title: Hepatocyte growth factor inhibition: a novel therapeutic approach in pancreatic cancer.
abstract: BACKGROUND
  Pancreatic stellate cells (PSCs, which produce the stroma of pancreatic cancer (PC)) interact with cancer cells to facilitate PC growth. A candidate growth factor pathway that may mediate this interaction is the HGF-c-MET pathway.
  
  
  METHODS
  Effects of HGF inhibition (using a neutralising antibody AMG102) alone or in combination with gemcitabine were assessed (i) in vivo using an orthotopic model of PC, and (ii) in vitro using cultured PC cells (AsPC-1) and human PSCs.
  
  
  RESULTS
  We have shown that human PSCs (hPSCs) secrete HGF but do not express the receptor c-MET, which is present predominantly on cancer cells. HGF inhibition was as effective as standard chemotherapy in inhibiting local tumour growth but was significantly more effective than gemcitabine in reducing tumour angiogenesis and metastasis. HGF inhibition has resulted in reduced metastasis; however, interestingly this antimetastatic effect was lost when combined with gemcitabine. This suggests that gemcitabine treatment selects out a subpopulation of cancer cells with increased epithelial-mesenchymal transition (EMT) and stem-cell characteristics, as supported by our findings of increased expression of EMT and stem-cell markers in tumour sections from our animal model. In vitro studies showed that hPSC secretions induced proliferation and migration, but inhibited apoptosis, of cancer cells. These effects were countered by pretreatment of hPSC secretions with a HGF-neutralising antibody but not by gemcitabine, indicating a key role for HGF in PSC-PC interactions.
  
  
  CONCLUSIONS
  Our studies suggest that targeted therapy to inhibit stromal-tumour interactions mediated by the HGF-c-MET pathway may represent a novel therapeutic approach in PC that will require careful modelling for optimal integration with existing treatment modalities.
authors.affiliation: Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.|Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.
authors.forename: Srinivasa P
authors.initials: SP
authors.lastname: Pothula
authors.affiliation: Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.|Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Medical Oncology, Prince of Wales Hospital, Sydney, New South Wales, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
authors.affiliation: Cancer Research Division, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Biankin
authors.affiliation: Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.|Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.
authors.forename: Romano C
authors.initials: RC
authors.lastname: Pirola
authors.affiliation: Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.|Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Wilson
authors.affiliation: Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.|Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.
authors.forename: Minoti V
authors.initials: MV
authors.lastname: Apte
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D058954:Pancreatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C066855:HGF protein, human; D003841:Deoxycytidine; C524459:rilotumumab; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D000093542:Gemcitabine