Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma

Abstract

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. Mol Cancer Ther; 15(5); 1095-105. Ó2016 AACR.

Drug development against the hippo pathway in mesothelioma

“…In a rat xenograft model, vismodegib has been shown to downregulate SHH target genes of Gli1 and Ptch1 as well as reducing tumor volume and tumor growth (6). Combining stem cell pathway inhibitors with standard chemotherapy can improve the efficacy of chemotherapy, for example in the Wnt stem cell pathway combining cisplatin with Wnt pathway inhibitors in vitro induces synergistic cell cycle arrest and colony formation (7).…”

Hedgehog inhibition enhances efficacy of radiation and cisplatin in orthotopic cervical cancer xenografts

“…Translocation of GLI to the nucleus affects a number of cellular functions including promotion of cell cycle progression, EMT, anti-apoptotic proteins and production of vascular endothelial growth factor (VEGF) (Pasca di Magliano and Hebrok, 2003; Hooper and Scott, 2005; Shevde and Samant, 2014; Azzi et al , 2015). Studies in a number of tumour types indicate stromal activation of Hh may be critical in tumourigenesis (Yauch et al , 2008; Meerang et al , 2016). …”

Tracking cellular and molecular changes in a species-specific manner during experimental tumor progression in vivo

“…The more immature nature of tumor-bearing CAMs is also evidenced by PCA analysis, where T7 CAMs group together with E14 CAMs, whereas E17 CAMs are placed clear away from this group (Figure 5 ). Among the top 40 regulated genes, we also found increased expression of hedgehog-interacting protein ( HHIP) , which plays important roles in promoting cancer cell growth in the stromal compartment [ 36 ].…”