Monday, May 29, 2023

Telocytes and ezrin expression in normal-appearing tissues adjacent to urothelial bladder carcinoma as predictors of invasiveness and recurrence – Scientific Reports

Urinary bladder cancer (BC) represents 3.0% of all newly diagnosed cancer cases each year which represents 573,000 worldwide in 2020, with 440,864 males and 132,414 females, with 212,536 new deaths and it accounts for 2.1% of all cancer deaths1. The global age-standardized incidence rate (per 100,000 person/year) is 9.5 in men and 2.4 in women1,2.

More than 80% of patients with BC present with non-muscle invasive bladder cancer (NMIBC) confined to the mucosa such as noninvasive papillary carcinoma (stage pTa) and carcinoma in situ (stage pTis) or involving the submucosa; (stage pT1), with urothelial blabber carcinoma (UBC) the most frequent histological subtype. Patients with NMIBC have long-term survival and a lower risk of cancer-specific mortality in many cases compared to patients with muscle-invasive bladder cancer (MIBC) in the pT2-4 stages3.

The treatment modalities for BC rely on the nature of the tumor specimen, and the status of the adjacent normal-appearing mucosa as determined by cystoscopic appearances and light microscopy4,5. Management of NMIBC includes transurethral resection of the visible bladder tumor (TURBT), with or without intravesical instillation of bacillus Calmette-Guérin (BCG), to prevent recurrence and progression. MIBC is treated with cystectomy and neoadjuvant or adjuvant chemotherapy. However, NMIBC has a high risk of recurrence (about 25% of cases) and progression to MIBC, which is associated with a high risk of metastases and mortality3,6.

Diagnosis of BC is based on the TURBT findings of the lesion visible during cystoscopy examination with or without biopsy of adjacent normal-appearing mucosa6. Although still controversial, mapping biopsies from the normal-appearing mucosa during cystoscopy are recommended especially in cases of positive urine cytology or non-papillary tumors, or high-grade lesions, to exclude concurrent CIS which would change the postoperative therapy and follow‐up schedule6,7. In this study we characterized these adjacent normal-looking biopsies that were located 2–5 cm from the original tumor.

In patients with NMIBC at first diagnosis, the normal-appearing mucosa is often the site of recurrence and cancer progression during follow-up after BCG instillation. Recurrence arises in these sites with the same or higher grade. So, normal-appearing bladder tissues in MIBC and high-risk NMIBC harbor cancerous potentials6,7,8. As a result, there is a critical need for additional biomarkers that can predict the risk of recurrence and progression in patients with early-stage tumors.

Telocytes (TCs) are special stromal cells present in various organs and tissues that play an important role in cell communication via membrane-to-membrane linkage. They form a network through interconnecting long thin cytoplasmic processes called telopodes (Tps) which are 20–80 μm monofilament prolongations that emerge from a small oval cell body9. They express CD117 (c-Kit), CD34, and PDGF, but none of these markers are specific immunohistochemical markers. Transmission electron microscopy (TEM) is the specific method for identifying TCs. They can be subtyped into different phenotypes based on their ultrastructural and immunohistochemical properties10,11. They have a distinct role in tissue regeneration, regulation of immune response, as well as the regulation of cell adhesion and the cytoskeleton in tumor stromal remodeling and progression12,13,14,15.

Ezrin is a protein that regulates cell networks by linking the membrane proteins and the actin filaments of the cytoskeleton. It is a member of the ERM family of proteins (ezrin, radixin, and moesin). These proteins contribute to the tumorigenesis of many cancer types by affecting cell survival, migration, and invasion16,17.

Accordingly, this study was conducted to investigate the expression of c-Kit + TCs and characterize their morphology and distribution, as well as to evaluate the expression of ezrin in the normal-appearing bladder tissues adjacent to the UBC to explore their potential as predictors of progression and recurrence of the tumor.

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