P2X1 and P2X7 Receptor Overexpression Is a Negative Predictor of Survival in Muscle-Invasive Bladder Cancer

SIMPLE SUMMARY: Bladder cancer is one of the most common malignancies. The prognosis is particularly poor for advanced cancer. There is a need for new prognostic markers to guide treatment decisions and promote the development of novel therapeutic strategies to increase the success rate of current treatment regimens. The tumor microenvironment is characterized by an increase in extracellular ATP levels. ATP-recognizing P2X receptors have been implicated in the growth and metastasis of various malignant cancers. Here, we analyzed the potential of different P2X receptor subtypes as prognostic markers in muscle-invasive bladder cancer. In vitro experiments confirmed a growth-promoting effect of extracellular ATP and P2X receptors on bladder cancer cells. In agreement, our analyses of cancer tissue samples from 173 patients showed that expression of P2X1 and P2X7 receptors is an independent negative predictor of survival and a potential therapeutic target in muscle-invasive bladder cancer. ABSTRACT: Bladder cancer is amongst the most common causes of cancer death worldwide. Muscle-invasive bladder cancer (MIBC) bears a particularly poor prognosis. Overexpression of purinergic P2X receptors (P2XRs) has been associated with worse outcome in several malignant tumors. Here, we investigated the role of P2XRs in bladder cancer cell proliferation in vitro and the prognostic value of P2XR expression in MIBC patients. Cell culture experiments with T24, RT4, and non-transformed TRT-HU-1 cells revealed a link between high ATP concentrations in the cell culture supernatants of bladder cell lines and a higher grade of malignancy. Furthermore, proliferation of highly malignant T24 bladder cancer cells depended on autocrine signaling through P2X receptors. P2X1R, P2X4R, and P2X7R expression was immunohistochemically analyzed in tumor specimens from 173 patients with MIBC. High P2X1R expression was associated with pathological parameters of disease progression and reduced survival time. High combined expression of P2X1R and P2X7R increased the risk of distant metastasis and was an independent negative predictor of overall and tumor-specific survival in multivariate analyses. Our results suggest that P2X1R/P2X7R expression scores are powerful negative prognostic markers in MIBC patients and that P2XR-mediated pathways are potential targets for novel therapeutic strategies in bladder cancer.