Medulloblastoma: recurrence and metastasis

Aref, Donya; Croul, Sidney

doi:10.2217/cns.13.30

Cited by 30 publications

(26 citation statements)

References 86 publications

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“…Xenograft specimen tissues were subjected to antigen retrieval by pressure cooking (citrate buffer, pH 6, 20 minutes) and 0.3% H 2 O 2 endogenous peroxidase blocking. Primary antibody: JPO2 antibody [1:500, rabbit, in-house (6,22)], Ki-67 (1:150; Dako, Agilent Technologies), were incubated overnight at 4 C and detected using biotinylated secondary IgG antibodies for 30 minutes using ABC Reagent Kit and DAB Chromagen (Vector Laboratories). A final counterstain was performed in hematoxylin followed by dehydration in 70%, 80%, and 100% ethanol series to xylene and mounted in Permount (Thermo Fisher Scientific).…”

Section: Histology and Ihcmentioning

confidence: 99%

“…Although mechanisms of Myc-mediated transformation in medulloblastoma remain largely unknown, multiple lines of data suggest Mycdriven medulloblastoma are dependent on PI3K/AKT signaling (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) and point to the PI3K/AKT axis as a critical downstream effector of Myc in group 3 medulloblastoma (7,16,17). Activation of PI3K/AKT signaling has been shown to promote various oncogenic phenotypes in medulloblastoma including enhanced tumor growth, metastasis, and chemoresistance (14,(18)(19)(20)(21)(22). Thus, defining the scope of Myc regulatory network in medulloblastoma will clearly be important for informing more effective targeting of the Myc-PI3K/AKT axis.…”

Section: Introductionmentioning

confidence: 99%

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JPO2/CDCA7L and LEDGF/p75 Are Novel Mediators of PI3K/AKT Signaling and Aggressive Phenotypes in Medulloblastoma

et al. 2016

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Substantial evidence links Myc-PI3K/AKT signaling to the most aggressive subtype of medulloblastoma and this axis in medulloblastoma therapy. In this study, we advance understanding of how Myc-PI3K/AKT signaling contributes to this malignancy, specifically, in identifying the Myc-interacting protein JPO2 and its partner binding protein LEDGF/p75 as critical modulators of PI3K/AKT signaling and metastasis in medulloblastoma. JPO2 overexpression induced metastatic medulloblastoma in vivo through two synergistic feed-forward regulatory circuits involving LEDGF/p75 and AKT that promote metastatic phenotypes in this setting. Overall, our findings highlight two novel prometastatic loci in medulloblastoma and point to the JPO2:LEDGF/p75 protein complex as a potentially new targetable component of PI3K/AKT signaling in medulloblastoma. Cancer Res; 76(9);

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Section: Histology and Ihcmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

JPO2/CDCA7L and LEDGF/p75 Are Novel Mediators of PI3K/AKT Signaling and Aggressive Phenotypes in Medulloblastoma

et al. 2016

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“…4 Medulloblastoma is sensitive to a wide range of chemotherapeutic medicines, such as cisplatin, 5 procarbazine, 6 methotrexate, 7 and cyclophosphamide. 9,10 There is an urgent need to develop new targeted therapeutic approaches for medulloblastoma. 9,10 There is an urgent need to develop new targeted therapeutic approaches for medulloblastoma.…”

Section: Introductionmentioning

confidence: 99%

Retracted: Triptolide inhibits the proliferation and migration of medulloblastoma Daoy cells by upregulation of microRNA‐138

