Targeting PDGFR-β in Cholangiocarcinoma

Christian D. Fingas, Joachim C. Mertens, Nataliya Razumilava, Steven F. Bronk, Alphonse E. Sirica, Gregory J. Gores

Research output: Contribution to journalArticle

27 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)400-409
Number of pages10
JournalLiver International
Volume32
Issue number3
DOIs
StatePublished - Mar 2012

Keywords

  • Derived growth factor receptor beta
  • Hepatic stellate cells
  • Imatinib mesylate/STI-571
  • Linifanib/ABT-869
  • Myofibroblasts
  • Platelet

ASJC Scopus subject areas

  • Hepatology

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  • Cite this

    Fingas, C. D., Mertens, J. C., Razumilava, N., Bronk, S. F., Sirica, A. E., & Gores, G. J. (2012). Targeting PDGFR-β in Cholangiocarcinoma. Liver International, 32(3), 400-409. https://doi.org/10.1111/j.1478-3231.2011.02687.x