TY - JOUR
T1 - Targeting PDGFR-β in Cholangiocarcinoma
AU - Fingas, Christian D.
AU - Mertens, Joachim C.
AU - Razumilava, Nataliya
AU - Bronk, Steven F.
AU - Sirica, Alphonse E.
AU - Gores, Gregory J.
PY - 2012/3
Y1 - 2012/3
N2 - 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.
AB - 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.
KW - Derived growth factor receptor beta
KW - Hepatic stellate cells
KW - Imatinib mesylate/STI-571
KW - Linifanib/ABT-869
KW - Myofibroblasts
KW - Platelet
UR - http://www.scopus.com/inward/record.url?scp=84856681625&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84856681625&partnerID=8YFLogxK
U2 - 10.1111/j.1478-3231.2011.02687.x
DO - 10.1111/j.1478-3231.2011.02687.x
M3 - Article
C2 - 22133064
AN - SCOPUS:84856681625
SN - 1478-3223
VL - 32
SP - 400
EP - 409
JO - Liver International
JF - Liver International
IS - 3
ER -