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Targeting PDGFR ‐β in Cholangiocarcinoma
Author(s) -
Fingas Christian D.,
Mertens Joachim C.,
Razumilava Nataliya,
Bronk Steven F.,
Sirica Alphonse E.,
Gores Gregory J.
Publication year - 2012
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2011.02687.x
Subject(s) - platelet derived growth factor receptor , imatinib mesylate , cancer research , stromal cell , receptor tyrosine kinase , in vivo , apoptosis , cell culture , cytoprotection , cell growth , growth factor , tyrosine kinase , biology , imatinib , medicine , pharmacology , receptor , biochemistry , genetics , microbiology and biotechnology , myeloid leukemia
Background Cholangiocarcinomas ( CCA s) are highly desmoplastic neoplasms with a tumour microenvironment plentiful in myofibroblasts ( MFB s). 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 sh PDGFR ‐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 MFB s 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 sh PDGFR ‐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 .