Metabolomic Profiling Reveals Potential Markers and Bioprocesses Altered in Bladder Cancer Progression

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 24; pp. 7376 - 7386
• Main Authors: PUTLURI, Nagireddy, SHOJAIE, Ali, SANDA, Theodore R, FISCHER, Steven M, SICA, Gabriel, BRAT, Daniel J, HUIDONG SHI, PALAPATTU, Ganesh S, LOTAN, Yair, WEIZER, Alon Z, TERRIS, Martha K, SHARIAT, Shahrokh F, VASU, Vihas T, MICHAILIDIS, George, SREEKUMAR, Arun, VAREED, Shaiju K, NALLURI, Srilatha, PUTLURI, Vasanta, THANGJAM, Gagan Singh, PANZITT, Katrin, TALIMAN, Christopher T, BUTLER, Charles
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.12.2011
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic agents; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; Biological and medical sciences; Biomarkers, Tumor - urine; Blotting, Western; Cell Line, Tumor; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1A1 - metabolism; Cytochrome P-450 CYP1B1; Disease Progression; DNA Methylation; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mass Spectrometry; Medical sciences; Metabolomics - methods; Middle Aged; Neoplasm Staging; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Promoter Regions, Genetic - genetics; Reverse Transcriptase Polymerase Chain Reaction; Tumors; Tumors of the urinary system; Urinary Bladder - metabolism; Urinary Bladder - pathology; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - urine; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; Young Adult; Metabolomics; Urinary system disease; Metabonomics; Tumor progression; Biological marker; Bladder disease; Urinary tract disease; Malignant tumor; Bladder cancer; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-11-1154

Although alterations in xenobiotic metabolism are considered causal in the development of bladder cancer, the precise mechanisms involved are poorly understood. In this study, we used high-throughput mass spectrometry to measure over 2,000 compounds in 58 clinical specimens, identifying 35 metabolites which exhibited significant changes in bladder cancer. This metabolic signature distinguished both normal and benign bladder from bladder cancer. Exploratory analyses of this metabolomic signature in urine showed promise in distinguishing bladder cancer from controls and also nonmuscle from muscle-invasive bladder cancer. Subsequent enrichment-based bioprocess mapping revealed alterations in phase I/II metabolism and suggested a possible role for DNA methylation in perturbing xenobiotic metabolism in bladder cancer. In particular, we validated tumor-associated hypermethylation in the cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) promoters of bladder cancer tissues by bisulfite sequence analysis and methylation-specific PCR and also by in vitro treatment of T-24 bladder cancer cell line with the DNA demethylating agent 5-aza-2'-deoxycytidine. Furthermore, we showed that expression of CYP1A1 and CYP1B1 was reduced significantly in an independent cohort of bladder cancer specimens compared with matched benign adjacent tissues. In summary, our findings identified candidate diagnostic and prognostic markers and highlighted mechanisms associated with the silencing of xenobiotic metabolism. The metabolomic signature we describe offers potential as a urinary biomarker for early detection and staging of bladder cancer, highlighting the utility of evaluating metabolomic profiles of cancer to gain insights into bioprocesses perturbed during tumor development and progression.