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Urokinase and the mechanism of osteoblastic metastases by prostate cancer

Urokinase and the mechanism of osteoblastic metastases by prostate cancer

Fibrinolysis 6(Suppl. 1): 63-69

We have examined the pathogenesis of osteoblastic metastases by attempting to identify growth factors for cells of the osteoblast phenotype which are produced by prostatic cancer tissue. In initial studies, surgical specimens of human prostate cancer (CA) and benign prostatic hyperplasia (BPH) tissue were employed as a source of prostatic tissue, and mitogenic activity for osteoblastic cells was assessed in primary cultures of fetal calvarial cells and in osteosarcoma cells. These studies identified the presence of acid stable peptide mitogens for osteoblasts in both CA and BPH. To pursue these findings, the prostate cancer cell line PC-3 was employed. Biochemical analysis of serum-free conditioned PC-3 medium, using mainly reverse-phase high pressure liquid chromatography, disclosed the presence of a mitogen for osteoblastic cells with a molecular weight of approximately 15 kDa. Amino acid sequencing indicated that this was an amino-terminal fragment of urokinase (UK). Further studies demonstrated abundant plasminogen activator activity in PC-3 conditioned medium and substantial messenger RNA encoding UK in PC-3 cells. High molecular weight (HMW) UK but not low molecular weight (LMW) UK was mitogenic and increased cell numbers in osteoblastic cultures but not in control fibroblast cultures. Specific, competitive binding of HMW but not LMW UK to osteoblastic cells was observed. These studies indicated that the mitogenic activity of UK indeed resides in the amino-terminal region. This was confirmed by demonstrating mitogenic activity for osteoblastic cells using a peptide containing the ‘growth factor domain’ of UK. In summary, these studies have shown that an amino-terminal fragment of UK produced by PC-3 cells has growth factor activity for cells of the osteoblast phenotype. UK fragments may therefore be of importance in the pathogenesis of osteoblastic metastases produced by prostatic cancer cells.

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Accession: 034144099

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DOI: 10.1016/0268-9499(92)90096-z

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