An autocrine loop for vascular endothelial growth factor is established in prostate cancer cells generated after prolonged treatment with interleukin 6.

ABSTRACT

Concentrations of interleukin 6 (IL-6) and its receptor are increased in human prostate cancer. Prostate cancer LNCaP-IL-6+ cells, established after prolonged treatment with IL-6, have been found to acquire a growth advantage. Vascular endothelial growth factor (VEGF) may accelerate the growth of various tumours by stimulation of VEGF receptor 2 (VEGFR-2). To understand better the regulation of proliferation of LNCaP-IL-6+ cells, the expression of VEGF and VEGFR-2 was here investigated in the LNCaP-IL-6+ subline. VEGF was measured in cellular supernatants by enzyme-linked immunoassay. The expression of VEGFR-2 was assessed by Western blot. LNCaP-IL-6+ and control LNCaP-IL-6- cells were treated with a neutralising antibody against VEGFR-2. VEGF concentrations were 20-fold higher in LNCaP-IL-6+ than in LNCaP-IL-6- cells. The stimulatory effect of IL-6 on VEGF production was abolished by an inhibitor of the signalling pathway for phosphoinositol 3 kinase in LNCaP-IL-6+ and LNCaP-IL-6- cells. Exogenous VEGF did not stimulate proliferation in either LNCaP-IL-6+ cells or controls. VEGFR-2 was detected only in LNCaP-IL-6+ cells, in which the neutralising antibody caused a partial inhibition of cell proliferation. It was concluded that a VEGF autocrine loop is established in prostate cancer cells generated after chronic treatment with IL-6. Because of the upregulation of IL-6 in patients with prostate cancer, these findings might be clinically relevant.