Interleukin-6 (IL-6) and IL-6 receptor levels are increased in human prostate cancer. We demonstrated that prostate cancer cells LNCaP-IL-6+, selected after prolonged treatment with IL-6, acquire a growth advantage in vitro and in vivo. Vascular endothelial growth factor (VEGF) enhances growth of various tumors by acting on blood vessels and by stimulation of cell proliferation through VEGF receptor-2 (VEGFR-2). To better understand growth-regulatory mechanisms in LNCaP-IL-6+ cells, we measured the expression of VEGF and VEGFR-2 by ELISA and Western blot, respectively. LNCaP-IL-6+ cells and controls passaged in the absence of IL-6 were treated with a neutralizing antibody against VEGFR-2. VEGF secretion was 20-fold higher in LNCaP-IL-6+ than in LNCaP-IL-6- cells (743.6 ± 83.9 vs. 36.8 ± 0.2 pg/105 cells/72 h). Either the synthetic androgen R1881 or IL-6 stimulated VEGF secretion in LNCaP-IL-6+ cells and in controls. In the LNCaP-IL-6+ subline, IL-6-induced VEGF secretion was reduced by the inhbitor of the phoshatidylinositol 3-kinase pathway LY 294002 but not by inhibitors of the Janus kinase AG 490 or mitogen-activated protein kinase kinase PD 98059. Exogenous VEGF did not exert a proliferative effect on LNCaP-IL-6+ cells. VEGFR-2 was detectable in the subline selected in the presence of IL-6. Anti-VEGFR-2 caused partial (25%), but statistically significant inhibition of proliferation of LNCaP-IL-6+ cells. Our results show that a VEGF autocrine loop is established in prostate cancer cells generated after chronic exposure to IL-6. These findings might have clinical significance in patients with advanced carcinoma of the prostate.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]