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DOI | 10.1158/1535-7163.MCT-15-0583 |
Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma | |
Meerang, Mayura1; Berard, Karima1; Felley-Bosco, Emanuela2; Lauk, Olivia1; Vrugt, Bart3; Boss, Andreas4; Kenkel, David4; Broggini-Tenzer, Angela5; Stahel, Rolf A.6; Arni, Stephan1; Weder, Walter1; Opitz, Isabelle1 | |
通讯作者 | Opitz, Isabelle |
来源期刊 | MOLECULAR CANCER THERAPEUTICS |
ISSN | 1535-7163 |
EISSN | 1538-8514 |
出版年 | 2016 |
卷号 | 15期号:5页码:1095-1105 |
英文摘要 | An autocrine-driven upregulation of the Hedgehog (Hh) signaling pathway has been described in malignant pleural mesothelioma (MPM), in which the ligand, desert Hh (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 orally). 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 downregulated GLI1 and HHIP in the stromal compartment along with a reduced expression of previously described fibroblast Hh-responsive genes such as Fibronectin (Fn1) and Vegfa. Primary cells isolated from the rat model cultured in 3% O-2 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. (C) 2016 AACR. |
类型 | Article |
语种 | 英语 |
国家 | Switzerland |
收录类别 | SCI-E |
WOS记录号 | WOS:000375857400030 |
WOS关键词 | SONIC HEDGEHOG ; INHIBITOR GDC-0449 ; PANCREATIC-CANCER ; CELL-GROWTH ; RAT MODEL ; EXPRESSION ; PROGRESSION ; SURVIVAL ; ABCG2/BCRP ; CISPLATIN |
WOS类目 | Oncology |
WOS研究方向 | Oncology |
资源类型 | 期刊论文 |
条目标识符 | http://119.78.100.177/qdio/handle/2XILL650/195094 |
作者单位 | 1.Univ Zurich Hosp, Div Thorac Surg, Ramistr 100, CH-8091 Zurich, Switzerland; 2.Univ Zurich Hosp, Lab Mol Oncol, CH-8091 Zurich, Switzerland; 3.Univ Zurich Hosp, Inst Surg Pathol, CH-8091 Zurich, Switzerland; 4.Univ Zurich Hosp, Inst Diagnost & Intervent Radiol, CH-8091 Zurich, Switzerland; 5.Univ Zurich Hosp, Lab Mol Radiobiol, Radiat Oncol, CH-8091 Zurich, Switzerland; 6.Univ Zurich Hosp, Clin Oncol, CH-8091 Zurich, Switzerland |
推荐引用方式 GB/T 7714 | Meerang, Mayura,Berard, Karima,Felley-Bosco, Emanuela,et al. Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma[J],2016,15(5):1095-1105. |
APA | Meerang, Mayura.,Berard, Karima.,Felley-Bosco, Emanuela.,Lauk, Olivia.,Vrugt, Bart.,...&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. |
MLA | Meerang, Mayura,et al."Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma".MOLECULAR CANCER THERAPEUTICS 15.5(2016):1095-1105. |
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