Abstract

Histological staining of reactive stroma has been shown to be a predictor of biochemical recurrence in prostate cancer, however, molecular markers of the stromal response to prostate cancer have not yet been fully delineated. The objective of this study was to determine whether or not the stromal biomarkers detected with a thioredoxin-targeted nanodevice could be used to distinguish the stroma associated with benign prostatic hyperplasia from that associated with PCA. In this regard, we recently demonstrated that a thioredoxin-targeted nanodevice selectively binds to reactive stroma in frozen prostate tumor tissue sections. To accomplish this, random frozen prostate tissue sections from each of 35 patients who underwent resection were incubated with the nanodevice and graded for fluorescent intensity. An adjacent section from each case was stained with Hematoxylin & Eosin to confirm the diagnosis. Select cases were stained with Masson's Trichrome or immunohistochemically using antibodies to thioredoxin reductase 1, thioredoxin reductase 2 or peroxiredoxin 1. Our results demonstrate that the graded intensity of nanodevice binding to the stroma associated with PCA was significantly higher (p = 0.0127) than that of benign prostatic hyperplasia using the t-test. Immunohistochemical staining of adjacent sections in representative cases showed that none of the two commonly studied thioredoxin interacting protein partners mirrored the fluorescence pattern seen with the nanodevice. However, thioredoxin reductase 2 protein was clearly shown to be a biomarker of prostate cancer-associated reactive stroma whose presence distinguishes the stroma associated with benign prostatic hyperplasia from that associated with prostate cancer. We conclude that the signal detected by the nanodevice, in contrast to individual targets detected with antibodies used in this study, originates from multiple thioredoxin interacting protein partners that distinguish the M2 neutrophil and macrophage associated inflammatory response in prostate cancer-associated stroma from the CD4+ T-Lymphocyte linked inflammation in benign prostatic hyperplasia.

Highlights

  • In considering the role of inflammation in prostate cancer, one of the confounding observations is that chronic immune inflammation appears to play a crucial role in both Prostate Cancer (PCA) [1] and Benign Prostatic Hyperplasia (BPH) [2]

  • Since thioredoxin expression appears to be a link between reactive oxygen species (ROS) and RNS stress due to its ability to act as a chemoattractant for neutrophils, monocytes and T-cells [6], the presence of thioredoxin interacting protein partners in the tumor adjacent stroma detected by the thioredoxin-targeted nanodevice appears to indicate ongoing ROS and RNS stress and inflammation in fluorescent regions of the tissue sections

  • Since TXNRD2 reduces H2O2 to H2O [7], its up-regulation is expected to protect stromal cells from ROS damage in a region populated by M1 macrophages or neutrophils which are absent from inflammation in BPH

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Summary

Introduction

In considering the role of inflammation in prostate cancer, one of the confounding observations is that chronic immune inflammation appears to play a crucial role in both Prostate Cancer (PCA) [1] and Benign Prostatic Hyperplasia (BPH) [2]. BPH is clearly a late-onset phenomenon, and results from the PCPT trial strongly suggest that a diagnosis of BPH is not associated with elevated prostate cancer risk [3], a recent report suggests that hospitalization and surgery for BPH can increase the risk of prostate cancer specific death by as much as 8 fold [4]. Close examination of the type of inflammation associated with BPH suggests that it consists largely of IL-15 and c-interferon recruited CD4+ T-Lymphocytes [2]. This contrasts with the tumor-associated macrophages present in the tumor microenvironment. In general these macrophages are thought to gradually switch from an M1 to an M2 phenotype during tumor progression, leaving an M2-like phenotype [1] that still produces reactive nitrogen (RNS) [5] and reactive oxygen species (ROS) [1]

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