Nodule Formation and Desmoplasia in Medulloblastomas—Defining the Nodular/Desmoplastic Variant and Its Biological Behavior

McManamy, Charles S.; Pears, Jane; Weston, Claire; Hanzely, Zoltan; Ironside, James W.; Taylor, Roger; Grundy, Richard G.; Clifford, Steven C.; Ellison, David W.

doi:10.1111/j.1750-3639.2007.00058.x

Cited by 129 publications

(121 citation statements)

References 38 publications

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“…The extensive nodular subtype and large-cell/anaplastic MBs are the least frequent. 21, 31 The latter has been associated with poor prognosis, similar to the results of the present study. 10 Recent molecular analyses identified 4 distinct molecular subtypes within MBs depending on the predominantly activated signaling pathways.…”

Section: Discussionsupporting

confidence: 91%

Expression of heat shock proteins in medulloblastoma

Alexiou

Vartholomatos

Stefanaki

et al. 2013

PED

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Object Medulloblastoma (MB) is the most common malignant brain tumor in children. Heat shock proteins (HSPs) comprise a superfamily of proteins that serve as molecular chaperones and are overexpressed in a wide range of human cancers. The purpose of the present study was to investigate the expression of HSP27 (pSer82), HSP27 (pSer15), HSP40, HSP60, HSP70, HSP90-α, Akt, and phospho-Akt by multiplex bead array assay of MBs. The results of HSP and Akt expression were correlated with MB subtype; immunohistochemical expression of Ki-67 index, bcl-2, and p53; and patients' prognosis. Methods The authors retrospectively evaluated 25 children with MB who underwent surgery. Immunohistochemical analysis of Ki-67, p53, and bcl-2 expression was performed in all cases. By using multiplex bead array assay, a simultaneous detection of HSP27 (pSer82), HSP27 (pSer15), HSP40, HSP60, HSP70, HSP90-α, Akt, and phospho-Akt was performed. Results Medulloblastoma with extensive nodularity had significantly lower HSP27 (pSer15) expression (p = 0.039) but significantly higher HSP60 expression (p = 0.021) than classic MB. Large-cell MB had significantly higher HSP70 expression (p = 0.028) than classic MB. No significant difference was found between HSP27 (pSer82), HSP40, HSP90-α, Akt, or phospho-Akt expression and MB subtype. Large-cell MBs had significantly higher Ki-67 index compared with classic MBs (p = 0.033). When analyzing all MBs, there was a significant negative correlation between HSP27 (pSer15) and Ki-67 index (r = −0.475, p = 0.016); a significant positive correlation between HSP70 expression and Ki-67 index (r = 0.407, p = 0.043); and a significant positive correlation between HSP70 expression and bcl-2 index (r = 0.491, p = 0.023). Patients with large-cell MB had a worse survival than those with classic MB, but the difference did not reach statistical significance (p = 0.076). Conclusions A substantial expression of several HSPs in MB was observed. Given that HSPs represent an attractive strategy for anticancer therapy, further studies, involving larger series of patients, are obviously necessary to clarify the relationship of HSPs with tumor aggressiveness and prognosis.

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Section: Discussionsupporting

confidence: 91%

Expression of heat shock proteins in medulloblastoma

Alexiou

Vartholomatos

Stefanaki

et al. 2013

PED

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“…The other was a desmoplastic medulloblastoma, a histologically less aggressive subtype with better prognosis than the classic type. 15 The single desmoplastic medulloblastoma in the series of Rumboldt et al 9 did have restricted diffusion. Whether there are differences in imaging features of desmoplastic and conventional medulloblastoma is not well studied, but one might expect the less aggressive desmoplastic type to have less highly restricted diffusion than the classic type.…”

Section: Discussionmentioning

confidence: 92%

Value and Limitations of Diffusion-Weighted Imaging in Grading and Diagnosis of Pediatric Posterior Fossa Tumors: Fig 1.

