Myofibroblast-derived PDGF-BB promotes hedgehog survival signaling in cholangiocarcinoma cells

Christian D. Fingas, Steven F. Bronk, Nathan W. Werneburg, Justin L Mott, Maria E. Guicciardi, Sophie C. Cazanave, Joachim C. Mertens, Alphonse E. Sirica, Gregory J. Gores

Research output: Contribution to journalArticle

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Abstract

Cholangiocarcinoma (CCA) cells paradoxically express the death ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and, therefore, are dependent upon potent survival signals to circumvent TRAIL cytotoxicity. CCAs are also highly desmoplastic cancers with a tumor microenvironment rich in myofibroblasts (MFBs). Herein, we examine a role for MFB-derived CCA survival signals. We employed human KMCH-1, KMBC, HuCCT-1, TFK-1, and Mz-ChA-1 CCA cells, as well as human primary hepatic stellate and myofibroblastic LX-2 cells, for these studies. In vivo experiments were conducted using a syngeneic rat orthotopic CCA model. Coculturing CCA cells with myofibroblastic human primary hepatic stellate cells or LX-2 cells significantly decreased TRAIL-induced apoptosis in CCA cells, a cytoprotective effect abrogated by neutralizing platelet-derived growth factor (PDGF)-BB antiserum. Cytoprotection by PDGF-BB was dependent upon Hedgehog (Hh) signaling, because it was abolished by the smoothened (SMO; the transducer of Hh signaling) inhibitor, cyclopamine. PDGF-BB induced cyclic adenosine monophosphate-dependent protein kinase-dependent trafficking of SMO to the plasma membrane, resulting in glioma-associated oncogene (GLI)2 nuclear translocation and activation of a consensus GLI reporter gene-based luciferase assay. A genome-wide messenger RNA expression analysis identified 67 target genes to be commonly up- (50 genes) or down-regulated (17 genes) by both Sonic hedgehog and PDGF-BB in a cyclopamine-dependent manner in CCA cells. Finally, in a rodent CCA in vivo model, cyclopamine administration increased apoptosis in CCA cells, resulting in tumor suppression. Conclusions: MFB-derived PDGF-BB protects CCA cells from TRAIL cytotoxicity by a Hh-signaling-dependent process. These results have therapeutical implications for the treatment of human CCA. (HEPATOLOGY 2011;)

Original languageEnglish (US)
Pages (from-to)2076-2088
Number of pages13
JournalHepatology
Volume54
Issue number6
DOIs
StatePublished - Dec 1 2011

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Myofibroblasts
Cholangiocarcinoma
Hedgehogs
Apoptosis
Oncogenes
Glioma
platelet-derived growth factor BB
Genes
Ligands
Hepatic Stellate Cells
Tumor Microenvironment
Cytoprotection
Survival
Cyclic AMP-Dependent Protein Kinases
Luciferases
Transducers
Reporter Genes
Immune Sera
Rodentia
Neoplasms

ASJC Scopus subject areas

  • Hepatology

Cite this

Fingas, C. D., Bronk, S. F., Werneburg, N. W., Mott, J. L., Guicciardi, M. E., Cazanave, S. C., ... Gores, G. J. (2011). Myofibroblast-derived PDGF-BB promotes hedgehog survival signaling in cholangiocarcinoma cells. Hepatology, 54(6), 2076-2088. https://doi.org/10.1002/hep.24588

Myofibroblast-derived PDGF-BB promotes hedgehog survival signaling in cholangiocarcinoma cells. / Fingas, Christian D.; Bronk, Steven F.; Werneburg, Nathan W.; Mott, Justin L; Guicciardi, Maria E.; Cazanave, Sophie C.; Mertens, Joachim C.; Sirica, Alphonse E.; Gores, Gregory J.

In: Hepatology, Vol. 54, No. 6, 01.12.2011, p. 2076-2088.

Research output: Contribution to journalArticle

Fingas, CD, Bronk, SF, Werneburg, NW, Mott, JL, Guicciardi, ME, Cazanave, SC, Mertens, JC, Sirica, AE & Gores, GJ 2011, 'Myofibroblast-derived PDGF-BB promotes hedgehog survival signaling in cholangiocarcinoma cells', Hepatology, vol. 54, no. 6, pp. 2076-2088. https://doi.org/10.1002/hep.24588
Fingas CD, Bronk SF, Werneburg NW, Mott JL, Guicciardi ME, Cazanave SC et al. Myofibroblast-derived PDGF-BB promotes hedgehog survival signaling in cholangiocarcinoma cells. Hepatology. 2011 Dec 1;54(6):2076-2088. https://doi.org/10.1002/hep.24588
Fingas, Christian D. ; Bronk, Steven F. ; Werneburg, Nathan W. ; Mott, Justin L ; Guicciardi, Maria E. ; Cazanave, Sophie C. ; Mertens, Joachim C. ; Sirica, Alphonse E. ; Gores, Gregory J. / Myofibroblast-derived PDGF-BB promotes hedgehog survival signaling in cholangiocarcinoma cells. In: Hepatology. 2011 ; Vol. 54, No. 6. pp. 2076-2088.
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AU - Guicciardi, Maria E.

AU - Cazanave, Sophie C.

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