Molecular pathways in bladder cancer

Abstract

The aim of this review is to provide a contemporary outline of our current understanding of the molecular and genetic events associated with tumorigenesis and the progression of bladder cancer. A comprehensive review of the literature was performed on the molecular alterations associated with transitional cell carcinoma (TCC) of the bladder. Intense research efforts are being made to better identify and characterize various bladder cancers and their true biologic potential. The need to predict which superficial tumors will recur or progress, and which invasive tumors will metastasize has led to a much better understanding of the molecular pathways associated with bladder cancer. The molecular changes that occur in TCC of the bladder are numerous and can be categorized into: (1) chromosomal alterations leading to carcinogenesis, (2) loss of cell cycle regulation accounting for cellular proliferation, and (3) metastasis, guided by events such as angiogenesis. It is becoming apparent that the accumulation of genetic and molecular changes ultimately determines a tumors phenotype and subsequent clinical behavior. At the present time, conventional histopathologic evaluation of bladder cancer (tumor grade and stage) is inadequate to accurately predict the behavior of most bladder tumors. While new laboratory techniques have allowed us to better understand how bladder cancer develops and ultimately progresses, few of these techniques are currently available for use in the clinical setting. The ultimate goal is to develop reliable prognostic markers which will accurately predict not only the expected clinical course of an individual bladder tumor but also the response of that tumor to currently available therapies. More importantly, this information may be employed in the future to dictate altogether new treatments for the prevention and/or stabilization of the early molecular events that lead to the development of bladder cancer.

The Transcripts of <i>SFRP1,</i><i>CEP63</i> and <i>EIF4G2</i> Genes Are Frequently Downregulated in Transitional Cell Carcinomas of the Bladder

“…Several genetic alterations including oncogene activation (c- Ha - ras , c- myc, NMM2 ,c- erbB-2 and amplification of chromosomal regions without a known target gene) and tumor suppressor gene inactivation ( p16 , p53 , Rb1 and deletions on several chromosomal regions without a known target gene) have been associated with the tumorigenic process of the bladder [5, 6]. In addition, with the application of high throughput technologies, such as cDNA microarrays, there is an ongoing effort to better understand the tumorigenic process of the bladder and to identify subsets of genes that can improve diagnosis, prognosis and treatment of the disease [7, 8].…”

Dose and temporal effects on gene expression profiles of urothelial cells from rats exposed to diuron

“…Our examination of the genome-wide transcriptional response of the rat urothelium after short-term exposure to diuron demonstrated a dose-response relationship in terms of the number of transcriptionally-altered genes. Major functions associated with these deregulated genes included those involved in cell-to-cell interactions and tissue disorganization, which play a critical role in urinary bladder carcinogenesis (Sanchez-Carbayo et al, 2003;Williams and Stein, 2004), and therefore may reflect early events associated with diuron-associated cytotoxicity. Data gathered by the present study suggest that after 7 days of exposure, 125 ppm may be considered the no observable adverse effect level (NOAEL) of diuron for both morphological and transcriptional changes.…”

Antrodia camphorata extract induces replicative senescence in superficial TCC, and inhibits the absolute migration capability in invasive bladder carcinoma cells

“…Many molecular and genetic changes in TCC of the bladder have exploded, which include (1) chromosomal alternations leading to carcinogenesis, e.g. mutations (point and insertional/deletional), translocation, and loss of alleles, each insult may effect the translated protein products; oncogenes such as c-H-ras, c-myc, and c-erB-2 are believed to be categorized in this event, (2) loss of cell cycle regulation accounting for tumor cell proliferation, several tumor suppressor genes (TSGs) acting at the G 0 /G 1 check point of the cell cycle are now recognized, and their protein products -p53, pRb, p16 and p14 -are vital for preventing cell cycle progression in bladder tumors: inactivation of the Rb gene or increased p53 immunoreactivity has been found in higher grade and stage bladder cancers, which is associated with the disease progression, and the overall and disease-specific survival rates, but these two proteins act in an independent yet synergistic manner in patients with bladder cancers, and (3) metastasis guided by events such as angiogenesis and loss of cell adhesion (Williams and Stein, 2004). This varied presentation results in widely divergent clinical outcomes.…”