Adenocarcinoma of the prostate is the most common internal cancer of men in the United States and the second most frequent cause of cancer deaths. Long-term objectives are to define the molecular basis of human prostate cancer development and progression, to design methods for identifying cancers with aggressive potential and to delineate improved strategies for therapeutic intervention. An immunological subtraction approach, surface-epitope masking (SEM), generated the Pro series of monoclonal antibodies (MAbs) that detect a surface antigen of approximately 35 to 42 kDa expressed on human prostate carcinoma cell lines and patient-derived carcinomas, but not on normal prostate or benign prostatic hypertrophy (BPH) tissue. In nude mouse xenografts, the Pro 1.5 MAbs inhibit the growth of well-established DU-145 human prostate tumors. If the Pro MAbs display appropriate cancer tissue specificity in humans, they could be useful therapeutic reagents. Expression cloning using the Pro 1.5 MAb identifies a novel gene, prostate carcinoma tumor antigen-1 (PCTA-1). Based on nucleotide and amino acid sequence, PCTA-1 is a new member of the galactose-binding lectin (galectin) gene family, galectin-8HT. As with other galectins, PCTA-1 is shed from cells by an atypical secretory process. Specific galectins mediate cell-cell and cell-matrix interactions and contribute to tumorigenesis and metastasis. PCTA-1 expression is detected by Northern blotting, NRase protection and RT-PCR in human prostate carcinomas, but not in normal prostate or BPH tissue. These experimental results support an association between PCTA-1 and human prostate cancer. Studies will define the functional role of PCTA-1 in prostate cancer and characterize the structure of the PCTA-1 gene. Experiments will determine if PCTA-1 is useful for staging prostate cancers and identifying prostate cancer cells escaping into the circulation. The potential utility of the ProMAbs for the therapy of human prostate cancer will be evaluated in nude mouse xenograft models. The role of PCTA-1 in normal prostate development will be analyzed in transgenic mice using a prostate specific rat probasin promoter. The approaches to achieve these aims will include DNA transfection with sense and antisense expression plasmid and adenoviral vectors, and RNA, genomic DNA and protein analyses. The PCTA-1 gene and the Pro MAbs are excellent tools to further our understanding of prostate cancer development and progression. Findings from these proposed studies should provide the background for direct translational applications for the improved diagnosis, staging and therapy of prostate cancer.
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