Prostate stem cell antigen is overexpressed in human transitional cell carcinoma

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, In addition t o its expression in normal and malignant prostate, we recently reported tha t PSCA is expressed at low levels in the transitional epithelium of normal bladder. In the present study, we compared the expression of PSCA in normal and malignant urothelial tissues to assess its potential as an immunothera peutic target in transitional cell carcinoma (TCC), Immunohistochemical ana lysis of PSCA protein expression was performed on tissue sections from 32 n ormal bladder specimens, as well as 11 cases of low-grade transitional cell dysplasia, 21 cases of carcinoma in situ (CIS), 38 superficial transitiona l cell tumors (STCC, stages T-a-T-1), 65 muscle-invasive TCCs (ITCCs, stage s T-2-T-4), and 7 bladder cancer metastases, The level of PSCA protein expr ession was scored semiquantitatively by assessing both the intensity and fr equency (i.e., percentage of positive tumor cells) of staining. We also exa mined PSCA mRNA expression in a representative sample of normal and maligna nt human transitional cell tissues. In normal bladder, PSCA immunostaining was weak and confined almost exclusively to the superficial umbrella cell l ayer. Staining in CIS and STCC was more intense and uniform than that seen in normal bladder epithelium (P < 0.001), with staining detected in 21 (100 %) of 21 cases of CIS and 37 (97%) of 38 superficial tumors. PSCA protein w as also detected in 42 (65%) of 65 of muscle-invasive and 4 (57%) of 7 meta static cancers, with the highest levels of PSCA expression (i.e., moderate- strong staining in > 50% of tumor cells) seen in 32% of invasive and 43% of metastatic samples. Higher levels of PSCA expression correlated with incre asing tumor grade for both STCCs and ITCCs (P < 0.001), Northern blot analy sis confirmed the immunohistochemical data, showing a dramatic increase in PSCA mRNA expression in two of Five muscle-invasive transitional cell tumor s when compared with normal samples. Confocal microscopy demonstrated that PSCA expression in TCC is confined to the cell surface. These data demonstr ate that PSCA is overexpressed in a majority of human TCCs, particularly CI S and superficial tumors, and may be a useful target for bladder cancer dia gnosis and therapy.