Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies

Mimeault, Murielle; Batra, Surinder K.

doi:10.1124/pr.109.002329

Cited by 105 publications

(100 citation statements)

References 286 publications

(690 reference statements)

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“…GLI1 has been shown to be activated in Hh-independent fashion, via cross-talking with other oncogenic pathways such as KRAS, EGFR, and mTOR (8,37). A recent study demonstrated that GLI1 was highly expressed in some MPM tumors of which SHH expression was absent (7), suggesting a possible role of GLI1 activation in Hh signaling independent manner (13).…”

Section: Discussionmentioning

confidence: 99%

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

Meerang

Bérard

Felley-Bosco

et al. 2016

Molecular Cancer Therapeutics

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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.

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Section: Discussionmentioning

confidence: 99%

“…The Hh pathway is one of the crucial stem cell signaling pathways that regulate embryonic development and adult tissue repair (8). In the absence of Hh ligand binding, the receptor Patched (PTCH1) represses the transmembrane G protein-coupled receptor Smoothened (SMO).…”

Section: Introductionmentioning

confidence: 99%

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

Meerang

Bérard

Felley-Bosco

et al. 2016

Molecular Cancer Therapeutics

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“…The EGFR signaling pathway represents such overlap. Activated EGFR can form the Grb2/SOS complex to activate the p21 RAS pathway and MAPK/ERK-AP-1 activation (11). EGFR is amplified or mutated in approximately 60% of primary GBM tumors (12).…”

Section: Introductionmentioning

confidence: 99%

Temozolomide Induces the Production of Epidermal Growth Factor to Regulate MDR1 Expression in Glioblastoma Cells

Munoz

Rodriguez-Cruz

Greco

et al. 2014

Molecular Cancer Therapeutics

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Glioblastoma multiforme (GBM) commonly resists the frontline chemotherapy treatment temozolomide. The multidrug resistance gene (MDR1) and its protein, P-glycoprotein (P-gp), are associated with chemoresistance. This study investigated the mechanisms underlying MDR1-mediated resistance by GBM to temozolomide. P-gp trafficking was studied by flow cytometry and Western blot analysis. MDR1 expression was analyzed by real-time PCR and reporter gene assays. AP-1 interaction with MDR1 was studied by chromatin immunoprecipitation assay. EGF production was analyzed by ELISA, EGFR signaling was determined by Western blot analysis, and in vivo response to erlotinib and/or temozolomide was studied in nude mice. During the early phase of temozolomide treatment, intracellular P-gp was trafficked to the cell membrane, followed by conformational change into active P-gp. At the later phase, gene transcription of MDR1 was induced by temozolomide-mediated production of EGF. EGF activated ERK1/2-JNK-AP-1 cofactors (c-jun and c-fos). An inhibitor of EGFR kinase (erlotinib) given to nude mice with GBM prevented temozolomideinduced resistance. The results identified an essential role for activated EGFR in the resistance of GBM to temozolomide. Temozolomide resistance occurred through a biphasic response; first, by a conformational change in P-gp into the active form and, second, by releasing EGF, which caused autocrine stimulation of GBM cells to induce MDR1. Pharmacologic inhibition of EGFR kinase blunted the ability of GBM cells to resist temozolomide. These findings may explain reports on the common occurrence of mutant EGFR (EGFRvIII) and EGFR expansion in the resistance of GBM cells. Mol Cancer Ther; 13(10); 2399-411. Ó2014 AACR.

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“…Hedgehog signaling plays a critical role in the regulation of growth, pattern formation, and stem cell maintenance and selfrenewal in many organs during development (Baker, 2007;Mimeault and Batra, 2010). It has been implicated that alterations in hedgehog signaling cause abnormal regulation of cellular events, which is closely associated with tumorigenesis in several cancers (Gupta et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Constitutive Activation of Smoothened Leads to Impaired Developments of Postnatal Bone in Mice

Cho

Lim

Hwang

et al. 2012

Molecules and Cells

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Sonic hedgehog (Shh) signaling regulates patterning, proliferation, and stem cell self-renewal in many organs. Smoothened (Smo) plays a key role in transducing Shh signaling into the nucleus by activating a glioma family of transcription factors; however, the cellular and molecular mechanisms underlying the role of sustained Smo activation in postnatal development are still unclear. In this study, we explored the effects of Shh signaling on bone development using a conditional knock-in mouse model that expresses a constitutively activated form of Smo (SmoM2) upon osteocalcin (OCN)-Cre-mediated recombination (SmoM2; OCN-Cre mice). We also evaluated the expression pattern of bone formation-related factors in primary calvarial cultures of mutant and control mice. The SmoM2;OCN-Cre mutant showed growth retardation and reduction of bone mineral density compared to control mice. Constitutively activated SmoM2 also repressed mRNA expression of Runx2, osterix, type I collagen, and osteocalcin. Further, sustained SmoM2 induction suppressed mineralization in calvarial primary osteoblasts cultures, whereas such induction did not affect cell proliferation in the mutant cultures as compared with SmoM2 only control cultures. These results suggest that sustained Smo activation inhibits postnatal development of bone by suppressing gene expression of bone formation regulatory factors in mice.

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Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies

Cited by 105 publications

References 286 publications

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

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

Temozolomide Induces the Production of Epidermal Growth Factor to Regulate MDR1 Expression in Glioblastoma Cells

Constitutive Activation of Smoothened Leads to Impaired Developments of Postnatal Bone in Mice

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