title: Tyrosine kinase receptor RON in human pancreatic cancer: expression, function, and validation as a target.
abstract: BACKGROUND
  Specific tyrosine kinase receptors such as c-MET mediate epithelial-mesenchymal (EMT) transition, leading to phenotypic alterations associated with increased cell motility. It was hypothesized that RON, a tyrosine kinase receptor related to c-MET, would be expressed in human pancreatic cancer cells, induce EMT, and would thus serve as a target for therapy in a preclinical model.
  
  
  METHODS
  RON expression in human pancreatic cancer specimens was assessed by immunohistochemistry. In pancreatic cancer cell lines, RON expression was assessed by reverse-transcriptase polymerase chain reaction (PCR) and Western blot analysis. The human pancreatic cancer cell line L3.6pl, with high RON expression, was exposed to macrophage stimulating protein (MSP), the RON ligand, and assessed for cell migration, invasion, and changes associated with EMT. Western blot analysis and immunofluorescent staining were used to assess alterations in protein expression and cellular location, respectively. A RON monoclonal antibody (MoAb) was used to block ligand-induced activation of RON.
  
  
  RESULTS
  Immunohistochemical staining revealed RON overexpression in 93% of human pancreatic cancer specimens relative to nonmalignant ductal tissue. RON mRNA and protein was expressed in 9 of 9 human pancreatic cancer cell lines. Treatment of L3.6pl cells with MSP increased Erk phosphorylation, cell migration, and invasion (P < .001). RON activation led to a decrease in membrane-bound E-cadherin in association with nuclear translocation of beta-catenin. RON MoAb inhibited downstream signaling as well as cell migration and invasion. In nude mice, RON MoAb inhibited subcutaneous and orthotopic tumor growth by about 60%.
  
  
  CONCLUSIONS
  RON activation induced molecular and cellular alterations consistent with EMT. Inhibition of RON activation inhibited tumor growth in vivo. Novel antineoplastic therapies designed to inhibit RON activity may hinder mechanisms critical for pancreatic tumor progression.
authors.affiliation: Department of Surgical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: E Ramsay
authors.initials: ER
authors.lastname: Camp
authors.forename: Anthony
authors.initials: A
authors.lastname: Yang
authors.forename: Mike J
authors.initials: MJ
authors.lastname: Gray
authors.forename: Fan
authors.initials: F
authors.lastname: Fan
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Hamilton
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Evans
authors.forename: Andrea T
authors.initials: AT
authors.lastname: Hooper
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Pereira
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Lee M
authors.initials: LM
authors.lastname: Ellis
mesh_terms: D021581:Active Transport, Cell Nucleus; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004848:Epithelium / Q000473:pathology; D006801:Humans; D008648:Mesoderm / Q000473:pathology; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D015820:Cadherins; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases