# A Serum Metabolomic Signature for the Detection and Grading of Bladder Cancer
## 4 Discussion
Moreover, because lactic acid production increases in many hypoxic conditions, it promotes the IL-8-driven angiogenesis [41]. Neo-angiogenesis supports neoplasm growth by supplying cells with increased nutrients and oxygen. Another Warburg-related effect illustrated by the BC serum metabolomic signature is the lower glutamine and citric acid levels in BC patients: indeed, it could be considered a \"glutamine addiction\" [42]. The conversion of pyruvate to lactate by LDH drastically decreases acetyl-CoA production that is crucial in cancer to produce the fatty acids needed to build the new cell membranes. For this reason, the bypass of the TCA is often not complete in many cancer cells. Indeed, pyruvate from glycolysis could enter in a truncated TCA cycle that ends as citrate which is shuttled from the mitochondria to the cytosol (see Figure 5). This is a survival strategy to ensure enough acetyl-CoA for fatty acid synthesis. This truncated TCA cycle results in a build-up of metabolites that need to be countered. In bladder cancer, as  
Figure 5: Metabolic representation of Warburg-related modifications in a typical bladder cell which could explain the metabolic perturbations observed in the analyzed serum samples. Blu lines represent reactions generally slower in cancer cells, while red lines reaction generally faster. Orange squares indicated metabolite increased in our bladder cancer cohort, while purple squares indicated metabolites showing lower concentrations in bladder cancer patients. Abbreviations: GLUT = Glucose Transporter; MCT = Monocarboxylate transporter; DHAP = Dihydroxyacetone phosphate; GAP = Glyceraldehyde-3-phosphate. well in other cancers, glutamine solves this issue. Glutamine is converted to glutamate and then to a-ketoglutarate, a TCA intermediate [31]. [PERSON] et al. [43] found, although glucose is the precursor for >90% of secreted lactate in cancer cells, oxidative conversion of glutamine accounts for as much as 40% of TCA cycle intermediates and 30% of the generated energy. This leads to a great glutamine consumption by cancer cells, which could explain the lower glutamine levels found in our BC patients. Several studies have shown that different methods are able to identify the metabolomic profiles of BC from cell lines, tissues, urine or serum [44]. Of these, [PERSON] et al. [45] developed a plasma pseudotargeted metabolomic method based on GC-MS-SIM to study the plasma metabolic profile of BC patients, wherein, they showed alterations in the pentose phosphate pathway (PPP) and nucleotide and fatty acid synthesis. [PERSON] et al. [46] examined changes in the urinary metabolome of NMIC patients before and after TURBT using liquid chromatography combined with time of flight mass spectrometry, revealing perturbed phenylalanine, arginine, proline, and tryptophan metabolisms as putative biomarkers of recurrence risk. Urinary metabolic changes of BC patients were also studied using gas chromatography-mass spectrometry by [PERSON] et al. [47]. Although our study differed by biological matrix, a slightly older population, and no information about genetic background or food habits were reported, a few comparisons are appropriate. Metabolites 2-hydroxy-3-methyl pentanoic, aminomalonic, glyceric, glycolic, hippuric, and lactic acid as well as glycerol, glycine, phosphate, threonine, and xylose showed different mean concentrations in CTRL and BC patients in both studies. Conversely, aspartic, galactonic, glutamic, oxalic, stearic, and tartaric acid as well as creatinine, galactose, lactose, ornithine, phenylalanine, proline, uridine, and valine concentrations were significantly different between our CTRL and BC samples. This difference was not seen in the urinary signature reported by [PERSON] et al. [47]. [PERSON] et al. [48], compared urine samples from early stage BC patients versus late-stage BC patients.