Jaremko¹,

Jans²,

Coleman³

et al. 2010

AJNR Am J Neuroradiol

111

107

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SUMMARY: DWI reportedly accurately differentiates pediatric posterior fossa tumors, but anecdotal experience suggests limitations. In 3 years, medulloblastoma and JPA were differentiated by DWI alone in 23/26 cases (88%). Ependymoma (n ϭ 5) could not be reliably differentiated from medulloblastoma or JPA. A trend toward increased diffusion restriction in higher grade tumors (1/14 grade I, 7%; 9/12 grade IV, 75%) had too much overlap to predict the grade of individual cases. The overlap in ADC between tumor types appeared partly due to technical factors (in small, heterogeneous, calcific, or hemorrhagic tumors) but also likely reflected true histologic variability, given that our 3 overlap cases included a desmoplastic medulloblastoma, an anaplastic ependymoma, and a JPA with restricted diffusion in its nodule. Simple structural features (macrocystic tumor, location off midline) aided in distinguishing JPA from the other tumors in these cases.ABBREVIATIONS: ADC ϭ apparent diffusion coefficient; ADCmean ϭ mean value of ADC; ADCmin ϭ minimum value of ADC; DWI ϭ diffusion-weighted imaging; FLAIR ϭ fluid-attenuated inversion recovery; JPA ϭ juvenile pilocytic astrocytoma; WHO ϭ World Health Organization D WI might, in theory, effectively distinguish tumor types and histologic grades because higher grade tumors with more densely packed cells should have increasingly restricted diffusion (with a lower ADC).

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“…2A), Ptch LacZ/+ ; p53 À/À mouse MB cells, and the DAOY MB cell line. It is of note that the Vandy-MB-11 cells were established from an 11-yr-old male patient who developed MBEN in the cerebellar vermis (Supplemental Table 1) and that the DAOY cells were originally established from a desmoplastic MB, suggesting that these cells likely belonged to the SHH-MB subgroup (McManamy et al 2007;Ellison et al 2011). These RNAi treatments selectively reduced the EAG2 expression level but did not affect EAG1 expression (Fig.…”

Section: Eag2 Up-regulation Is a Hallmark Of A Subset Of Human Mbsmentioning

confidence: 93%

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

et al. 2012

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Medulloblastoma (MB) is the most common pediatric CNS malignancy. We identify EAG2 as an overexpressed potassium channel in MBs across different molecular and histological subgroups. EAG2 knockdown not only impairs MB cell growth in vitro, but also reduces tumor burden in vivo and enhances survival in xenograft studies. Mechanistically, we demonstrate that EAG2 protein is confined intracellularly during interphase but is enriched in the plasma membrane during late G2 phase and mitosis. Disruption of EAG2 expression results in G2 arrest and mitotic catastrophe associated with failure of premitotic cytoplasmic condensation. While the tumor suppression function of EAG2 knockdown is independent of p53 activation, DNA damage checkpoint activation, or changes in the AKT pathway, this defective cell volume control is specifically associated with hyperactivation of the p38 MAPK pathway. Inhibition of the p38 pathway significantly rescues the growth defect and G2 arrest. Strikingly, ectopic membrane expression of EAG2 in cells at interphase results in cell volume reduction and mitotic-like morphology. Our study establishes the functional significance of EAG2 in promoting MB tumor progression via regulating cell volume dynamics, the perturbation of which activates the tumor suppressor p38 MAPK pathway, and provides clinical relevance for targeting this ion channel in human MBs.

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Nodule Formation and Desmoplasia in Medulloblastomas—Defining the Nodular/Desmoplastic Variant and Its Biological Behavior

Cited by 129 publications

References 38 publications

Expression of heat shock proteins in medulloblastoma

Expression of heat shock proteins in medulloblastoma

Value and Limitations of Diffusion-Weighted Imaging in Grading and Diagnosis of Pediatric Posterior Fossa Tumors: Fig 1.

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

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