(13)C Natural Isotope Abundance in Urothelium as a New Marker in the Follow-Up of Patients with Bladder Cancer

SIMPLE SUMMARY: Bladder cancer (BC) is a common urological cancer and has a high incidence of recurrence. Metabolic changes are one of the hallmarks of cancer. Differences in metabolic pathways between normal and cancerous tissues lead to a heterogeneous distribution of natural isotope abundance. We analyzed the isotope ratio of carbon, nitrogen, and sulfur in normal urothelium and bladder cancer samples and correlated these data with clinical parameters. We found that bladder cancers are (13)C- and (15)N-depleted when compared to normal urothelium. Furthermore, decreased (13)C abundance in normal urothelium is correlated with shorter disease-free survival in bladder cancer patients. Determination of the isotopic signature of normal and cancerous bladder biopsies can provide important information about the risk of recurrence and improve patients’ management by avoiding invasiveness and unnecessary diagnostic procedures such as cystoscopy. ABSTRACT: Bladder cancer (BC) is the most common urological malignancy and has a high incidence of recurrence. BC cells alter their nutrient uptake and metabolic pathways in order to continue the production of sufficient levels of ATP and metabolic intermediates for proliferation and survival. Changes in metabolic pathways regarding the rate of the enzymatic reaction and transport lead to differences in the content of natural isotopes ((13)C, (15)N, (34)S) between normal and cancerous tissues. The assessment of the stable isotopes of carbon, nitrogen, and sulfur in normal urothelium and bladder cancer samples was performed using Isotope Ratio Mass Spectrometry (IRMS). The natural abundance of (15)N and (13)C was decreased in bladder cancer samples when compared to normal urothelium. No significant correlation was observed in BC specimens depending on the tumor grade and stage. Samples derived from bladder tumors and normal urothelium had a different pattern of (15)N and (13)C isotope abundance. Decreased (13)C natural isotopes in the normal urothelium of BC patients were significantly associated with a shorter DFS. Our results suggest that isotopic analysis of normal urothelium of BC patients can be used to predict bladder cancer recurrence.