Infiltrating mast cells enhance prostate cancer invasion via altering LncRNA-HOTAIR/PRC2-androgen receptor (AR)-MMP9 signals and increased stem/progenitor cell population.

Lei Li,Chawnshang Chang,Liang Liang,Qiang Dang,Dalin He,Shuyuan Yeh,Wenbing Song,Hongjun Xie,Zhao Yang

doi:10.18632/oncotarget.3651

Abstract

Early studies indicated that selective inflammatory immune cells in the prostate tumor microenvironment might be able to influence prostate cancer (PCa) progression. Here we found treating PCa cells with androgen deprivation therapy (ADT) results in the recruitment of more mast cells, which might then increase PCa cell invasion via down-regulation of AR signals in 4 different PCa cell lines. Mechanism dissection revealed infiltrating mast cells could decrease AR transcription via modulation of the PRC2 complex with LncRNA-HOTAIR at the AR 5' promoter region in PCa cells. The consequences of suppressing AR may then increase PCa cell invasion via increased MMP9 expression and/or increased stem/progenitor cell population. The in vivo mouse model with orthotopically xenografted PCa CWR22Rv1 cells with/without mast cells also confirmed that infiltrating mast cells could increase PCa cell invasion via suppression of AR signals. Together, our results provide a new mechanism for the ADT-enhanced PCa metastasis via altering the infiltrating mast cells to modulate PCa AR-MMP9 signals and/or AR-stem/progenitor cell population. Targeting these newly identified inflammatory mast cells-AR signals may help us to better suppress PCa metastasis at the castration resistant stage.

Highlights

Prostate cancer (PCa) is the second most commonly diagnosed cancer worldwide [1]
PCa cells treated with androgen deprivation therapy (ADT) using casodex or enzalutamide recruit more mast cells Early studies suggested that mast cells could be recruited to various tumors cells, including PCa [12]
We applied IHC staining in the human PCa samples using the tryptase as a marker of mast cells, and found more mast cells were recruited to the PCa as compared to the adjacent normal prostate tissue (Figure S1A-B)

Summary

Introduction

Prostate cancer (PCa) is the second most commonly diagnosed cancer worldwide [1]. The androgen receptor (AR) signals play critical roles for PCa initiation and progression [2, 3] and androgen deprivation therapy (ADT) is the standard treatment for PCa at late stages, with better efficacy during the first 12-24 months before development into castration resistance [4,5,6].A growing body of evidence suggests that several immune cells (including macrophages, T cells, neutrophils and mast cells) with their secreted inflammatory cytokines may play roles to influence the PCa progression [7,8,9].Mast cells function in many conditions including allergies, angiogenesis, tissue remodeling, and immunomodulation of cancer [10, 11]. A growing body of evidence suggests that several immune cells (including macrophages, T cells, neutrophils and mast cells) with their secreted inflammatory cytokines may play roles to influence the PCa progression [7,8,9]. Mast cells were detected in the prostate tumor microenvironment (pTME) and their expression has been linked to the PCa progression [12]. There are two different types of mast cells in tumors, intra- and peri-tumoral mast cells. They may play different roles in tumor progression [12]. The intra-tumoral mast cells play a protective role in tumor development yet the peritumoral mast cells play a negative role to promote tumor progression [12]. Most mast cells were detected around the peri-tumoral area in the pTME, and ADT with castration may increase the recruitment of mast cells to PCa [13]

Methods

Results

Conclusion