PubMed · 7265382
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M Haid. 1981. Bladder carcinoma.. https://doi.org/10.1016/s0022-5347(17)54482-1
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Inactivation of relevant tumor-suppressor genes by allelic or homozygous deletion is a characteristic event in tumor cells. Here, the prognostic value of allelic deletions on 5p13-12 at the putative del-27 tumor-suppressor locus and in the APC tumor-suppressor gene on 5q21, as well as homozygous deletions of the MTS1 (p16INK4, CDKN 2) tumor-suppressor gene on 9p21 was assessed in 87 bladder cancers using microdissection and PCR-based assays. Tumor-specific LOH was detected in 10 of 38 (26%, del-27), and 15 of 30 (50%, APC) informative specimens. Homozygous deletion of the MTS1 gene was detected in 33% of 84 tumors investigated. These deletion frequencies implicate the 3 tumor-suppressor regions in the genesis of transitional-cell carcinoma. In contrast to deletions of the APC or MTS1 genes, LOH at the del-27 locus correlated with tumor progression. This suggests that loss of the putative tumor-suppressor gene DEL-27 is involved in an aggressive behavior of the tumor cells and appears to be a prognostic marker for the clinical outcome of patients with transitional-cell carcinoma.
BACKGROUND AND PURPOSE: The plasminogen activators urokinase and tissue plasminogen activator are enzymes that degrade proteins in tissue basement membranes and the extracellular matrix (a biomolecular complex surrounding individual cells in tissues that serves as a barrier between the cells and the vascular and lymph systems). The action of these enzymes allows tumor cells to escape their local environment and metastasize. Plasminogen activator activity can be influenced by the urokinase receptor, which is expressed on the surface of cells, and by the plasminogen activator inhibitors 1 and 2. Because bladder tumors differ in their propensity to invade local areas and distant sites, we studied the expression of both plasminogen activators, the two plasminogen activator inhibitors, and the urokinase receptor in four human bladder cancer cell lines (RT4, 253J, EJ, and T24) to see if there was an association between the expression of these proteins and tumor cell invasiveness in vitro. METHODS: The expression of urokinase, tissue plasminogen activator, and the two inhibitors was measured by enzyme-linked immunosorbent assays of serum-free, cell-conditioned media (i.e., culture fluids). Cell surface expression of the urokinase receptor was assayed by flow cytometry, using an anti-receptor monoclonal antibody (Mab3936). The invasive capacity of untreated cells and of cells exposed to exogenous, high-molecular-weight urokinase was analyzed by use of Matrigel invasion chambers. RESULTS: The four bladder cancer cell lines demonstrated differential expression of both plasminogen activators and both inhibitors; three of the cell lines (T24, EJ, and 253J) expressed the urokinase receptor. The four cell lines differed in their invasive potential in vitro. Neither expression of tissue plasminogen activator nor production of the inhibitors appeared to influence Matrigel invasion. EJ cells and 253J cells produced the highest levels of urokinase and demonstrated the greatest propensity for invasion; T24 cells, which produced only small amounts of urokinase, exhibited a low invasive potential. Pretreatment of T24 cells with exogenous high-molecular-weight urokinase markedly increased their invasiveness. Similar pretreatment of EJ and 253J cells increased their invasiveness as well. RT4 cells, which lacked urokinase receptor expression but produced moderate amounts of urokinase, were not invasive and did not become so after exposure to exogenous high-molecular-weight urokinase. Binding of Mab3936 to urokinase receptors inhibited Matrigel invasion. CONCLUSIONS: To our knowledge, this is the first study demonstrating that bladder tumor cells express the urokinase receptor and that both receptor expression and urokinase expression are required for bladder tumor cell invasion in vitro.
Altered patterns of p53 and pRB expression have been reported to be frequent events and to have prognostic significance in bladder cancer. To assess the potential adverse consequences of having altered patterns of both p53 and pRB proteins in patients with bladder neoplasms compared with having one or neither abnormality, we have studied a cohort of superficial transitional cell carcinomas of the urinary bladder by immunohistochemical analysis. The present study included 59 well-characterized superficial transitional cell carcinomas (Ta, n = 28; T1, n = 31) for which clinicopathological variables were available. Nuclear overexpression of p53 was identified in 22 cases (37%). A statistically significant association was observed between the p53-positive phenotype and disease progression (P < 0.001), as well as reduced survival (P < 0.001). Undetectable levels of pRB were observed in 11 cases (19%). Patients with a pRB-negative phenotype had a more frequent disease progression (P = 0.014) and decreased overall survival (P = 0.014). We also observed a significant association between altered p53 and undetectable pRB expression patterns (P = 0.001). Nine tumors showed both a p53-positive and a pRB-negative phenotype. There was an even more marked increase in progression (P = 0.00005) and decreased overall survival (P = 0.0004) in patients whose tumors had both alterations after controlling for tumor stage, tumor grade, and suspicion of vascular invasion. These data suggest that alterations of p53 and pRB have a cooperative negative effect on both progression and survival in primary bladder cancer. It may be postulated that aberrant p53 and pRB expression deregulates cell cycle control at the G1 checkpoint and engenders tumor cells with reduced response to programmed cell death. The imbalance produced by an enhanced proliferative activity and a decreased apoptotic rate may determine the aggressive clinical course of the bladder tumors harboring both p53 and pRB alterations.