Metabolomics analysis reveals distinct profiles of nonmuscle‐invasive and muscle‐invasive bladder cancer

Abstract

Urothelial carcinoma is the most common form of bladder cancer, but pathway changes that occur with stage‐wise progression have not been well defined. We used a metabolomics approach to identify potential metabolic pathways uniquely altered in normal urothelium, nonmuscle‐invasive bladder cancer (NMIBC), and muscle‐invasive bladder cancer (MIBC). We performed global metabolomic profiling using GC‐mass spectrometry (MS) and LC‐MS platforms to identify metabolite signatures between normal urothelium and high‐grade urothelial carcinoma of different stages. Pathways globally dysregulated in cancer relative to normal urothelium included glucose, tricarboxylic acid (TCA) cycle, lipid, amino acid, and nucleotide pathways. Urothelial carcinoma showed elevated glucose utilization for glycolysis and increased sorbitol pathway intermediates, consistent with Warburg effect. Anaplerosis to sustain energy production suggested by increased late TCA cycle intermediates, amino acids, and dipeptides occurs in bladder cancer. Urothelial carcinoma also shows altered membrane lipid membrane metabolism and differential derivation of nucleic acid components pyrimidine and purine. In stage comparison, MIBC appears to preferentially enhance cyclooxygenase (COX) and lipoxygenase (LOX) signaling, increase heme catabolism, and alter nicotinamide adenine dinucleotide (NAD+) synthesis with a possible influence from associated inflammatory cells. We identify numerous metabolomic alterations in NMIBC and MIBC that likely reflect underlying pathway changes. Differential pathway activity may have value in designing stage‐specific novel therapeutics in urothelial carcinoma.

UPLC-MS based urine untargeted metabolomic analyses to differentiate bladder cancer from renal cell carcinoma

“…The COX and LOX pathways are closely associated with a function of inflammatory cell regulation, tumorigenesis, cell proliferation, and angiogenesis. Our results were supported by a previous metabolomic analysis of urothelial carcinoma 35 , illustrating a hyperactive tumor metabolism and the consequent inflammtion.…”

“…enrolled 96 samples(including 72 urothelial carcinoma patients and 24 normal patients) and analysed their differential metabolites by performing UHPLC-MS/MS. As a result, both the purine and the puring metabolites were increased in urothelial cancer, suggesting the accelerated synthesis and degradation of nucleotides 35 . In a meta-analysis of 11 articles, the levels of guanine, cytosine, thymine, hypoxanthine, uracil and ribose were found eleveted in the urine of BC patients, indicating a higher level of nucleotide metabolism 36 .…”

Label‐free grading and staging of urothelial carcinoma through multimodal fibre‐probe spectroscopy

“…These bands include Raman peaks typically associated with the presence of amino acids (such as tryptophan and phenylalanine), nucleic acids, amide II and III, lipids and proteins (such as collagen). Although the presented approach is not able to quantitatively assess the spectral contribution of each molecular component, our results seem to reflect the altered metabolism of UC, which is characterised by higher levels of amino acids and by an increased production in the majority of lipid classes with respect to healthy bladder. We found a linear combination of PCs for discriminating normal and tumour biopsies with 95% specificity, 87% sensitivity and 95% accuracy.…”

Malignancy Grade-Dependent Mapping of Metabolic Landscapes in Human Urothelial Bladder Cancer: Identification of Novel, Diagnostic, and Druggable Biomarkers

“…Malignant hallmarks, such as cell survival under stress conditions, as well as tumors' ability to utilize nutrients and successfully encounter high-energy demands, are tightly correlated with metabolic alterations, thus indicating the major roles of metabolic landscapes in Cancer Biology [11][12][13][14]. Metabolic activities may significantly differ among distinct subtypes or malignancy grades/stages of the same type of cancer, leading to different metabolic networks and metabolomes [15,16]. Metabolomics has gained great value, power, and importance for cancer research, not only as a multifaceted tool in early diagnosis, but also as a valuable platform for the discovery of novel mechanisms controlling tumorigenesis, thus paving the way to new treatment strategies and therapies.…”

“…Research on several cancers has significantly profited from the engagement of metabolomics technology. However, its application to early detection, progression, and the chemotherapeutic management of human malignancies and especially UBC remains still limited, and it needs to be further expanded [15][16][17][18][19][20].…”