Abstract
The mechanisms of bladder cancer progression are unknown, and new treatments and biomarkers are needed. Patient urinary extracellular vesicles (EVs) derive in part from bladder cancer cells and contain a specific protein cargo which may provide information about the disease. We conducted a proteomics study comparing EVs from the muscle-invasive bladder cancer (MIBC) cell line TCCSUP to EVs from normal urothelial line SVHUC. GO term analysis showed that TCCSUP EVs are enriched in proteins associated with the cell membrane, extracellular matrix, and inflammation and angiogenesis signaling pathways. Proteins characteristic of cancer EVs were further screened at the mRNA level in bladder cancer cell lines. In Western blots, three of six proteins examined showed greater than fifteenfold enrichment in patient urinary EVs compared to healthy volunteers (n = 6). Finally, we performed immunohistochemical staining of bladder tissue microarrays for three proteins of interest. One of them, transaldolase (TALDO1), is a nearly ubiquitous enzyme and normally thought to reside in the cytoplasm. To our surprise, nuclei were stained for transaldolase in 94% of MIBC tissue samples (n = 51). While cytoplasmic transaldolase was found in 89–90% of both normal urothelium (n = 79) and non-muscle-invasive samples (n = 71), the rate falls to 39% in MIBC samples (P < 0.001), and negative cytoplasmic staining was correlated with worse cancer-specific survival in MIBC patients (P = 0.008). The differential EV proteomics strategy reported here successfully identified a number of proteins associated with bladder cancer and points the way to future investigation.
Highlights
Bladder cancer is the sixth most commonly diagnosed malignancy in the United States, resulting in an estimated 79,030 new patients and 16,870 deaths in 2017 [1]
While cytoplasmic transaldolase was found in 89–90% of both normal urothelium (n = 79) and non-muscle-invasive samples (n = 71), the rate falls to 39% in muscle-invasive bladder cancer (MIBC) samples (P < 0.001), and negative cytoplasmic staining was correlated with worse cancer-specific survival in MIBC patients (P = 0.008)
Bladder cancer extracellular vesicles (EVs) accumulate in the urine where they are stable and accessible, making them attractive subjects of study
Summary
Bladder cancer is the sixth most commonly diagnosed malignancy in the United States, resulting in an estimated 79,030 new patients and 16,870 deaths in 2017 [1]. More than 70% of newly diagnosed cases are non-muscle-invasive bladder cancer (NMIBC) [2, 3]. 25–30% of bladder cancer patients have more advanced, muscle-invasive disease (MIBC) at diagnosis [4]. More than 50% of MIBC patients (including those with more advanced disease) will develop metastatic disease, which in turn has only a 10% five-year survival rate. The high rate of recurrence, significant risk of disease progression, and need for continued surveillance make bladder cancer one of the most expensive cancers to treat and manage [5]
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