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

Abstract

Background: Urothelial bladder cancer (UBC) is one of the cancers with the highest mortality rate and prevalence worldwide; however, the clinical management of the disease remains challenging. Metabolomics has emerged as a powerful tool with beneficial applications in cancer biology and thus can provide new insights on the underlying mechanisms of UBC progression and/or reveal novel diagnostic and therapeutic schemes. Methods: A collection of four human UBC cell lines that critically reflect the different malignancy grades of UBC was employed; RT4 (grade I), RT112 (grade II), T24 (grade III), and TCCSUP (grade IV). They were examined using Nuclear Magnetic Resonance, Mass Spectrometry, and advanced statistical approaches, with the goal of creating new metabolic profiles that are mechanistically associated with UBC progression toward metastasis. Results: Distinct metabolic profiles were observed for each cell line group, with T24 (grade III) cells exhibiting the most abundant metabolite contents. AMP and creatine phosphate were highly increased in the T24 cell line compared to the RT4 (grade I) cell line, indicating the major energetic transformation to which UBC cells are being subjected during metastasis. Thymosin β4 and β10 were also profiled with grade-specific patterns of expression, strongly suggesting the importance of actin-cytoskeleton dynamics for UBC advancement to metastatic and drug-tolerant forms. Conclusions: The present study unveils a novel and putatively druggable metabolic signature that holds strong promise for early diagnosis and the successful chemotherapy of UBC disease.

Immunotherapy in Bladder Cancer: Current Methods and Future Perspectives

“…Occupational factors are considered the second most important risk factor for BC [3]. Workers exposed to aromatic amines, polycyclic aromatic hydrocarbons, tobacco and tobacco smoke, combustion products, and heavy metals are at an increased risk [4].…”

The LINC01929/miR-6875-5p/ADAMTS12 Axis in the ceRNA Network Regulates the Development of Advanced Bladder Cancer

“…Two conjectures accounted for the conflicting IHC results. DE between ADAMTS12 at the transcriptional and translational levels had been neglected before experimental design; T24, EJ, and 5637 cell lines were recently applied in studies exploring the invasive, progressive, and metastatic capabilities of advanced BCa, suggesting that they could be viewed as high-grade BCa cells (ACS-BCa) ( 45 – 47 ). This also supported the inconsistent expression of CDH11 in 5637, and COL6A1 in EJ and 5637, cell lines.…”

Exploratory Metabolomics Underscores the Folate Enzyme ALDH1L1 as a Regulator of Glycine and Methylation Reactions

“…It should be noted though that the link between the tumor grade and energy-related metabolic profiles is more complex. For example, a study of metabotypes of urothelial bladder cancer cell lines of different grades indicated that metabolic pattern for grade I cells (RT4) is more similar to grade IV (more advanced tumors) than grade III [ 24 ].…”

“…We have recently found a cancer cell line, RT4, expressing high levels of ALDH1L1. These cells were derived from a grade I urothelial carcinoma and they represent a low-grade bladder cancer [ 22 , 23 , 24 ]. Our previous [ 25 ] experiments confirmed presence of high levels of ALDH1L1 in these cells.…”