Human Prostate Fibroblasts Induce Growth and Confer Castration Resistance and Metastatic Potential in LNCaP Cells

Abstract

Background-The tumor microenvironment is important for progressive and metastatic disease.Objective-To study the hypothesis that prostate fibroblasts have differential ability to induce castration-resistant prostate cancer (PCa) and metastatic progression and whether this effect might vary depending on the zonal origin of the fibroblast.Design, setting, and participants-Human prostate fibroblasts from the peripheral (PZ), transition (TZ) and central (CZ) zones of radical prostatectomy specimens (n = 13) were isolated and compared for their ability to promote androgen independence and metastatic progression in androgen-responsive PCa lymph node carcinoma of the prostate (LNCaP) cells in vivo. Interventions-By Take-home messageThe tumor microenvironment is important for disease progression and development of metastatic disease. Prostate fibroblasts can induce prostate cancer cell growth and confer castration resistance and the development of a metastatic phenotype. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript P4-2 (derivatives from interaction with PZ), T4, and T4-2 (derivatives from interaction with TZ)-were established and characterized.Measurements-In vivo and in vitro evaluation of induction of tumor growth and metastatic potential.Results and limitations-1) LNCaP sublines were permanently altered in their cytogenetic and biologic profiles after cellular interaction with prostate stromal fibroblasts. LNCaP sublines grew faster under anchorage-dependent and -independent conditions, expressed 1-12-fold more prostatespecific antigen in vitro than LNCaP cells, and gained metastatic potential; 2) zonal differences of stromal fibroblasts in their ability to induce the growth and progression of LNCaP tumors as xenografts in mice may exist but need further analysis; 3) PZ-conditioned medium induced more anchorage-independent growth of LNCaP cells in vitro. TZ had a higher growth rate and were more sensitive to dihydrotestosterone.Conclusions-We demonstrate that prostate fibroblasts have growth inductive potential on PCa cells and affect their subsequent progression to castration resistance and development of a metastatic phenotype.

Loss of TGF-β Responsiveness in Prostate Stromal Cells Alters Chemokine Levels and Facilitates the Development of Mixed Osteoblastic/Osteolytic Bone Lesions

“…In contrast, patients with advanced prostate cancer often develop osteoblastic bone metastasis. Both primary prostate cancer CAFs and bone stroma have been known to induce prostate cancer growth and confer castration resistance and metastatic potential (5, 32–34). However, the role of TGF-β signaling in osteoblastic lesion development in bone remains largely unclear, further the effect of TGF-β signaling in the primary site on eventual prostate cancer bone metastasis is unknown.…”

“…Bone metastatic studies have generally focused on examining the interactions of cancer cells with the bone microenvironment due to a lack of appropriate animal models and cells that recapitulate the whole process of metastasis from the orthotopic site. Recently, it has been appreciated that the primary tumor microenvironment not only provides fertile soil for cancer growth but also exerts dominant influences that trigger changes in cancer cells, conferring their selective growth and survival in metastatic sites (5–7). …”

Phenotypic characterization of human prostatic stromal cells in primary cultures derived from human tissue samples

“…The specific nature of the human PCa stromal phenotype has been shown to be an independent clinical prognostic marker (26,27), underlining the importance of paracrine interactions in human disease. The prostate tumor microenvironment is complex, including cells of many different lineages (28)(29)(30)(31). These include, but are not limited to, smooth muscle, various types of fibroblasts, senescent stromal cells, nerves and blood vessels and a wide variety of immune and inflammatory cell types.…”

Influence of stromal–epithelial interactions on androgen action

“…Similar findings associated with CAF induction and hormone-stimulated growth have also been reported (Hayward et al 2001). In addition, Thalmann et al (2010) have demonstrated the ability of CAFs to promote castration resistance in an LNCaP model, indicating that the CAFs contribute to lethal disease. We demonstrated that distinct populations of stromal cells reside in the prostate tumor microenvironment relative to stromal cells from normal prostate peripheral zone tissue and, more importantly, relative to stromal cells in BPH tissue (Barclay et al 2005).…”

“…1, a schematic of androgen-regulated signaling pathways in prostate cancer is shown. CAFs from both the peripheral and transitional zones can induce a metastatic phenotype in the normally non-metastatic LNCaP cell line in vivo, but the mechanisms are unclear (Thalmann et al 2010). Reactive stroma is also a major problem in prostate cancer progression.…”