Abstract
Muscle-invasive bladder cancer (MIBC) is an aggressive malignancy with high mortality, and heterogeneity in MIBC results in variable clinical outcomes, posing challenges for clinical management. Extracellular vesicles (EVs) derived from MIBC have been shown to promote cancer progression. EVs derived from bladder cell lines were subjected to proteomic analysis, and periostin was chosen for further characterization due to its stage-specific gene expression profile. Knockdown of periostin by RNA interference reduces invasiveness in vitro and produces a rounder morphology. Importantly, treating low grade BC cells with periostin-rich EVs promotes cell aggressiveness and activates ERK oncogenic signals, and periostin suppression reverses these effects. These data suggest that MIBC might transfer periostin in an EV-mediated paracrine manner to promote the disease. To determine the potential of periostin as a bladder cancer indicator, patient urinary EVs were examined and found to have markedly higher levels of periostin than controls. In addition, immunohistochemical staining of a bladder cancer tissue microarray revealed that the presence of periostin in MIBC cells is correlated with worse prognosis. In conclusion, periostin is a component of bladder cancer cells associated with poor clinical outcome, and EVs can transfer oncogenic molecules such as periostin to affect the tumor environment and promote cancer progression.
Highlights
Bladder cancer is the seventh most common cancer in the world, with 74,000 cases estimated to have occurred in the United States in 2014 [1]
In the screening of Extracellular vesicles (EVs) proteins by mass spectrometry detailed in our recent study [7], periostin was found to be abundant in the EVs collected from Muscle-invasive bladder cancer (MIBC) cell line TCC-SUP and was not observed in the EVs of nonmalignant urothelial cell line SV-HUC
The stage-specific expression of POSTN mRNA in bladder cancer patient tissue samples was further examined in three published gene expression data sets aggregated by Oncomine at https://www. oncomine.org/
Summary
Bladder cancer is the seventh most common cancer in the world, with 74,000 cases estimated to have occurred in the United States in 2014 [1]. More than 70% of newly diagnosed bladder cancers are non-muscle-invasive invasive (NMIBC), designated as stages Ta, T1, and Tis, for which the mainstay of treatment is repeated transurethral resection of bladder tumor (TURBT); 50–70% of tumors recur. 25–30% of bladder cancer patients have a diagnosis of muscle-invasive (MIBC) disease, and more than 50% of MIBC patients develop metastatic disease. The high recurrence rate and high morbidity and mortality of bladder cancer make it one of the most burdensome cancers to manage and treat [3]. It is difficult to predict the outcome of such heterogeneous tumors, and this poses challenges for clinical management; new strategies are needed to catch the disease earlier, and biomarkers for monitoring disease status will aid in the development of new treatments
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