The RON tyrosine kinase receptor regulates vascular endothelial growth factor production in pancreatic cancer cells.
OBJECTIVE
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.
Thomas
Ryan M
RM
Division of Surgical Oncology, Department of Surgery, University of Cincinnati, Cincinnati, OH, USA.
Jaquish
Dawn V
DV
French
Randall P
RP
Lowy
Andrew M
AM
D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000494:pharmacology
D017077:Culture Media, Conditioned; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D020794:Receptor Protein-Tyrosine Kinases; D042461:Vascular Endothelial Growth Factor A; C080835:RON protein