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.
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.
Authors: Siân Jones; Xiaosong Zhang; D Williams Parsons; Jimmy Cheng-Ho Lin; Rebecca J Leary; Philipp Angenendt; Parminder Mankoo; Hannah Carter; Hirohiko Kamiyama; Antonio Jimeno; Seung-Mo Hong; Baojin Fu; Ming-Tseh Lin; Eric S Calhoun; Mihoko Kamiyama; Kimberly Walter; Tatiana Nikolskaya; Yuri Nikolsky; James Hartigan; Douglas R Smith; Manuel Hidalgo; Steven D Leach; Alison P Klein; Elizabeth M Jaffee; Michael Goggins; Anirban Maitra; Christine Iacobuzio-Donahue; James R Eshleman; Scott E Kern; Ralph H Hruban; Rachel Karchin; Nickolas Papadopoulos; Giovanni Parmigiani; Bert Vogelstein; Victor E Velculescu; Kenneth W Kinzler Journal: Science Date: 2008-09-04 Impact factor: 47.728
Authors: Nancy M Benight; Purnima K Wagh; Glendon M Zinser; Belinda E Peace; William D Stuart; Juozas Vasiliauskas; Peterson Pathrose; Sandra L Starnes; Susan E Waltz Journal: Oncotarget Date: 2015-07-10