Targeting PDGFR-β in Cholangiocarcinoma

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

Research output: Contribution to journalArticle

26 Citations (Scopus)

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

Fingerprint

Cholangiocarcinoma
Myofibroblasts
N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N1-(2-fluoro-5-methylphenyl)urea
Apoptosis
Tumor Microenvironment
Cytoprotection
Protein-Tyrosine Kinases
Rodentia
Neoplasms
Intercellular Signaling Peptides and Proteins
Tumor Necrosis Factor-alpha

Keywords

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

ASJC Scopus subject areas

  • Hepatology

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

Targeting PDGFR-β in Cholangiocarcinoma. / Fingas, Christian D.; Mertens, Joachim C.; Razumilava, Nataliya; Bronk, Steven F.; Sirica, Alphonse E.; Gores, Gregory James.

In: Liver International, Vol. 32, No. 3, 03.2012, p. 400-409.

Research output: Contribution to journalArticle

Fingas, CD, Mertens, JC, Razumilava, N, Bronk, SF, Sirica, AE & Gores, GJ 2012, 'Targeting PDGFR-β in Cholangiocarcinoma', Liver International, vol. 32, no. 3, pp. 400-409. https://doi.org/10.1111/j.1478-3231.2011.02687.x
Fingas CD, Mertens JC, Razumilava N, Bronk SF, Sirica AE, Gores GJ. Targeting PDGFR-β in Cholangiocarcinoma. Liver International. 2012 Mar;32(3):400-409. https://doi.org/10.1111/j.1478-3231.2011.02687.x
Fingas, Christian D. ; Mertens, Joachim C. ; Razumilava, Nataliya ; Bronk, Steven F. ; Sirica, Alphonse E. ; Gores, Gregory James. / Targeting PDGFR-β in Cholangiocarcinoma. In: Liver International. 2012 ; Vol. 32, No. 3. pp. 400-409.
@article{00b67f19140349a58f5ac1f2d5ac7ed8,
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. 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.",
keywords = "Derived growth factor receptor beta, Hepatic stellate cells, Imatinib mesylate/STI-571, Linifanib/ABT-869, Myofibroblasts, Platelet",
author = "Fingas, {Christian D.} and Mertens, {Joachim C.} and Nataliya Razumilava and Bronk, {Steven F.} and Sirica, {Alphonse E.} and Gores, {Gregory James}",
year = "2012",
month = "3",
doi = "10.1111/j.1478-3231.2011.02687.x",
language = "English (US)",
volume = "32",
pages = "400--409",
journal = "Liver International",
issn = "1478-3223",
publisher = "Wiley-Blackwell",
number = "3",

}

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 James

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

VL - 32

SP - 400

EP - 409

JO - Liver International

JF - Liver International

SN - 1478-3223

IS - 3

ER -