title: The role of the hepatocyte growth factor/c-MET pathway in pancreatic stellate cell-endothelial cell interactions: antiangiogenic implications in pancreatic cancer.
abstract: Activated cancer-associated human pancreatic stellate cells (CAhPSCs, which produce the collagenous stroma of pancreatic cancer [PC]) are known to play a major role in PC progression. Apart from inducing cancer cell proliferation and migration, CAhPSCs have also been implicated in neoangiogenesis in PC. However, the mechanisms mediating the observed angiogenic effects of CAhPSCs are unknown. A candidate pathway that may be involved in this process is the hepatocyte growth factor (HGF)/c-MET pathway and its helper molecule, urokinase-type plasminogen activator (uPA). This study investigated the effects of CAhPSC secretions on endothelial cell function in the presence and absence of HGF, c-MET and uPA inhibitors. HGF levels in CAhPSC secretions were quantified using ELISA. CAhPSC secretions were then incubated with human microvascular endothelial cells (HMEC-1) and angiogenesis assessed by quantifying HMEC-1 tube formation and proliferation. CAhPSC-secreted HGF significantly increased HMEC-1 tube formation and proliferation; notably, these effects were downregulated by inhibition of HGF, its receptor c-MET and uPA. Phosphorylation of p38 mitogen-activated protein kinase was downregulated during inhibition of the HGF/c-MET pathway, whereas phosphatidylinositol-3 kinase and ERK1/2 remained unaffected. Our studies have shown for the first time that CAhPSCs induce proliferation and tube formation of HMEC-1 and that the HGF/c-MET pathway plays a major role in this induction. Given that standard antiangiogenic treatment targeting vascular endothelial growth factor has had limited success in the clinical setting, the findings of the current study provide strong support for a novel, alternative antiangiogenic approach targeting the HGF/c-MET and uPA pathways in PC.
authors.affiliation: Pancreatic Research Group, South Western Sydney Clinical School, Ingham Institute for Applied Medical Research and the School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2170, Australia.
authors.forename: Mishaal B
authors.initials: MB
authors.lastname: Patel
authors.affiliation: Pancreatic Research Group, South Western Sydney Clinical School, Ingham Institute for Applied Medical Research and the School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2170, Australia.
authors.forename: Srinivasa P
authors.initials: SP
authors.lastname: Pothula
authors.affiliation: Pancreatic Research Group, South Western Sydney Clinical School, Ingham Institute for Applied Medical Research and the School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2170, Australia.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Pancreatic Research Group, South Western Sydney Clinical School, Ingham Institute for Applied Medical Research and the School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2170, Australia.
authors.forename: Alexandra K
authors.initials: AK
authors.lastname: Lee
authors.affiliation: Pancreatic Research Group, South Western Sydney Clinical School, Ingham Institute for Applied Medical Research and the School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2170, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
authors.affiliation: Pancreatic Research Group, South Western Sydney Clinical School, Ingham Institute for Applied Medical Research and the School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2170, Australia.
authors.forename: Romano C
authors.initials: RC
authors.lastname: Pirola
authors.affiliation: Pancreatic Research Group, South Western Sydney Clinical School, Ingham Institute for Applied Medical Research and the School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2170, Australia. m.apte@unsw.edu.au.
authors.forename: Minoti V
authors.initials: MV
authors.lastname: Apte
authors.affiliation: Pancreatic Research Group, South Western Sydney Clinical School, Ingham Institute for Applied Medical Research and the School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2170, Australia.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Wilson
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D058954:Pancreatic Stellate Cells / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D048051:p38 Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator