Targeting PDGFR-β in Cholangiocarcinoma

Liver Int. 2012 Mar;32(3):400-9. doi: 10.1111/j.1478-3231.2011.02687.x. Epub 2011 Dec 2.

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.

Aims: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Becaplermin
  • Bile Duct Neoplasms / metabolism*
  • Bile Ducts, Extrahepatic / metabolism*
  • Bile Ducts, Intrahepatic / metabolism*
  • Cell Line, Tumor
  • Cholangiocarcinoma / drug therapy*
  • Cholangiocarcinoma / metabolism*
  • Cholangiocarcinoma / physiopathology
  • DNA Primers / genetics
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Keratin-7 / metabolism
  • Microscopy, Fluorescence
  • Myofibroblasts / metabolism
  • Proto-Oncogene Proteins c-kit / metabolism
  • Proto-Oncogene Proteins c-sis / metabolism
  • Proto-Oncogene Proteins c-sis / pharmacology
  • RNA, Small Interfering / metabolism
  • Rats
  • Real-Time Polymerase Chain Reaction
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand / metabolism

Substances

  • DNA Primers
  • Keratin-7
  • Proto-Oncogene Proteins c-sis
  • RNA, Small Interfering
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Becaplermin
  • Proto-Oncogene Proteins c-kit
  • Receptor, Platelet-Derived Growth Factor beta