Zhang

Liu

et al. 2018

J of Cellular Biochemistry

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Medulloblastoma is a primitive neuroectodermal-derived brain tumor and the most common malignant brain tumor in children. Triptolide (TPL) is the major active component extracted from Tripterygium wilfordii Hook F. This study aimed to explore the effects of TPL on medulloblastoma cell proliferation, migration, and apoptosis, as well as the underlying possible molecular mechanism. Viability, proliferation, and apoptosis of Daoy cells were measured using cell counting kit-8 assay, 5-bromo-2'-deoxyuridine incorporation assay, and Guava Nexin assay, respectively. Cell migration was detected using two-chamber transwell assay and wound healing assay. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to determine the relative expression of microRNA-138 (miR-138) in Daoy cells. Cell transfection was used to change the expression of miR-138 in cells. Western blot analysis was used to analyze the expression of key factors involved in cell apoptosis, cell migration, the phosphatidylinositol 3-kinase (PI3K)/protein kinase 3 (AKT) pathway, and the Notch pathway in Daoy cells. We found that TPL significantly inhibited the viability, proliferation, and migration of Daoy cells but promoted Daoy cell apoptosis. The expression levels of matrix metalloproteinases (MMP)-2 and MMP-9 after TPL treatment were decreased. The expression of miR-138 in Daoy cells after TPL treatment was increased. Suppression of miR-138 obviously reversed the TPL-induced Daoy cell proliferation, migration inhibition, and cell apoptosis enhancement, as well as the inactivation of the PI3K/AKT and Notch pathways. Cyclin-dependent kinase 6 (CDK6) was a direct target gene of miR-138, which might be involved in the antitumor effects of TPL on Daoy cells. In conclusion, our study verified that TPL exerted anticancer effects on medulloblastoma cells possibly via upregulating miR-138 and inactivating the PI3K/AKT and Notch pathways.

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“…MB tends to metastasize via spread through the cerebrospinal fluid (CSF) to the meninge and subarachnoid space over the brain and spinal cord. Leptomeningeal metastasis, frequently found at diagnosis and associated with poor prognosis, requires radiation and cytotoxic chemotherapy associated with debilitating sequelae in survivors (3–5). Nonetheless, relapse after standard treatment occurs, often accompanied by metastasis, leading almost universally to fatal consequence (5, 6).…”

Section: Introductionmentioning

confidence: 99%

ATOH1 Promotes Leptomeningeal Dissemination and Metastasis of Sonic Hedgehog Subgroup Medulloblastomas

et al. 2017

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Medulloblastoma (MB) arising from the cerebellum is the most common pediatric brain malignancy, with leptomeningeal metastases often present at diagnosis and recurrence associated with poor clinical outcome. In this study, we employed mouse MB models to explore the relationship of tumor pathophysiology and dysregulated expression of the NOTCH pathway transcription factor ATOH1, which is present in aggressive MB subtypes driven by aberrant Sonic Hedgehog/Patched (SHH/PTCH) signaling. In experiments with conditional ATOH1 mouse mutants crossed to Ptch1+/− mice which develop SHH-driven MB, animals with Atoh1 transgene expression developed highly penetrant MB at a young age with extensive leptomeningeal disease and metastasis to the spinal cord and brain, resembling xenografts of human SHH MB. Metastatic tumors retained abnormal SHH signaling like tumor xenografts. Conversely, ATOH1 expression was detected consistently in recurrent and metastatic SHH MB. ChIP-seq and gene expression profiling identified candidate ATOH1 targets in tumor cells involved in development and tumorigenesis. Among these targets specific to metastatic tumors, there was an enrichment in those implicated in extracellular matrix remodeling activity, cytoskeletal network and interaction with microenvironment, indicating a shift in transcriptomic and epigenomic landscapes during metastasis. Treatment with bone morphogenetic protein (BMP) or SHH pathway inhibitors decreased tumor cell proliferation and suppressed metastatic tumor growth, respectively. Our work reveals a dynamic ATOH1-driven molecular cascade underlying MB metastasis that offers possible therapeutic opportunities.

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Medulloblastoma: recurrence and metastasis

Cited by 30 publications

References 86 publications

JPO2/CDCA7L and LEDGF/p75 Are Novel Mediators of PI3K/AKT Signaling and Aggressive Phenotypes in Medulloblastoma

JPO2/CDCA7L and LEDGF/p75 Are Novel Mediators of PI3K/AKT Signaling and Aggressive Phenotypes in Medulloblastoma

Retracted: Triptolide inhibits the proliferation and migration of medulloblastoma Daoy cells by upregulation of microRNA‐138

ATOH1 Promotes Leptomeningeal Dissemination and Metastasis of Sonic Hedgehog Subgroup Medulloblastomas

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