Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity

Abstract

Correspondence to M.A.K. m.a.knowles@leeds.ac.uk 2 Preface Urothelial carcinoma of the bladder comprises two long-recognised disease entities with distinct molecular features and clinical outcome. Low-grade, non-muscle-invasive tumours recur frequently but rarely progress to muscle invasion, whereas muscle invasive tumours are usually diagnosed de novo and frequently metastasize. Recent genome-wide expression and sequencing studies identify genes and pathways that are key drivers of urothelial cancer and reveal a more complex picture with multiple molecular subclasses that cut across conventional grade and stage groupings. This improved understanding of molecular features, disease pathogenesis and heterogeneity provides new opportunities for prognostic application, disease monitoring and personalised therapy.Bladder cancer is the most common cancer of the urinary tract with approximately 380,000 new cases and 150,000 deaths per year worldwide 1 . It ranks fifth among cancers in men in Western countries.Epidemiological studies identify a range of environmental risk factors, many of which reflect exposure to excreted carcinogenic molecules (BOX 1). Recent genome-wide association studies have also identified germline variants that contribute to risk 2 .In Europe and North America, more than 90% of bladder cancers are urothelial carcinoma. These tumours are staged using the Tumour Nodes Metastasis (TNM) system 3 , which describes the extent of invasion (Tis-T4), and graded according to their cellular characteristics. Two classification systems are in current use 4, 5 .At diagnosis the majority of bladder cancers (~ 60%) are non-muscle-invasive (NMIBC) (stage Ta) NMIBCs frequently recur (50-70%) but infrequently progress to invasion (10-15%) 6 and five-year survival is ~90%. These patients are monitored by cystoscopy and may have multiple resections over many years.Improved monitoring is needed, ideally via urine analysis, which could reduce the morbidity and costs associated with cystoscopy. Although risk tables provide a prognostic tool 7 , no molecular biomarkers accurately predict disease progression. For these patients, localised therapies to remove residual neoplastic and preneoplastic cells post-resection may have major impacts on both quality of life and in health economic terms. MIBCs (>stage T2) have less favourable prognosis with five-year survival <50% and common progression to metastasis (BOX1). Treatment has not advanced for several decades and new approaches to systemic therapy are needed 8 .Improved treatment requires detailed understanding of urothelial carcinoma pathogenesis and molecular biology. A model has evolved, taking into account both histopathological and molecular features. This socalled 'two-pathway' model proposes that papillary NMIBC develops via epithelial hyperplasia and recruitment of a branching vasculature. MIBCs are proposed to develop via flat dysplasia and carcinoma in situ (CIS). The molecular characteristics of MIBC and NMIBC are highly distinct (Tables 1 and 2). Whilst 3 m...

Upregulated GAPLINC predicts a poor prognosis in bladder cancer patients and promotes tumor proliferation and invasion

“…Approximately 75% of the cases are non-muscle-invasive bladder cancer (NMIBC), which commonly recurs but rarely progresses. However, the remaining cases are muscle-invasive bladder cancer (MIBC), which have a worse prognosis and ultimately endanger the lives of patients (3,4). At present, little is known regarding the molecular mechanisms of bladder cancer, and no sensitive prognostic biomarker has been identified (5).…”

On Molecular Classification of Bladder Cancer: Out of One, Many

“…Working toward this goal, we and others have devised molecular stratification systems for UBC based on tumor mRNA expression patterns [4][5][6]. A recent comprehensive review has provided an excellent summary of the current state of knowledge of UBC biology [7]. Until recently however, the existing classification systems for UBC had not been simultaneously evaluated in independent data.…”

Evaluation of in vitro Antioxidant and Anticancer Activity of Simarouba glauca Leaf Extracts on T-24 Bladder Cancer Cell Line

“…1 Although endoscopic transurethral resection of bladder (TURB) is often performed as the primary therapy, 50-70 percent of patients have a recurrence within five years and approximately 20 percent progress to invasive disease. 2 The current treatment options like hormone therapy, radiotherapy, chemotherapy are into practice, but severe side effects limit its clinical use and underscore the need for unconventional therapies using less toxic substances.…”