Prostate cancer tissues with positive TMPRSS2-ERG-gene-fusion status may display enhanced nerve density

Abstract

Innervation of prostate cancer (CaP) tissue favors tumor progression and metastasis but the regulation of innervation in CaP is unclear. The oncogenic transcription factor ERG is commonly induced by a typical TMPRSS2-ERG (TE) gene fusion in CaP and may affect innervation. Here, we analyzed whether nerve density of CaP tissue is related to TE status or perineural infiltration status of CaP tissue. In parallel, we measured several members of the neuropilin/plexin/semaphorin family (NRP, PLXN, and SEMA) as possible targets mediating innervation. The TE-gene-fusion status was determined at the mRNA level in CaP tissues by nested RT-PCR. Transcript levels were analyzed by quantitative RT-PCR in CaP tissue or cell line homogenate. ERG was analyzed by immunostaining, and the nerve density was evaluated by immunostaining for PGP9.5 and axonal neurofilament. Data were analyzed by correlation (Spearman), linear regression, Mann–Whitney U test, and contingency table analyses. TE-positive (TE-1) vs. TE-negative (TE-0) CaP tissues displayed significantly enhanced ERG-mRNA levels (TE-0: −4.183; TE-1: −2.994, P < 0.001) and ERG immunostaining (Erg-IH score; TE-0: 0.4211; TE-1: 1.391; P < 0.0001). Notably, the nerve density was significantly increased in CaP tissue samples with positive TE status compared to negative TE status (TE-0, ND score = 1.5; TE-1, ND score = 2.0; P <0.01). NRP1, NRP2, PLXNA2, PLXNB1, SEMA3A, and SEMA4B mRNAs were detectable in CaP tissues and CaP cell lines at quite heterogeneous levels. In CaP tissues, we observed significant positive correlations of ERG with NRP2, PLXNA2, PLXNB1, and SEMA4B. TE-positive CaP tissues displayed enhanced nerve density. ERG correlated with some NRP/PLXN/SEMA components suggesting possible regulatory relevance of ERG for CaP innervation.