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Robo 4 - the double-edged sword in prostate cancer: impact on cancer cell aggressiveness and tumor vasculature

2019; Ivyspring International Publisher; Volume: 16; Issue: 1 Linguagem: Inglês

10.7150/ijms.28735

1449-1907

Andreas Pircher, Georg Schäfer, Andrea Eigentler, Renate Pichler, Martin Puhr, Eberhard Steiner, Wolfgang Horninger, Eberhard Gunsilius, Helmut Klocker, Isabel Heidegger,

Wnt/β-catenin signaling in development and cancer

Background:The magic roundabout receptor 4 (Robo 4) is a tumor endothelial marker expressed in the vascular network of various tumor entities.However, the role of Robo 4 in prostate cancer (PCa), the second common cause of cancer death among men in -developed countries, has not been described yet.Thus, the present study investigates for the first time the impact of Robo 4 in PCa both in the clinical setting and in vitro.Methods and Results: Immunohistochemical analyses of benign and malignant prostate tissue samples of 95 PCa patients, who underwent radical prostatectomy (RPE), revealed a significant elevated expression of Robo 4 as well as its ligand Slit 2 protein in cancerous tissue compared to benign.Moreover, increased Robo 4 expression was associated with higher Gleason score and pT stage.In advanced stage we observed a hypothesis-generating trend that high Robo 4 and Slit 2 expression is associated with delayed development of tumor recurrence compared to patients with low Robo 4 and Slit 2 expression, respectively.In contrast to so far described exclusive expression of Robo 4 in the tumor vascular network, our analyses showed that in PCa Robo 4 is not only expressed in the tumor stroma but also in cancer epithelial cells.This finding was also confirmed in vitro as PC3 PCa cells express Robo 4 on mRNA as well as protein level.Overexpression of Robo 4 in PC3 as well as in Robo 4 negative DU145 and LNCaP PCa cells was associated with a significant decrease in cell-proliferation and cell-viability.Conclusion: In summary we observed that Robo 4 plays a considerable role in PCa development as it is expressed in cancer epithelial cells as well as in the surrounding tumor stroma.Moreover, higher histological tumor grade was associated with increased Robo 4 expression; controversially patients with high Robo 4 tend to exert lower biochemical recurrence possibly reflecting a protective role of Robo 4.