Molecular Pathogenesis and Diagnostics of Bladder Cancer

Abstract

Despite elaborate characterization of the risk factors, bladder cancer is still a major epidemiological problem whose incidence continues to rise each year. Urothelial carcinoma is now recognized as a disease of alterations in several cellular processes. The more prevalent, less aggressive, recurrent, noninvasive tumors are characterized by constitutive activation of the Ras-MAPK pathway. The less common but more aggressive invasive tumors, which have a higher mortality rate, are characterized by alterations in the p53 and retinoblastoma pathways. Several diagnostic tests have attempted to identify these molecular alterations in tumor cells exfoliated in the urine, whereas prognostic tests have tried to identify aberrations so as to predict tumor behavior and identify therapeutic targets. The future of bladder cancer patient management will rely on the use of molecular tests to reliably diagnose the presence of disease, predict individual tumor behavior, and suggest potential targeted therapeutics.

Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL

“…In superficial Ta bladder tumours, activation of Ras signalling is caused by gain-of-function mutations in HRAS, KRAS, NRAS and FGFR3. Although these mutations are less frequent in T 2 -T 4 bladder cancers, the RAS pathway seems to be affected in highstage tumours as well as by amplification/overexpression of different RTKs, including ERBB2 and ERBB1 (Knowles, 2008;Mitra and Cote, 2009). Two levels of Fra-1 upregulation via the RAS pathway, transcriptional and protein stabilisation, have been described previously (Casalino et al, 2003;.…”

“…Bladder cancer is the fifth most common cancer worldwide and patients with invasive disease have poor prognosis, with a 50% 5-year survival. The absolute majority of bladder tumours are classified as transitional cell carcinoma (TCC), which is divided into two types, superficial (75%) and muscle-invasive (25%) (Mitra and Cote, 2009). In many cases, muscleinvasive TCCs manifest metastatic features that represent the major cause of patient death.…”

Establishment and characterization of a bladder cancer cell line with enhanced doxorubicin resistance by mevalonate pathway activation

“…The fatal outcome results mainly from advanced muscle-invasive tumours progressing to metastatic disease; such tumours can develop either from flat dysplastic carcinoma in situ lesions or by progression of otherwise prognostically favourable superficial papillary tumours [2,3]. Two combination chemotherapeutic regimens dominate the systemic treatment of advanced urothelial carcinoma, with methotrexate, vinblastine, adriamycin and cisplatin (M-VAC) being more and more replaced by the comparably efficient but less toxic gemcitabine and cisplatin (GC) combination [4,5].…”

Novel targeted agents for the treatment of bladder cancer: translating laboratory advances into clinical application

“…Two distinct developmental pathways for bladder tumors have been characterized (17). The first is that of a noninvasive papillary lesion without penetration of the epithelial basement membrane (Ta tumor).…”

“…Aberrant expression of fibroblast growth factor receptor 3 (FGFR3), RAS and PIK3CA appear to play a critical role in the development of low grade and generally non-invasive bladder tumors (18). Approximately 20% of tumors are muscle invasive at diagnosis and the prognosis in these cases is poor, with less than 50% survival at 5 years (17). Tumors that penetrate the basement membrane (T1) or invade the bladder muscle (T2) are therefore much more clinically concerning and are associated with different biologic aberrancy, including common p53 mutations.…”