Extratumoral Heme Oxygenase-1 (HO-1) Expressing Macrophages Likely Promote Primary and Metastatic Prostate Tumor Growth.

Sofia Halin Bergström,Maria Nilsson,Elin Thysell,Anders Widmark,Emma Jernberg,Hanibal Adamo,Pernilla Wikström,Anders Bergh,Pär Stattin,Joseph Najbauer

doi:10.1371/journal.pone.0157280

Abstract

Aggressive tumors induce tumor-supporting changes in the benign parts of the prostate. One factor that has increased expression outside prostate tumors is hemoxygenase-1 (HO-1). To investigate HO-1 expression in more detail, we analyzed samples of tumor tissue and peritumoral normal prostate tissue from rats carrying cancers with different metastatic capacity, and human prostate cancer tissue samples from primary tumors and bone metastases. In rat prostate tumor samples, immunohistochemistry and quantitative RT-PCR showed that the main site of HO-1 synthesis was HO-1+ macrophages that accumulated in the tumor-bearing organ, and at the tumor-invasive front. Small metastatic tumors were considerably more effective in attracting HO-1+ macrophages than larger non-metastatic ones. In clinical samples, accumulation of HO-1+ macrophages was seen at the tumor invasive front, almost exclusively in high-grade tumors, and it correlated with the presence of bone metastases. HO-1+ macrophages, located at the tumor invasive front, were more abundant in bone metastases than in primary tumors. HO-1 expression in bone metastases was variable, and positively correlated with the expression of macrophage markers but negatively correlated with androgen receptor expression, suggesting that elevated HO-1 could be a marker for a subgroup of bone metastases. Together with another recent observation showing that selective knockout of HO-1 in macrophages reduced prostate tumor growth and metastatic capacity in animals, the results of this study suggest that extratumoral HO-1+ macrophages may have an important role in prostate cancer.

Highlights

In order to grow and spread, cancers need to instruct adjacent cells as well as remote organs to cooperate
We examined HO-1 mRNA expression in rat prostate tumors and in the benign parts of the tumor-bearing prostate lobe
Using our previously published transcriptome data [41], we found that the inter-patient variation in HO-1 mRNA levels in metastases was large and castration-resistant prostate cancer (CRPC) cases showed an inverse correlation to AR mRNA levels (Rs = -0.41, p = 0.022, n = 31) while being positively correlated to mRNA levels for CD68 (Rs = 0.70, p = 0.000013, n = 31) and CD163 (Rs = 0.53, p = 0.002, n = 31), but not iNOS (Rs = -0.17, p = 0.38, n = 31), indicating HO-1 expression in M2 macrophages in human PC bone metastases with less AR activity

Summary

Introduction

In order to grow and spread, cancers need to instruct adjacent cells as well as remote organs to cooperate. Often neglected, site that adapts to support tumor growth is the tumor-bearing organ [3]. We found that tumor growth resulted in several modifications in the tumor-bearing organ–for example, growth of the vasculature and alterations in the extracellular matrix [6, 8, 9]. These changes were found to be partially mediated by accumulating inflammatory cells such as macrophages and mast cells [10,11,12]. Already when small, fast-growing and metastatic tumors induced more pronounced changes than larger, slow-growing and nonmetastatic tumors [5]

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Results

Conclusion