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

Abstract

BackgroundThe tumor microenvironment is important for progressive and metastatic disease. ObjectiveTo 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 participantsHuman 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. InterventionsBy coinoculating marginally tumorigenic LNCaP cells with PZ or TZ and by altering host hormonal milieu, a series of tumorigenic and metastatic LNCaP epithelial sublines–P4, P4-2 (derivatives from interaction with PZ), T4, and T4-2 (derivatives from interaction with TZ)–were established and characterized. MeasurementsIn vivo and in vitro evaluation of induction of tumor growth and metastatic potential. Results and limitations1) 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 prostate-specific 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. ConclusionsWe 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.