Prostate stromal cells express the progesterone receptor to control cancer cell mobility.

Yue Yu,Estelle Li,Stephen Plymate,Michael Cox,Martin Gleave,Antonio Hurtado-Coll,Ning Xie,Xuesen Dong,Jennifer Suehyun Lee,Ladan Fazli,Allen Gao

doi:10.1371/journal.pone.0092714

Abstract

BackgroundReciprocal interactions between epithelium and stroma play vital roles for prostate cancer development and progression. Enhanced secretions of cytokines and growth factors by cancer associated fibroblasts in prostate tumors create a favorable microenvironment for cancer cells to grow and metastasize. Our previous work showed that the progesterone receptor (PR) was expressed specifically in prostate stromal fibroblasts and smooth muscle cells. However, the expression levels of PR and its impact to tumor microenvironment in prostate tumors are poorly understood.MethodsImmunohistochemistry assays are applied to human prostate tissue biopsies. Cell migration, invasion and proliferation assays are performed using human prostate cells. Real-time PCR and ELISA are applied to measure gene expression at molecular levels.ResultsImmunohistochemistry assays showed that PR protein levels were decreased in cancer associated stroma when compared with paired normal prostate stroma. Using in vitro prostate stromal cell models, we showed that conditioned media collected from PR positive stromal cells inhibited prostate cancer cell migration and invasion, but had minor suppressive impacts on cancer cell proliferation. PR suppressed the secretion of stromal derived factor-1 (SDF-1) and interlukin-6 (IL-6) by stromal cells independent to PR ligands. Blocking PR expression by siRNA or supplementation of exogenous SDF-1 or IL-6 to conditioned media from PR positive stromal cells counteracted the inhibitory effects of PR to cancer cell migration and invasion.ConclusionsDecreased expression of the PR in cancer associated stroma may contribute to the elevated SDF-1 and IL-6 levels in prostate tumors and enhance prostate tumor progression.

Highlights

Decreased expression of the progesterone receptor (PR) in cancer associated stroma may contribute to the elevated stromal derived factor-1 (SDF-1) and IL-6 levels in prostate tumors and enhance prostate tumor progression
PR protein levels are decreased in Prostate Tumors We have collected 27 whole mount sections of human prostate tissue biopsies from patients treated with radical prostatectomy (Table 1)
Given the fact that both total PR and PRB decrease in similar degrees, it is likely that the PRA expression levels follow the same trend as PRB

Summary

Introduction

When combined with carcinoma associated fibroblasts (CAFs) and grafted into renal capsule, BPH-1 cells formed tumors [3]. These findings demonstrate that stromal cells play crucial roles in malignant transformation. Through secreting cytokines and growth factors, CAFs provide a supportive microenvironment to facilitate tumor growth, invasion and metastasis [4,5]. Despite these critical roles of stroma in prostate cancer (PCa), the therapeutic strategy targeting prostate stroma is greatly under appreciated. The expression levels of PR and its impact to tumor microenvironment in prostate tumors are poorly understood

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Conclusion