Differential expression of progression-related genes in the evolution of superficial to invasive transitional cell carcinoma of the bladder

Abstract

It is generally accepted that there are dichotomous biologic pathways that lead to the development of either: i) superficial papillary (Ta) transitional cell carcinoma (TCC) or ii) precursor lesions to muscle-invasive (CIS, T1) TCC and muscle-invasive (> or =T2) TCC. We investigated the expression of several progression-related genes to characterize the phenotype of these tumors within these divergent developmental pathways. Using a colorimetric in situ hybridization technique, we examined the expression of mRNAs of several progression-related genes in archival, pathologic specimens from 77 patients with bladder TCC. These genes included basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), interleukin (IL)-8, matrix metalloproteinase (MMP)-9, and epidermal growth factor receptor (EGFR). Relative gene expression was quantified using image analysis. Gene expression was normalized using poly (dT) and the expression of each factor in a panel of specimens of normal urothelium. Patients were stratified according to disease stage, and the level of gene expression among the stratified groups was compared. VEGF, bFGF, IL-8, and MMP-9 expression was increased in muscle-invasive compared with superficial papillary tumors, (p<0.05) and VEGF expression was increased in muscle-invasive tumors compared with CIS specimens (p<0. 05). bFGF, IL-8, and EGFR expression was increased in CIS specimens compared with superficial papillary tumors (p<0.05). The pattern of expression of bFGF, VEGF, IL-8, MMP-9, and EGFR represent the divergent developmental pathways in the pathogenesis of bladder TCC, which characterizes superficial or invasive bladder cancer. bFGF, IL-8, and EGFR appear to be upregulated in early precursor lesions (CIS), whereas VEGF appears to be upregulated at later stages in the development of muscle-invasive TCC.