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Antagonizing the hedgehog pathway with vismodegib impairs malignant pleural mesothelioma growth in vivo by affecting stroma


Meerang, Mayura; Bérard, Karima; Felley-Bosco, Emanuela; Lauk, Olivia; Vrugt, Bart; Boss, Andreas; Kenkel, David; Broggini-Tenzer, Angela; Stahel, Rolf A; Arni, Stephan; Weder, Walter; Opitz, Isabelle (2016). Antagonizing the hedgehog pathway with vismodegib impairs malignant pleural mesothelioma growth in vivo by affecting stroma. Molecular Cancer Therapeutics, 15(5):1095-1105.

Abstract

An autocrine driven upregulation of the Hedgehog (Hh) signaling pathway has been described in malignant pleural mesothelioma (MPM), in which the ligand, desert hedgehog (DHH), was produced from tumor cells. However, our investigation revealed that the Hh pathway is activated in both tumor and stroma of MPM tumor specimens and an orthotopic immunocompetent rat MPM model. This was demonstrated by positive immunohistochemical staining of Glioma associated oncogene 1 (GLI1) and Patched1 (PTCH1) in both tumor and stromal fractions. DHH was predominantly expressed in the tumor fractions. To further investigate the role of the Hh pathway in MPM stroma, we antagonized Hh signaling in the rat model of MPM using a Hh antagonist, vismodegib, (100 mg/kg peroral). Daily treatment with vismodegib efficiently downregulated Hh target genes, Gli1, Hedgehog Interacting Protein (Hhip) and Ptch1, and caused a significant reduction of tumor volume, and tumor growth delay. Immunohistochemical analyses revealed that vismodegib treatment primarily down regulated GLI1 and HHIP in the stromal compartment along with a reduced expression of previously described fibroblast Hh responsive genes such as Fibronectin (Fn1) and Vegf. Primary cells isolated from the rat model cultured in 3%O2 continued to express Dhh but did not respond to vismodegib in vitro. However, culture supernatant from these cells stimulated Gli1, Ptch1, and Fn1 expression in mouse embryonic fibroblasts which was suppressed by vismodegib. Our study provides new evidence regarding the role of Hh signaling in MPM stroma in the maintenance of tumor growth, emphasizing Hh signaling as a treatment target for MPM.

Abstract

An autocrine driven upregulation of the Hedgehog (Hh) signaling pathway has been described in malignant pleural mesothelioma (MPM), in which the ligand, desert hedgehog (DHH), was produced from tumor cells. However, our investigation revealed that the Hh pathway is activated in both tumor and stroma of MPM tumor specimens and an orthotopic immunocompetent rat MPM model. This was demonstrated by positive immunohistochemical staining of Glioma associated oncogene 1 (GLI1) and Patched1 (PTCH1) in both tumor and stromal fractions. DHH was predominantly expressed in the tumor fractions. To further investigate the role of the Hh pathway in MPM stroma, we antagonized Hh signaling in the rat model of MPM using a Hh antagonist, vismodegib, (100 mg/kg peroral). Daily treatment with vismodegib efficiently downregulated Hh target genes, Gli1, Hedgehog Interacting Protein (Hhip) and Ptch1, and caused a significant reduction of tumor volume, and tumor growth delay. Immunohistochemical analyses revealed that vismodegib treatment primarily down regulated GLI1 and HHIP in the stromal compartment along with a reduced expression of previously described fibroblast Hh responsive genes such as Fibronectin (Fn1) and Vegf. Primary cells isolated from the rat model cultured in 3%O2 continued to express Dhh but did not respond to vismodegib in vitro. However, culture supernatant from these cells stimulated Gli1, Ptch1, and Fn1 expression in mouse embryonic fibroblasts which was suppressed by vismodegib. Our study provides new evidence regarding the role of Hh signaling in MPM stroma in the maintenance of tumor growth, emphasizing Hh signaling as a treatment target for MPM.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Diagnostic and Interventional Radiology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Radiation Oncology
04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Oncology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Thoracic Surgery
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2 February 2016
Deposited On:09 Feb 2016 14:56
Last Modified:02 Feb 2018 09:51
Publisher:American Association for Cancer Research
ISSN:1535-7163
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1158/1535-7163.MCT-15-0583
PubMed ID:26839306

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