Alterations in transcription clusters underlie development of bladder cancer along papillary and nonpapillary pathways

Abstract

Bladder cancer develops in the urothelial lining from intraurothelial preneoplasia via two pathways, papillary and nonpapillary, which correspond to nonaggressive and aggressive forms of the disease. Because these two forms of cancer may develop via distinct molecular events, we examined the gene expression patterns in the development of bladder cancer from preneoplasia along papillary and nonpapillary pathways. The expression profiles of 19 pairs of RNA samples from adjacent urothelium and tumors were analyzed using cDNA microarrays. For selected genes their expressions were verified on a cohort of 251 bladder cancer patients using tissue microarray and immunohistochemistry and were related to clinicopathological parameters including follow-up data. We identified alterations in seven gene clusters controlling proliferation, differentiation, and programmed cell death that were common for papillary and nonpapillary cancer. In contrast, genes controlling cellular and stromal interactions were altered in the nonpapillary cancer. The expression levels of only two genes from this group could be used to define an aggressive form of the disease. Tumors characterized by the low expression of e-cadherin and the high expression of DNA a-topoisomerase II had a high propensity for distant metastasis and were associated with poor survival. Laboratory Investigation (2005) 85, 532-549. doi:10.1038/labinvest.3700250Keywords: cDNA microarray; bladder cancer; gene expression profile; tissue microarray; preneoplasia Many common human epithelial malignancies develop by progression of microscopically identifiable precursor conditions ranging from mild dysplasia to carcinoma in situ. 1 These conditions progress to clinically aggressive invasive cancer by multiple cumulative molecular events. 2 In fact, the earliest incipient changes occur in normal tissue even before preneoplastic lesions can be microscopically identified. The identification of abnormally expressed genes in such occult preneoplastic lesions may provide important clues as to the molecular pathways involved in the development of human cancer and facilitate early cancer detection and prevention.Carcinoma of the bladder is an exceptionally good candidate for such studies representing a model epithelial malignancy, which develops from microscopically recognizable intraurothelial preneoplastic lesions. [2][3][4] The fifth most frequent human cancer, it primarily affects people over the age of 50 years, and accounts for approximately 3% of all cancerrelated deaths. 5 The common bladder carcinomas arise via two distinct, but sometimes overlapping pathways, papillary and nonpapillary. 6-9 Approximately 80% of bladder tumors are superficially growing lesions that originate from urothelial hyperplasia. They frequently recur after excision but usually do not aggressively invade the bladder wall or metastasize. Most aggressive bladder cancers are of the solid, nonpapillary type and originate from intraurothelial precursor conditions such as dysplasia and carcinoma in situ. They a...

Gene expression profile and enrichment pathways in different stages of bladder cancer

“…In some aggressive tumors, collagen type I is overexpressed and plays a role in tumor development (Yang et al, 2007;Liang et al, 2008). Overexpression of FN1 has been found to correlate with a high histologic grade and an invasive phenotype (Kim et al, 2005). Niu et al (2009) also identified differences in FN1 expression between superficial bladder transitional cell carcinoma and normal urothelial cells.…”

Antiangiogenic antitumor activities of IGFBP-3 are mediated by IGF-independent suppression of Erk1/2 activation and Egr-1–mediated transcriptional events

“…27 The primer sequences used are described in supplemental Methods. To avoid amplification of genomic DNA, each gene primer was chosen from different exons.…”

Molecular characterization of early-stage bladder carcinomas by expression profiles, FGFR3 mutation status, and loss of 9q

“…Microarray analyses have not only delineated gene expression profiles distinct for different histological subtypes (Thykjaer et al, 2001;Dyrskjt et al, 2003Dyrskjt et al, , 2004Sanchez-Carbayo et al, 2003;Blaveri et al, 2005;Wild et al, 2005), but also gene expression signatures of importance for tumor recurrence and progression (Dyrskjt et al, 2003(Dyrskjt et al, , 2005Modlich et al, 2004;Wild et al, 2005), and patient survival (Blaveri et al, 2005;Kim et al, 2005). Whereas previous microarray studies of bladder cancer mostly have been dedicated to isolate gene expression profiles and predictors that classify tumors according to stage, recurrence and outcome, we focus on a comprehensive molecular characterization of Ta and T1 tumors.…”

“…In recent years, genome-wide expression profiling by the use of microarray technology has contributed to extensive and new insights into the complex gene expression patterns and dysregulation of genes occurring in urothelial neoplasias (Thykjaer et al, 2001;Dyrskjt et al, 2003Dyrskjt et al, , 2004Dyrskjt et al, , 2005Mor et al, 2003;SanchezCarbayo et al, 2003;Modlich et al, 2004;Blaveri et al, 2005;Kim et al, 2005;Wild et al, 2005). Microarray analyses have not only delineated gene expression profiles distinct for different histological subtypes (Thykjaer et al, 2001;Dyrskjt et al, 2003Dyrskjt et al, , 2004Sanchez-Carbayo et al, 2003;Blaveri et al, 2005;Wild et al, 2005), but also gene expression signatures of importance for tumor recurrence and progression (Dyrskjt et al, 2003(Dyrskjt et al, , 2005Modlich et al, 2004;Wild et al, 2005), and patient survival (Blaveri et al, 2005;Kim et al, 2005).…”