Prostate cancer (PrCa) commonly metastasizes to bone; however, the factors involved are largely unknown. Bone marrow endothelial cells are potentially the first cell contact for PrCa upon reaching the bone marrow. We have previously shown that bone marrow endothelial cells (HBME–1) growing in collagen gels are growth inhibited (20–30%) by PrCa cells (PC–3 and LNCaP) or conditioned media (CM). The more aggressive PC–3 cells or CM also induced HBME–1 cells to differentiate, forming cord–like aggregates mimicking angiogenesis, as visualized by fluorescent confocal microscopy. Another endothelial cell line (HMEC–1) was also growth inhibited (27%) by PC–3 CM, but only showed minimal aggregate formation. Further studies suggest that TGFβ plays a key role in mediating the effects of PrCa cells on bone marrow endothelial cells. cDNA array analysis showed that PC–3 CM altered the expression of TGFβ–regulated genes in HBME–1 cells. Neutralizing antibodies targeting TGFβ1, 2, or 3 and their receptor, TGFβRII, all reversed the growth inhibition conferred by the PC–3 CM. VEGF neutralizing antibodies had no effect on growth and FGFb neutralizing antibodies induced further growth inhibition. TGFβ cytokines (1, 2, or 3) inhibited HBME–1 cell growth and partially induced cord formation. Additionally, ELISA analysis revealed that PC–3 CM (36 hr.) contained TGFβ1 and TGFβ2 (36 pg and 48 pg per 1x105 cells), whereas LNCaP CM (36 hr.) contained no detectable TGFβ. These findings suggest that TGFβ mediates the growth inhibition, and to some extent differentiation, of HBME–1 cells attributed to PC–3 cells. Preliminary data also suggests latent TGFβ is activated by PrCa cells. Further studies are underway.
[Proc Amer Assoc Cancer Res, Volume 45, 2004]