Disease relevance of PSCA

• Prostate stem cell antigen (PSCA) is emerging as an important diagnostic marker and therapeutic target in prostate cancer [1].
• Prostate carcinogenesis driven by T antigen in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model results in an increased percentage and intensity level for PSCA promoter-driven GFP-positive cells [2].
• There is moderate to strong PSCA expression in 111 of 126 (88%) prostate cancer specimens examined by in situ analysis, including high-grade prostatic intraepithelial neoplasia and androgen-dependent and androgen-independent tumors [3].
• In the present study, we compared the expression of PSCA in normal and malignant urothelial tissues to assess its potential as an immunotherapeutic target in transitional cell carcinoma (TCC) [4].
• PSCA protein expression was identified in 105/112 (94%) primary prostate tumors and 9/9 (100%) bone metastases [5].
• Recent exciting findings that genetic variations of PSCA conferred increased risks of gastric cancer and bladder cancer have opened up a new avenue of research about the pathological function of PSCA [6].

High impact information on PSCA

• The prostate stem cell antigen (PSCA, named for its strong sequence homology to the thymocyte marker stem cell antigen 2) is a cell surface molecule associated with human and murine prostate cancer [2].
• This transgenic system helps define the range of cellular changes associated with altered expression of PSCA, shows that transcriptional control is a major component regulating PSCA levels, and provides a useful tool to study subpopulations of prostate epithelial cells and factors that regulate the PSCA promoter [2].
• To help define the regulation of this molecule, we created a transgenic mouse strain, which uses the human PSCA promoter region to control the expression of enhanced green fluorescent protein (GFP) [2].
• Anti-PSCA mAbs inhibit tumor growth and metastasis formation and prolong the survival of mice bearing human prostate cancer xenografts [7].
• In situ mRNA analysis localizes PSCA expression in normal prostate to the basal cell epithelium, the putative stem cell compartment of the prostate [3].

Chemical compound and disease context of PSCA

• PSCA mRNA expression is prostate-specific in normal male tissues and is highly up-regulated in both androgen-dependent and -independent prostate cancer xenografts [3].
• Prostate stem cell antigen (PSCA), a 123-amino acid cell surface glycoprotein, is highly expressed in both local and metastatic prostate cancers as well as in a large proportion of bladder and pancreatic cancers [8].
• We used TRAMP C1 murine prostate cancer cells to examine potential mechanisms through which RFB could regulate psca [9].
• Gene expression profiling in R-flurbiprofen-treated prostate cancer: R-Flurbiprofen regulates prostate stem cell antigen through activation of AKT kinase [9].

Biological context of PSCA

• We discuss the structural organization of the PSCA enhancer and compare it with that found in other AR-regulated genes [1].
• These findings suggest that PSCA is a unique marker of an intermediate subpopulation of PrEC in transition from a basal to a terminally differentiated secretory phenotype and may be a useful marker for the study of normal and malignant prostate development [10].
• Prostate stem cell antigen (PSCA, named for its strong sequence homology to the thymocyte marker stem cell antigen 2) is a cell surface antigen expressed in normal prostate and associated with human and murine prostate cancer [10].
• Fluorescent in situ hybridization analysis localizes the PSCA gene to chromosome 8q24.2, a region of allelic gain in more than 80% of prostate cancers [3].
• Using serial analysis of gene expression (SAGE), we identified PSCA as one of the most abundant transcripts in a differentiated urothelial tumor [11].

Anatomical context of PSCA

• PSCA was expressed in a subset of prostate epithelial cells that coexpress basal and secretory cytokeratins [10].
• In normal prostate, we observe PSCA expression in the terminally differentiated, secretory epithelium; strong expression was also seen in normal urothelium [12].
• Prostate stem cell antigen (PSCA) and p16 were also expressed in this cell line [13].
• PSCA staining was also seen in placental trophoblasts, renal collecting ducts and neuroendocrine cells in the stomach and colon [5].
• PSCA protein and mRNA expression levels were quantified and compared between available matched pairs of bone and lymph node or visceral metastases [14].

Associations of PSCA with chemical compounds

• PSCA expression correlates with tumor stage, grade and androgen independence and may have prognostic utility [5].
• RFB induced dose-dependent expression of PSCA protein, and activity of the psca promoter, in TRAMP C1 cells in culture [9].
• Phorbol ester markedly stimulated PSCA gene expression in a cycloheximide- and actinomycin-inhibitable manner after a lag phase of 10 h, indicating that transcription of the PSCA gene is regulated by protein kinase C and a newly synthesized protein [15].
• Increased psca promoter activity was also seen following treatment of cells with sulindac sulfone, another NSAID-like agent, but not with celecoxib treatment [9].

Other interactions of PSCA

• CK-20 and PSCA expression was not observed in blood samples from healthy donors [16].
• Fluorescence-activated cell sorter analysis of prostatic tissue from 11-18-month-old PTEN +/- mice showed elevated numbers of PSCA+ cells in the prostate, and immunohistochemical analysis showed high mPSCA expression in the tumors of these mice [17].
• One of the latter peptides, encompassing amino acid residues 14-22, was capable of generating a PSCA-specific T-cell response in a human lymphocyte culture from a patient with metastatic CaP [18].
• These results demonstrate that PSCA is co-overrepresented with MYC in a majority of cases, but may not be a necessary part of the 8q amplicon [19].
• Expression of PSCA and mesothelin was observed in pancreatic nonductal neoplasms but their expression was seen less frequently (0-50%) and weaker than that in pancreatic ductal adenocarcinomas (60-100%) [20].

Analytical, diagnostic and therapeutic context of PSCA

• Prostate stem cell antigen (PSCA), a homologue of the Ly-6/Thy-1 family of cell surface antigens, is expressed by a majority of human prostate cancers and is a promising target for prostate cancer immunotherapy [4].
• Northern blot analysis confirmed the immunohistochemical data, showing a dramatic increase in PSCA mRNA expression in two of five muscle-invasive transitional cell tumors when compared with normal samples [4].
• Confocal microscopy demonstrated that PSCA expression in TCC is confined to the cell surface [4].
• Thirty-six to forty months follow-up studies after radical retropubic prostatectomy were performed and aimed at assessing the correlation of PSCA mRNA expression level with local recurrences or metastases from the cancer [21].
• Based on these findings, enzyme-linked immunosorbent assay (ELISA) for the PSCA protein in the HeLaTR cells was established [22].

References