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

Abstract

While alterations in xenobiotic metabolism are considered causal in the development of bladder cancer (BCa), 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 BCa. This metabolic signature distinguished both normal and benign bladder from BCa. Exploratory analyses of this metabolomic signature in urine showed promise in distinguishing BCa from controls, and also non-muscle from muscle-invasive BCa. 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 BCa. In particular, we validated tumor-associated hypermethylation in the CYP1A1 and CYP1B1 promoters of BCa tissues by bisulfite sequence analysis and methylation-specific PCR, and also by in vitro treatment of T-24 BCa cell line with the DNA demethylating agent 5-aza-2′-deoxycytidine. Further, we showed that expression of CYP1A1 and CYP1B1 was reduced significantly in an independent cohort of BCa specimens compared to 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 BCa, highlighting the utility of evaluating metabolomic profiles of cancer to gain insights into bioprocesses perturbed during tumor development and progression.

Metabonomics studies on serum and urine of patients with breast cancer using 1H-NMR spectroscopy

“…Metabolomics methods could be used to monitor changes of specific metabolism in process of tumor development, to predict tumor progression, to monitor tumor response to intervention, to determining a characteristic metabolic pattern for cancer patients, to identify tumor associated biomarkers and to provide helps for early diagnosis, prognosis evaluation and efficacy analysis for cancer patients. Metabolomics has been successfully applied to biomarkers screening for many cancers, such as bladder [10], colon [11], lung [12] and prostate cancers [13]. However, metabolomics studies on breast cancer is rarely reported.…”

Lipid Metabolism Profiling and Bladder Cancer

“…These results suggest that β-oxidation may play an important role in BC tumorigenesis and possibly aggressiveness. Another study conducted by Putluri et al [20] also revealed that patients with BC have higher level of carnitine (Table 1).…”

Metabolomics for tumor marker discovery and identification based on chromatography–mass spectrometry

“…Although urine may be directly related to genitourinary malignancies, the study also indicated that the metabolic profiles in the serum may reflect tissue metabolites. In addition, there have been metabolomic studies on bladder cancer [89][90][91][92].…”