The RON tyrosine kinase receptor regulates vascular endothelial growth factor production in pancreatic cancer cells.

ABSTRACT

OBJECTIVES: The RON receptor mediates tumorigenic phenotypes in pancreatic cancer (PC), but no investigations currently have implicated RON signaling as a regulator of angiogenesis in PC. Angiogenesis is vital to oncogenesis, and vascular endothelial growth factor (VEGF) is the most well-characterized angiogenic protein. This study sought to determine the effect of RON stimulation on in vitro angiogenesis and VEGF production in PC cell lines. METHODS: Vascular endothelial growth factor levels from conditioned media of hepatocyte growth factor-like protein-stimulated BxPC-3 and FG cells were quantitated via enzyme-linked immunosorbent assay and likewise interrogated in the presence and absence of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase/AKT inhibitors. To determine in vitro angiogenesis, human microvascular endothelial cells were subsequently exposed to the same conditioned media to assay for microtubule formation. RESULTS: RON signaling resulted in a 52% and 34% increase in VEGF levels in BxPC-3 and FG cells, respectively. Vascular endothelial growth factor secretion was inhibited with MAPK or phosphatidylinositol-3-kinase blockade in BxPC-3 cells, but only MAPK inhibition resulted in decreased VEGF production in FG cells. BxPC-3 conditioned media induced tubule formation in human microvascular endothelial cells, which was abrogated by RON inhibition. CONCLUSIONS: RON signaling results in MAPK-mediated VEGF secretion by PC cells and promotion of microtubule formation. These findings suggest another mechanism by which RON signaling may promote PC progression.