Abstract
Simple SummaryThis is a novel description of (Pro)renin receptor (PRR) protein and its prognostic role in invasive urothelial cancer of the bladder. Using a tissue microarray, we investigated PRR expression and other immunohistochemical markers including p53, immune-checkpoint inhibition, and basal and luminal phenotypes in a series of patients with invasive urothelial carcinoma of the bladder treated with radical cystectomy. PRR expression is an independent prognostic marker and could be a potential target in urothelial carcinoma that should be further investigated.(Pro)renin receptor (PRR) is being investigated in several malignancies as it activates pathogenic pathways that contribute to cell proliferation, immunosuppressive microenvironments, and acquisition of aggressive neoplastic phenotypes. Its implication in urothelial cancer (UC) has not been evaluated so far. We retrospectively evaluate the prognostic role of PRR expression in a series of patients with invasive UC treated with radical cystectomy and other clinical and histopathological parameters including p53, markers of immune-checkpoint inhibition, and basal and luminal phenotypes evaluated by tissue microarray. Cox regression analyses using stepwise selection evaluated candidate prognostic factors and disease-specific survival. PRR was expressed in 77.3% of the primary tumors and in 70% of positive lymph nodes. PRR expression correlated with age (p = 0.006) and was associated with lower preoperatively hemoglobin levels. No other statistical association was evidenced with clinical and pathological variables (gender, ASA score, Charlson comorbidity index, grade, pT, pN) or immunohistochemical expressions evaluated (CK20, GA-TA3, CK5/6, CD44, PD-L1, PD-1, B7-H3, VISTA, and p53). PRR expression in primary tumors was associated with worse survival (log-rank, p = 0.008). Cox regression revealed that PRR expression (HR 1.85, 95% CI 1.22–2.8), pT (HR 7.02, 95% CI 2.68–18.39), pN (HR 2.3, 95% CI 1.27–4.19), and p53 expression (HR 1.95, 95% CI 1.1–3.45) were independent prognostic factors in this series. In conclusion, we describe PRR protein and its prognostic role in invasive UC for the first time. Likely mechanisms involved are MAPK/ERK activation, Wnt/β-catenin signaling, and v-ATPAse function.
Highlights
Urinary bladder cancer is the most prevalent genitourinary malignancy in industrialized countries, with more than half a million new diagnoses and approximately 200,000 deaths worldwide per year [1]
Despite the plethora of urothelial cancer (UC) prognostic markers identified in the last decades, there is still a role for definition of new tumor markers in this prevalent and serious malignancy
The prognostic role of PRR protein in different neoplasia is being currently investigated. We confirm this novel tumor marker could be of primary importance in UC, as different patterns of IHC expression of PRR define disease-specific survival in UC treated with radical cystectomy
Summary
Urinary bladder cancer is the most prevalent genitourinary malignancy in industrialized countries, with more than half a million new diagnoses and approximately 200,000 deaths worldwide per year [1]. There is a need for novel biomarkers to improve the utility of prediction tools for bladder cancer in an era in which novel immunotherapy is developing [4]. Immunotherapies with immune checkpoint inhibitors targeting the programmed death-1 (PD-1) receptor or its ligand (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) have demonstrated a role after failure of cisplatin-based chemotherapy, but the majority of the patients do not respond to this strategy [5], and biomarkers to predict patients who could benefit from checkpoint targeting therapy are presently lacking [6]. The role of chemokines as modulators of tumor angiogenesis and their potential as therapeutic targets is currently under investigation [7,8]
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