title: Targeting PDGFR-β in Cholangiocarcinoma.
abstract: BACKGROUND
  Cholangiocarcinomas (CCAs) are highly desmoplastic neoplasms with a tumour microenvironment plentiful in myofibroblasts (MFBs). MFB-derived PDGF-BB survival signalling is a mediator of CCA cell resistance to apoptotic stimuli. This raises the concept that targeting PDGFR-β, a cognate receptor of PDGF-BB, represents a potential strategy for the treatment of human CCA.
  
  
  OBJECTIVE
  Herein, we examine a role for inhibiting PDGFR-β in restoring CCA cell sensitivity to apoptotic stimuli in vitro and in vivo.
  
  
  METHODS
  We employed human CCA samples from 41 patients (19 intrahepatic and 22 extrahepatic CCA samples), the human CCA cell lines KMCH-1 and HUCCT-1 as well as shPDGFR-β-KMCH-1 and human myofibroblastic LX-2 cells for these studies. In vivo-experiments were conducted using a syngeneic rat orthotopic CCA model.
  
  
  RESULTS
  Of several MFB-derived growth factors profiled, PDGF-BB and CTGF were most abundantly expressed; however, only PDGF-BB attenuated tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) cytotoxicity. Co-culturing CCA cells with PDGF-BB-secreting MFBs significantly decreased TRAIL-induced CCA cell apoptosis when compared with monoculture conditions; this cytoprotective effect was abrogated in the presence of the tyrosine kinase inhibitors imatinib mesylate or linifanib, which inhibit PDGFR-β. Consistent with these findings, MFB-imparted cytoprotection also was abolished when PDGFR-β was knocked down as demonstrated in shPDGFR-β-KMCH-1 cells. Finally, administration of imatinib mesylate increased CCA cell apoptosis and reduced tumour growth in a rodent in vivo-CCA model that mimics the human disease.
  
  
  CONCLUSIONS
  Targeting PDGFR-β sensitizes CCA cells to apoptotic stimuli and appears to be therapeutic in vivo.
authors: Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: Christian D
authors: CD
authors: Fingas
authors: Joachim C
authors: JC
authors: Mertens
authors: Nataliya
authors: N
authors: Razumilava
authors: Steven F
authors: SF
authors: Bronk
authors: Alphonse E
authors: AE
authors: Sirica
authors: Gregory J
authors: GJ
authors: Gores
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D000077214:Becaplermin; D001650:Bile Duct Neoplasms / Q000378:metabolism*; D017734:Bile Ducts, Extrahepatic / Q000378:metabolism*; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism*; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D053552:Keratin-7 / Q000378:metabolism; D008856:Microscopy, Fluorescence; D058628:Myofibroblasts / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism
chemical_list: D017931:DNA Primers; D053552:Keratin-7; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D000077214:Becaplermin; D019009:Proto-Oncogene Proteins c-kit; D020797:Receptor, Platelet-Derived Growth Factor beta