Differences in vascular endothelial growth factor receptor expression and correlation with the degree of enhancement in medulloblastoma

Hervey-Jumper, Shawn L.; Garton, Hugh; Lau, Darryl; Altshuler, David; Quint, Douglas J.; Robertson, Patricia L.; Muraszko, Karin M.; Maher, Cormac O.

doi:10.3171/2014.4.peds13244

Cited by 17 publications

(8 citation statements)

References 41 publications

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“…Nevertheless, it is important to underline that our survival analyses were performed within the biologically relevant group of non-WNT/SHH tumours since WNT and SHH tumours have distinctive characteristics and should be analysed separately as independent cohorts. Very recent results published by Hervey-Jumper et al [ 19 ] indicated that the presence of enhancement did not correlate with worse patient prognosis, but the results were not related to biological subtypes. It was noticed in our work that majority of SHH tumours were extensively enhancing but patients are long term survivors.…”

Section: Discussionmentioning

confidence: 94%

Contrast enhancement pattern predicts poor survival for patients with non-WNT/SHH medulloblastoma tumours

et al. 2015

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Recent studies revealed the biological heterogeneity of medulloblastoma, with the existence of at least four groups which are associated with several clinical and morphological features. We investigated for further correlations between molecular types, location of tumours, their contrast enhancement pattern and survival of patients. Altogether 76 tumours were analyzed and molecular subtypes were identified by immunohistochemistry using representative antibodies, detection of chromosome 6 monosomy and CTNNB1 mutation. The site of the tumour was assessed on diagnosis using Magnetic Resonance images and intra-operative surgical reports. In addition, the gadolinium enhancement pattern was also investigated in pre-treatment tumours. Cerebellar hemispheric location was associated with SHH tumours (p < 0.001), as opposed to midline location being typical for WNT and non-WNT/SHH tumours. Remarkably, for patients with non-WNT/SHH tumours, the extensive gadolinium enhancement pattern (present in >75 % of tumour volume) predicted worse OS and EFS than for those with none/weak or heterogeneous enhancement (>10–75 % of tumour volume), (both p < 0.001). Our analysis indicates that distribution of the medulloblastoma tumours location is related to the biological characteristics of tumour. Importantly, the enhancement pattern of the tumour may be a clinically useful prognostic marker for patients with non-WNT/SHH medulloblastomas.Electronic supplementary materialThe online version of this article (doi:10.1007/s11060-015-1779-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 94%

Contrast enhancement pattern predicts poor survival for patients with non-WNT/SHH medulloblastoma tumours

et al. 2015

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“…In addition, the establishment of MRI protocols for longitudinal imaging over extended periods of time is crucial for dynamic qualitative and quantitative analysis of tumor progression, which should provide a better stratification of experimental cohorts based on tumor phenotype and behavior. Previous studies have used conventional MRI techniques for morphologic brain tumor imaging in mouse MB models, but similar to most human studies [36] , [37] , [38] , [39] , mouse MB MRI reports have largely focused on detection and monitoring of tumor burden at relatively advanced tumor stages. For example, T2-weighted (T2w) MRI has been used to define the location and extent of advanced MBs in mouse models [40] , [41] , [42] , while gadolinium-enhanced T1-weighted (T1w) imaging has been used to evaluate breakdown of the blood-brain barrier (BBB) and leakage of the contrast agent into MB tumors [40] .…”

Section: Introductionmentioning

confidence: 99%

In Vivo Mn-Enhanced MRI for Early Tumor Detection and Growth Rate Analysis in a Mouse Medulloblastoma Model

