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 - Mott, Justin L.

AU - Guicciardi, Maria E.

AU - Cazanave, Sophie C.

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