Scientific Facts

Clinical and Scientific Background

Bladder cancer (BC) is among the most common and costliest malignancies worldwide1. Although the majority of BC cases are non-

muscle invasive (NMIBC), BC is characterized by high recurrence (~70%) and progression rates (10-20%) to muscle-invasive disease

(MIBC)2-4. As such, NMIBC patients undergo life-long surveillance through invasive cystoscopy. Based on the guidelines, different

treatment schemes are recommended for NMIBC5 and MIBC6. High-grade NMIBC patients are treated with Bacillus Calmette-Guérin

(BCG) immunotherapy or intravesical instillation of mitomycin-C/epirubicin (chemotherapy)5, while MIBC patients undergo radical

cystectomy6. Extensive genomic characterization of BC revealed high tumor heterogeneity indicating the existence of distinct disease

molecular subtypes7,8. In fact, growing evidence suggests that BC represents a group of heterogeneous diseases, both molecularly

and clinicopathologically9,10.

As novel therapeutic interventions for BC are on the rise, including immune checkpoint inhibitors targeting Programmed cell Death

(PD)-1 receptor and its ligand PD-L1,  as well as cytotoxic T-lymphocyte-associated Protein 4 (CTLA4), guiding intervention

through the stratification of BC patients according to the risk for relapse and/or also according to the predicted drug response

becomes even more critical in the selection of optimal treatment approach. Therefore, complementary biomarkers are still needed to

improve prognostic certainty and guide clinical intervention.

 

Urinary Analysis - Mass Spectrometry

Urine has been already recognized as an exceptional source of biomarkers, due to the high stability of the proteome and non-invasive

means of collection17. Moreover, urinary peptides carry substantial information not only for on-site but also for systemic events that

are related to BC and depict molecular changes linked to disease pathophysiology e.g. tumor invasion and inflammation.

Mass spectrometry-derived (CE-MS) urinary profiling data have been previously explored for detection of BC18 as well as

discrimination of non- from muscle-invasive form of BC19. More recently, two diagnostic panels, based on the same technology, were

published for BC detection (BC-116) and monitoring of recurrence (BC-106)20. In the latter, the urinary profiles were also indicative

of disease molecular changes during BC progression.

Mass spectrometry has been already applied for acquiring BC specific proteomics and metabolomics profiling data and several

prognostic markers based on proteomics and metabolomics studies have been reported in the literature, highlighting the value of

omics features in improving BC management. Urine and serum proteomic-based biomarkers, like SPARC26, SH3 domain binding

glutamic acid-rich protein like 3 (SH3BGRL3)27 have been recently reported as prognostic markers for BC. For instance,

according to recent metabolomics studies, i.e. in a first study investigating metabolic profiles of smokers and non-smokers with

BC outcome28, catechol-O-methyltransferase (COMT), iodotyrosine deiodinase (IYD),  tubulin tyrosine ligase (TTL) were

correlated with BC survival, while in a study investigating population-based metabolic differences associated with BC29, high

expression of  lysine demethylase 2A (KDM2A) and prolyl 3‐hydroxylase 2 (P3H2) and low expression of mitochondrial malic

enzyme 3 (ME3) was correlated with poor survival of African American BC patients.

 

New results from BioMedBC Study

In BioMedBC study, a 36-peptide model is sufficient to embrace the heterogeneity of BC patients and forecast an accurate prognosis.

Among the 36 peptides, the majority of sequenced peptides originated from multiple collagen fragments (mainly collagen alpha-1)

and were found associated with both, good and poor prognosis depending on a specific sequence. Based on the literature and our

previous CE-MS studies, collagen increase and decrease are both involved in tumor progression20,30, as collagen initially acts as a

barrier and collagenases, such as metalloproteinases (MMPs) degrade it to expose active sites and promote a pro-tumorigenic

microenvironment to facilitate tumor progression. Collagen cross-linking and thickening is then necessary during extracellular matrix

(ECM) remodeling and invasion. Elevated levels of urinary fibrinogen have already been reported in BC patients and associated with

tumor invasiveness20,31. As such, the presence of the FGA among the peptides with high prognostic value is further confirming its

association with the disease. Increased levels of PIGR were also found associated with a higher risk of relapse. PIGR is a member of

the immunoglobulin superfamily, involved in transcytosis of IgA and other immune complexes. Transcription factor forkhead box

protein D2 (FOXD2) was found related to poor prognosis. Additionally, nuclear FOXOs are known to mediate cell cycle arrest and

promote apoptosis34. With regards to BC, a recent analysis of long non-coding RNAs linked high FOXD2-AS1 expression to BC

progression and recurrence by acting on Act/E2F1 axis35. Among the peptides indicative of good prognosis and lower risk of BC

relapse was CD99 antigen (CD99), which in line with the reports suggesting it’s oncosuppressive role in BC36,37.

 

 

References

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3          Schrier, B. P., Hollander, M. P., van Rhijn, B. W., Kiemeney, L. A. & Witjes, J. A. Prognosis of muscle-invasive bladder cancer: difference between primary and progressive tumours and implications for therapy. European urology 45, 292-296, doi:10.1016/j.eururo.2003.10.006 (2004).

4          Inamura, K. Bladder Cancer: New Insights into Its Molecular Pathology. Cancers 10, doi:10.3390/cancers10040100 (2018).

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BioMedBC is a Marie Sklodowska Curie Actions (MSCA) Individual Fellowship programme (H2020-MSCA-IF-2016)
funded by the European Union under the Horizon2020 Framework Programme (Grant Agreement:752755) and
coordinated by Mosaiques diagnostics