Defining a role for Sonic hedgehog pathway activation in desmoplastic medulloblastoma by identifying GLI1 target genes

Yoon, Joon Won; Gilbertson, Richard J.; Iannaccone, Stephen; Iannaccone, Philip M.; Walterhouse, David

doi:10.1002/ijc.23929

Cited by 67 publications

(64 citation statements)

References 66 publications

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“…Significantly higher activeto-inactive Smo ratios were detected in each of the desmoplastic MB samples (Fig. S1), the form of human MB most often associated with Shh pathway oncogenesis (4,8). Collectively, these results indicate that Shh pathway activity is elevated in multiple human MB variants.…”

Section: Resultsmentioning

confidence: 71%

“…Shh pathway mutations are thought to drive MB (4,8,9,47). The Shh ligand undergoes autocatalytic processing and modification that is critical for signaling activity.…”

Section: Resultsmentioning

confidence: 99%

“…Variants of MB have been defined (e.g., classic, desmoplastic, anaplastic, and extremely nodular) pathologically and by gene expression profiling (4)(5)(6)(7). Approximately one third of all MBs are characterized by up-regulation of genes in the Sonic hedgehog (Shh) pathway and are predominantly desmoplastic (5,7,8). Constitutive activation of the Shh pathway typically results from mutations in the Shh receptor [Patched (Ptc)] or downstream Smoothened (Smo), leading to hyperproliferation of granule neuron precursors (GNPs) and tumorigenesis (5,8,9).…”

mentioning

confidence: 99%

“…Approximately one third of all MBs are characterized by up-regulation of genes in the Sonic hedgehog (Shh) pathway and are predominantly desmoplastic (5,7,8). Constitutive activation of the Shh pathway typically results from mutations in the Shh receptor [Patched (Ptc)] or downstream Smoothened (Smo), leading to hyperproliferation of granule neuron precursors (GNPs) and tumorigenesis (5,8,9). Smoothened A1 (SmoA1) transgenic mice harbor a Smo activating mutation under regulatory control of the CNS specific neuronal differentiation 2 (Neurod2) promoter, which drives expression in GNPs (10)(11)(12).…”

mentioning

confidence: 99%

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T-cell TGF-β signaling abrogation restricts medulloblastoma progression

Gate

Danielpour

Rodríguez

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Cancer cell secretion of TGF-β is a potent mechanism for immune evasion. However, little is known about how central nervous system tumors guard against immune eradication. We sought to determine the impact of T-cell TGF-β signaling blockade on progression of medulloblastoma (MB), the most common pediatric brain tumor. Genetic abrogation of T-cell TGF-β signaling mitigated tumor progression in the smoothened A1 (SmoA1) transgenic MB mouse. T regulatory cells were nearly abolished and antitumor immunity was mediated by CD8 cytotoxic T lymphocytes. To define the CD8 T-cell subpopulation responsible, primed CD8 T cells were adoptively transferred into tumor-bearing immunocompromised SmoA1 recipients. This led to generation of CD8 + / killer cell lectin-like receptor G1 high (KLRG1 hi )/IL-7R lo short-lived effector cells that expressed granzyme B at the tumor. These results identify a cellular immune mechanism whereby TGF-β signaling blockade licenses the T-cell repertoire to kill pediatric brain tumor cells.cancer immunology | neuroimmunology | neuro-oncology

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Section: Resultsmentioning

confidence: 71%

“…Shh pathway mutations are thought to drive MB (4,8,9,47). The Shh ligand undergoes autocatalytic processing and modification that is critical for signaling activity.…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

T-cell TGF-β signaling abrogation restricts medulloblastoma progression

Gate

Danielpour

Rodríguez

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Показано, что GLI1 влияет на экспрессию MGMT, связываясь с GLI1-связывающим сайтом в его промотере [92]. У пациентов рецидивы мультиформной глиобластомы коррелировали с уровнем экспрессии GLI1.…”

Section: влияние на процессы химиорезистентностиunclassified

Hedgehog signaling in the pathogenesis of neuro-oncology diseases

et al. 2015

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The review summarizes current knowledge on the Hedgehog signaling pathway, its role in normal embryogenesis and/or initiation and progression of neuro-oncological diseases, especially of high-grade gliomas, the most malignant neuroepithelial tumors. The main proteins forming the Hedgehog signaling pathway include Shh, PTCH1, SMO, HHIP, SUFU and GLI1 isoforms. Effects of other signaling pathways on the family of transcription factors GLI and other proteins are described. The review summarizes modern data about the impact of the Hedgehog signaling pathway on proliferation, migration activity and invasiveness, and also on tumor neoangiogenesis and tumor cell chemoresistance. The role of the Hedgehog signaling pathway in origin of cancer stem cells and epithelial-mesenchymal transition is also analyzed. Some prospects for new anticancer drugs acting on components of the Hedgehog signaling pathway inhibitors are demonstrated.

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The antiretroviral nucleoside analogue Abacavir reduces cell growth and promotes differentiation of human medulloblastoma cells

Rossi

Russo

Puca

et al. 2009

Intl Journal of Cancer

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Abacavir is one of the most efficacious nucleoside analogues, with a well-characterized inhibitory activity on reverse transcriptase enzymes of retroviral origin, and has been clinically approved for the treatment of AIDS. Recently, Abacavir has been shown to inhibit also the human telomerase activity. Telomerase activity seems to be required in essentially all tumours for the immortalization of a subset of cells, including cancer stem cells. In fact, many cancer cells are dependent on telomerase for their continued replication and therefore telomerase is an attractive target for cancer therapy. Telomerase expression is upregulated in primary primitive neuroectodermal tumours and in the majority of medulloblastomas suggesting that its activation is associated with the development of these diseases. Therefore, we decided to test Abacavir activity on human medulloblastoma cell lines with high telomerase activity. We report that exposure to Abacavir induces a dose-dependent decrease in the proliferation rate of medulloblastoma cells. This is associated with a cell accumulation in the G 2 /M phase of the cell cycle in the Daoy cell line, and with increased cell death in the D283-MED cell line, and is likely to be dependent on the inhibition of telomerase activity. Interestingly, both cell lines showed features of senescence after Abacavir treatment. Moreover, after Abacavir exposure we detected, by immunofluorescence staining, increased protein expression of the glial marker glial fibrillary acidic protein and the neuronal marker synaptophysin in both medulloblastoma cell lines. In conclusion, our results suggest that Abacavir reduces proliferation and induces differentiation of human medulloblastoma cells through the downregulation of telomerase activity. Thus, using Abacavir, alone or in combination with current therapies, might be an effective therapeutic strategy for the treatment of medulloblastoma. ' 2009 UICC

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Defining a role for Sonic hedgehog pathway activation in desmoplastic medulloblastoma by identifying GLI1 target genes

Cited by 67 publications

References 66 publications

T-cell TGF-β signaling abrogation restricts medulloblastoma progression

T-cell TGF-β signaling abrogation restricts medulloblastoma progression

Hedgehog signaling in the pathogenesis of neuro-oncology diseases

The antiretroviral nucleoside analogue Abacavir reduces cell growth and promotes differentiation of human medulloblastoma cells

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