Abstract
BackgroundCancer associated fibroblasts (CAF) play important roles in tumor growth that involves inflammation and epithelial cell differentiation. Early studies suggested that estrogen receptor alpha (ERα) was expressed in stromal cells in normal prostates and prostate cancer (PCa), but the detailed functions of stromal ERα in the PCa remain to be further elucidated.MethodsMigration and invasion assays demonstrated the presence of high levels of ERα in CAF cells (CAF.ERα(+)) suppressed PCa invasion via influencing the infiltration of tumor associated macrophages. ERα decreased CAF CCL5 secretion via suppressing the CCL5 promoter activity was examined by luciferase assay. ERα decreased CCL5 and IL-6 expression in conditioned media that was collected from CAF cell only or CAF cell co-cultured with macrophages as measured by ELISA assay.ResultsBoth in vitro and in vivo studies demonstrated CAF.ERα(+) led to a reduced macrophage migration toward PCa via inhibiting CAF cells secreted chemokine CCL5. This CAF.ERα(+) suppressed macrophage infiltration affected the neighboring PCa cells invasion and the reduced invasiveness of PCa cells are at least partly due to reduced IL6 expression in the macrophages and CAF.ConclusionOur data suggest that CAF ERα could be applied as a prognostic marker to predict cancer progression, and targeting CCL5 and IL6 may be applied as an alternative therapeutic approach to reduce M2 type macrophages and PCa invasion in PCa patients with low or little ERα expression in CAF cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0488-9) contains supplementary material, which is available to authorized users.
Highlights
Cancer associated fibroblasts (CAF) play important roles in tumor growth that involves inflammation and epithelial cell differentiation
Using a transwell system of adding macrophage RAW-264.7 cells on the insert wells and seeding CAF.ERα(+) or CAF.ERα(−) cells in the bottom chambers, we found chambers seeded with CAF.ERα(+) had less macrophages infiltrated than with CAF.ERα(−) cells (Fig. 1a)
Our results indicated that E2 treatment can further reduce CAF.ERα(+) diminished macrophage recruitment and treatment with ICI182,780 can reverse E2 and ERα reduced macrophage infiltration (Fig. 1c)
Summary
Cancer associated fibroblasts (CAF) play important roles in tumor growth that involves inflammation and epithelial cell differentiation. An earlier study suggested that cancer associated fibroblasts (CAF) may play important roles to influence PCa progression and invasion [9]. In the prostate tumor microenvironment (TME), PCa epithelial cells can produce some growth factors, such as TGF-β, PDGF and FGF, to influence/activate peripheral stromal cells that result in transformation of normal fibroblasts into CAF. CAF can increase in population through transforming from normal fibroblasts [10], differentiation from bone marrow-derived mesenchymal stem cells [11] or by epithelial to mesenchymal transition (EMT). The important functions of CAF include the regulation of deposition of extracellular matrix (ECM), epithelial differentiation, tumor inflammation, and wound healing [12]. Ezer et al demonstrated that CAF could mediate inflammation and angiogenesis by recruiting macrophages to stimulate angiogenesis, which may promote tumor growth [13]
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