone histomorphometry. Concomitantly, a decrease in osteoclasts and eroded surface was observed.Conclusions:Our in vitro data suggest that PSA, dependent on the predominant form secreted, may decrease or increase invasive properties of prostate cancer cells. The in vivo results indicate that PSA in the bone microenvironment may contribute to the osteoblastic phenotype of bone metastasis frequently observed in prostate cancer.