Molecular Pathways in Invasive Bladder Cancer: New Insights Into Mechanisms, Progression, and Target Identification

Abstract

Papillary and invasive cancers of the urinary bladder appear to evolve and progress through distinct molecular pathways. Invasion in bladder cancer forebodes a graver prognosis, and these tumors are generally characterized by alterations in the p53 and retinoblastoma (RB) pathways that normally regulate the cell cycle by interacting with the Ras-mitogen activated protein kinase signal transduction pathway. Tumor angiogenesis further contributes to the neoplastic growth by providing a constant supply of oxygen and nutrients. Distinct epigenetic and genetic events characterize the interplay between the molecules involved in these pathways, thus affording their use as indicators of prognosis. Efforts are now underway to construct molecular panels comprising multiple markers that can serve as more robust predictors of outcome. While clinical trials for targeted chemotherapy for bladder cancer have commenced, novel genetic and pharmacologic agents that can target pathway-specific molecules are currently under development. The next generation of clinical management for urothelial carcinoma will witness the use of multimarker panels for prognostic prediction and combination therapy directed at novel molecular targets for treatment.

Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy

“…73,74 Deep genomic profiling with a comprehensive NGSbased diagnostic assay of metastatic UC identified an unexpectedly high frequency of potentially actionable GAs that can both influence therapy selection and direct patients to enter clinical trials using targeted therapies. Moreover, these opportunities for UC patients to receive targeted therapies include both commercially available agents approved for other indications and drugs in both early and late stages of clinical development.…”

“…[12][13][14][15] Characterization of the genomic drivers of UC development and progression has long been of interest to cancer biologists, urologists, genitourinary oncologists and pathologists. [16][17][18][19][20] Protein expression studies mostly performed on formalinfixed, paraffin-embedded (FFPE) specimens using immunohistochemistry (IHC) have been widely used to predict prognosis. [16][17][18][19][20] Increased DNA copy number determined by fluorescence in situ hybridization (FISH) has been used for both early UC detection 21,22 and prediction of prognosis.…”

“…[16][17][18][19][20] Protein expression studies mostly performed on formalinfixed, paraffin-embedded (FFPE) specimens using immunohistochemistry (IHC) have been widely used to predict prognosis. [16][17][18][19][20] Increased DNA copy number determined by fluorescence in situ hybridization (FISH) has been used for both early UC detection 21,22 and prediction of prognosis. 23,24 Studies on mRNA and miRNA expression in UC have also been carried out using RT-PCR and genomic microarrays, and have uncovered expression profiles linked to disease outcome.…”

The use of Urovysion™ fluorescence in situ hybridization in the diagnosis and surveillance of non-urothelial carcinoma of the bladder

“…Studies have shown that there are numerous reproducible molecular abnormalities that occur during the development and progression of urothelial carcinoma. 3,23,24 When normal urothelium undergoes mutations of chromosome 9p and fibroblast growth factor receptor 3, this may lead to the development of urothelial hyperplasia or low-grade papillary urothelial carcinoma. 3 Up to 70% of low-grade tumors recur, however they may Numerous studies have shown that high-grade urothelial carcinoma and in situ urothelial carcinoma show genetic alterations that are distinct from those seen in their low-grade counterparts.…”

“…Polysomy of chromosomes 3, 7 and 17 are associated with high-grade urothelial carcinoma and deletions of chromosome 9p21 (where the p16INK4a tumor suppressor gene resides) are seen in up to 60% of superficial lowgrade, papillary tumors. [22][23][24] Although Urovysiont FISH was initially approved for use in urine samples, it can also be applied to paraffin-embedded tissues.…”