c-myc in bladder cancer Clinical findings and analysis of mechanism

Abstract

The c-myc gene product is known to be involved in the regulation of cell proliferation and differentiation. Altered c-myc gene expression is a common event in a variety of tumors. This study was designed to investigate c-myc overexpression in transitional cell carcinoma (TCC). The first part was designed to investigate the frequency of c-myc overexpression in relation to tumor stage and tumor grade. A second set of experiments was directed at the mechanisms underlying c-myc overexpression in TCC. A total of 185 paraffin-embedded urothelial tissue specimens were investigated immunohistochemically for c-myc overexpression. A single case of overexpression (6%) was observed in normal urothelial tissue (n = 16). c-myc overexpression was also infrequent in carcinoma in situ (TIS) (7/39 = 18%). In contrast, papillary urothelial tumors (n = 65) yielded c-myc overexpression in 38 cases (58%). Investigation of infiltrating bladder tumors revealed c-myc overexpression in 56% of T1 tumors and 59% of muscle-infiltrating tumors. The staining pattern in multifocal tumors was heterogeneous in 10 of 18 cases. Similarly, only 12 of 28 patients with tumor recurrences showed the same c-myc staining pattern in the primary tumor and in tumor recurrences. c-myc overexpression did not correlate with tumor grade or tumor progression. Nevertheless, the high frequency of c-myc overexpression in urothelial carcinoma suggests an important role for this protein in urothelial carcinoma. Therefore, the mechanism underlying c-myc overexpression was further investigated in six bladder carcinoma cell lines. Southern blot experiments under standardized conditions showed no significant gene amplification. The comparison of c-myc mRNA expression to that of histone H3 as a measure of cell proliferation revealed a moderate correlation (r = 0.45) in the six cell lines examined. These data suggest that in accord with its established role as a cell cycle competence factor, c-myc may be necessary but not sufficient for the induction of proliferation in urothelial carcinoma.

Investigations in the molecular events of Transitional Cell Carcinoma of the Bladder

“…However, muscle invasion was significantly associated (p<0.05) with c-myc expression as 88.23% of invasive tumor patients showed positive c-myc expression. This finding is in agreement with Schmitz-Drager et al [24] who showed that 58% of their patients were c-myc positive. They also revealed that 59% of the positive cases were of muscle-invasive tumors.…”

ASP5878, a selective FGFR inhibitor, to treat FGFR3‐dependent urothelial cancer with or without chemoresistance

“…). Furthermore, c‐MYC overexpression has been observed in urothelial cancer tissues . Thus, c‐MYC is thought to be relevant to drug‐resistance in cancer.…”

Amplification pattern of 12q13-q15 genes (MDM2, CDK4, GLI) in urinary bladder cancer

“…A signi®cant role of MDM2 expression in bladder cancer has been suggested in several studies using immunohistochemical MDM2 analyses. Detectable MDM2 expression has been reported in 9 ± 44% of urinary bladder cancers (Ioachim et al, 2000;Jahnson and Karlsson, 2000;Korkolopoulou et al, 1997;Lianes et al, 1994;P®ster et al, 1999Schmitz-Drager et al, 1997;Shiina et al, 1999). Overall, these studies using immunohistochemistry have yielded con¯icting results, some of them linking MDM2 expression to high (Korkolopoulou et al, 1997) or to low (Lianes et al, 1994) grade and stage tumors while others did not ®nd an association (P®ster et al, 2000;SchmitzDrager et al, 1997;Shiina et al, 1999).…”