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The p15 gene which encodes a cyclin-dependent kinase inhibitor, is located in the 9p21 chromosomal region that is frequently deleted in human bladder transitional cell carcinomas (TCCs). The aim of the present paper is to study the potential involvement of thep15 gene in the evolution of TCCs. p15 mRNA expression was investigated by semi-quantitative RT-PCR in a series of 75 TCCs, 13 bladder cell lines and 6 normal bladder urothelia by semi-quantitative RT-PCR.p15 was expressed in the normal urothelium but p15 mRNA levels were significantly decreased in 66% of the superficial (Ta-T1) TCCs (P = 0.0015). In contrast, in muscle-invasive (T2-T4) TCCs, p15 expression differed widely between samples. p16 mRNA levels were also studied and there was no correlation between p15 and p16 mRNA levels, thus indicating that the two genes were regulated independently. Lower p15 expression in superficial tumours did not reflect a switch from quiescence to proliferative activity as normal proliferative urothelial controls did not present decreased p15 mRNA levels relative to quiescent normal urothelia. We further investigated the mechanisms underlyingp15 down regulation. Homozygous deletions of the p15 gene, also involving the contiguous p16 gene, were observed in 42% of the TCCs with decreased p15 expression. No hypermethylation at multiple methylation-sensitive restriction sites in the 5'-CpG island of p15 was encountered in the remaining tumours. Our data suggest that decreased expression of p15 may be an important step in early neoplastic transformation of the urothelium and that a mechanism other than homozygous deletions or hypermethylation, may be involved inp15 down regulation. [ABSTRACT FROM AUTHOR]

We studied E-cadherin down-regulation at the protein level in frozen sections of 111 bladder tumours and 13 normal bladder specimens by means of immunohistochemistry, and at the mRNA level by semi-quantitative RT-PCR in 40 of the same tumours. Results indicate that E-cadherin expression detected by immunohistochemistry correlated with both stage and grade (P < 0.0001 andP < 0.001, respectively). Analysis of recurrence, progression and survival over a mean period of 36 months after surgery in the entire cohort showed that abnormal E-cadherin immunoreactivity correlated strongly with poor outcome (log-rank test: P = 0.001, P = 0.0001 and P = 0.0003, respectively). In multistep logistic regression analysis, only E-cadherin status and stage had significant additional prognostic value (P = 0.008 and OR = 0.2;P = 0.03 and OR = 3.6, respectively). Survival estimates derived from RT-PCR transcript quantification differed significantly for low and high expression (log-rank test:P = 0.0006). These results suggest that the alteration occurs at the transcriptional level and support the clinical and biological relevance of cell adhesion molecules in bladder cancer. [ABSTRACT FROM AUTHOR]

Local immunotherapy with bacillus Calmette-Guerin (BCG) can prevent recurrences and progression of superficial bladder cancer, but the antitumoral mechanism of BCG is still unclear. The first event seems to be binding of BCG to urothelial cells via fibronectin, and processing of mycobacterial antigens by antigen-presenting cells. Experimental data suggest that bacterial antigens can also be processed by urothelial cells. CD4 lymphocytes subsequently recognize antigenic peptides presented by HLA class II molecules. The most common profile of urinary cytokines is interleukin-2 and interferon-gamma, suggesting the predominant involvement of the Th1 lymphocyte subpopulation. Natural killer cells, lymphocyte-activated killer cells, BCG-activated killer cells and macrophages are able to kill bladder tumor cells in vitro, but there is no evidence that a major histocompatibility complex (MHC)-restricted specific T cytotoxic response is involved in BCG antitumor activity. [ABSTRACT FROM AUTHOR]