Suero-Abreu¹,

Raju²,

Aristizábal³

et al. 2014

Neoplasia

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Mouse models have increased our understanding of the pathogenesis of medulloblastoma (MB), the most common malignant pediatric brain tumor that often forms in the cerebellum. A major goal of ongoing research is to better understand the early stages of tumorigenesis and to establish the genetic and environmental changes that underlie MB initiation and growth. However, studies of MB progression in mouse models are difficult due to the heterogeneity of tumor onset times and growth patterns and the lack of clinical symptoms at early stages. Magnetic resonance imaging (MRI) is critical for noninvasive, longitudinal, three-dimensional (3D) brain tumor imaging in the clinic but is limited in resolution and sensitivity for imaging early MBs in mice. In this study, high-resolution (100 μm in 2 hours) and high-throughput (150 μm in 15 minutes) manganese-enhanced MRI (MEMRI) protocols were optimized for early detection and monitoring of MBs in a Patched-1 (Ptch1) conditional knockout (CKO) model. The high tissue contrast obtained with MEMRI revealed detailed cerebellar morphology and enabled detection of MBs over a wide range of stages including pretumoral lesions as early as 2 to 3 weeks postnatal with volumes close to 0.1 mm3. Furthermore, longitudinal MEMRI allowed noninvasive monitoring of tumors and demonstrated that lesions within and between individuals have different tumorigenic potentials. 3D volumetric studies allowed quantitative analysis of MB tumor morphology and growth rates in individual Ptch1-CKO mice. These results show that MEMRI provides a powerful method for early in vivo detection and longitudinal imaging of MB progression in the mouse brain.

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“…Moreover, there is evidence that VEGF-A can act directly on some tumor cell types in an autocrine manner to promote tumor growth and invasion [ 20 , 21 ]. A number of studies reveal the elevated levels of VEGF-A and VEGFR2 in medulloblastoma of human patients [ 45 , 46 ]. Recent studies also show that medulloblastoma cells express both VEGF-A and VEGFR2 [ 22 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

Pancreatic Endoplasmic Reticulum Kinase Activation Promotes Medulloblastoma Cell Migration and Invasion through Induction of Vascular Endothelial Growth Factor A

Jamison

Lin

2015

PLoS ONE

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Evidence is accumulating that activation of the pancreatic endoplasmic reticulum kinase (PERK) in response to endoplasmic reticulum (ER) stress adapts tumor cells to the tumor microenvironment and enhances tumor angiogenesis by inducing vascular endothelial growth factor A (VEGF-A). Recent studies suggest that VEGF-A can act directly on certain tumor cell types in an autocrine manner, via binding to VEGF receptor 2 (VEGFR2), to promote tumor cell migration and invasion. Although several reports show that PERK activation increases VEGF-A expression in medulloblastoma, the most common solid malignancy of childhood, the role that either PERK or VEGF-A plays in medulloblastoma remains elusive. In this study, we mimicked the moderate enhancement of PERK activity observed in tumor patients using a genetic approach and a pharmacologic approach, and found that moderate activation of PERK signaling facilitated medulloblastoma cell migration and invasion and increased the production of VEGF-A. Moreover, using the VEGFR2 inhibitor SU5416 and the VEGF-A neutralizing antibody to block VEGF-A/VEGFR2 signaling, our results suggested that tumor cell-derived VEGF-A promoted medulloblastoma cell migration and invasion through VEGFR2 signaling, and that both VEGF-A and VEGFR2 were required for the promoting effects of PERK activation on medulloblastoma cell migration and invasion. Thus, these findings suggest that moderate PERK activation promotes medulloblastoma cell migration and invasion through enhancement of VEGF-A/VEGFR2 signaling.

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Differences in vascular endothelial growth factor receptor expression and correlation with the degree of enhancement in medulloblastoma

Cited by 17 publications

References 41 publications

Contrast enhancement pattern predicts poor survival for patients with non-WNT/SHH medulloblastoma tumours

Contrast enhancement pattern predicts poor survival for patients with non-WNT/SHH medulloblastoma tumours

In Vivo Mn-Enhanced MRI for Early Tumor Detection and Growth Rate Analysis in a Mouse Medulloblastoma Model

Pancreatic Endoplasmic Reticulum Kinase Activation Promotes Medulloblastoma Cell Migration and Invasion through Induction of Vascular Endothelial Growth Factor A

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