Increased p53 immunopositivity in anaplastic medulloblastoma and supratentorial PNET is not caused by JC virus

Eberhart, Charles G.; Chaudhry, Aneeka; Daniel, Richard; Khaki, Leila; Shah, Keerti V.; Gravitt, Patti E.

doi:10.1186/1471-2407-5-19

Cited by 35 publications

(31 citation statements)

References 48 publications

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“…A specific treatment strategy for these patients could also be hypothesized. Some reports have indicated that the p53 pathway is frequently altered in large cell/anaplastic medulloblastomas characterized by aggressive clinical behaviour, and that nuclear expression of p53 by this variant may be more common [8,27,28]. We did not find a significant increase in p53 immunoreactivity in anaplastic or large-cell MB.…”

Section: Discussioncontrasting

confidence: 74%

“…p53 nuclear protein accumulation, which is often associated with p53 loss-of-function, has been shown to be predictive of shorter survival in MB patients [8,[10][11][12][13]. Jaros [13] showed, by multivariate analysis, that overexpression of p53 enabled identification of a group of MB patients with a sevenfold greater risk of death.…”

Section: Discussionmentioning

confidence: 99%

“…Although usually expressed at low levels under normal homeostasis, p53 is up-regulated in response to cellular stress and, as transcriptional factor, may activate or repress a large variety of genes resulting in a wide range of effects which include halting cell proliferation or inducing apoptosis [6,7]. Use of p53 protein expression to predict poor prognosis in many human cancers, including standard-risk MB patients, has been widely reported [8][9][10][11][12][13]. Although p53 RNA was significantly differently expressed in metastatic (M?)…”

Section: Introductionmentioning

confidence: 99%

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p53 expression predicts dismal outcome for medulloblastoma patients with metastatic disease

et al. 2011

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Medulloblastoma (MB) is the most common malignant primary brain tumour in childhood. Metastatic disease (M+) at diagnosis is the most important negative prognostic clinical marker and, despite craniospinal irradiation and intensive chemotherapy, it remains one of the leading causes of treatment failure. To date, few clinical and biological data have been evaluated to obtain an additional prognostic profile for these high-risk patients. In this study, 169 patients with metastatic MB registered in the multicentre HIT2000 trial of the German Society of Pediatric Oncology and Haematology (GPOH) have been investigated to determine the importance of p53 protein expression in predicting survival. At a median follow-up of 4.1 years, 159 patients with p53-negative tumours had significantly better four-year event-free survival (EFS) and progression-free survival (PFS) (56 ± 11, 59 ± 4%) than 10 patients with p53-positive tumours (40 ± 16, 40 ± 16%; P = 0.018 for EFS, P = 0.007 for PFS, respectively). Furthermore, four-year overall survival (OS) of children with p53-negative tumours was higher than for children with p53-positive tumours (72 ± 4 vs. 35 ± 18%, P = 0.05). Three of the p53-positive MBs harbored a point mutation in the TP53 gene. p53 protein assessment by immunohistochemistry may be a useful tool for sub-stratification of metastatic high-risk MB patients.

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Section: Discussioncontrasting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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p53 expression predicts dismal outcome for medulloblastoma patients with metastatic disease

et al. 2011

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“…Immunopositivity for p53 has also been shown to be a negative prognostic factor (6,29,30). In addition, there is ample evidence that myc plays an important role in medulloblastoma biology.…”

Section: Discussionmentioning

confidence: 99%

c-Myc Overexpression Causes Anaplasia in Medulloblastoma

et al. 2006

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Both anaplasia and increased c-myc gene expression have been shown to be negative prognostic indicators for survival in medulloblastoma patients. myc gene amplification has been identified in many large cell/anaplastic medulloblastoma, but no causative link between c-myc and anaplastic changes has been established. To address this, we stably overexpressed c-myc in two medulloblastoma cell lines, DAOY and UW228, and examined the changes in growth characteristics. When analyzed in vitro, cell lines with increased levels of c-myc had higher rates of growth and apoptosis as well as significantly improved ability to form colonies in soft agar compared with control. When injected s.c. into nu/nu mice, flank xenograft tumors with high levels of c-myc in DAOY cell line background were 75% larger than those derived from control. Overexpression of c-myc was required for tumor formation by UW228 cells. Most remarkably, the histopathology of the Myc tumors was severely anaplastic, with large areas of necrosis/ apoptosis, increased nuclear size, and macronucleoli. Indices of proliferation and apoptosis were also significantly higher in Myc xenografts. Thus, c-myc seems to play a causal role in inducing anaplasia in medulloblastoma. Because anaplastic changes are often observed in recurrent medulloblastoma, we propose that c-myc dysregulation is involved in the progression of these malignant embryonal neoplasms. (Cancer Res 2006; 66(2): 673-81)

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“…However, p53 is wild type in 92%-99% of human sporadic medulloblastomas (Cogen and McDonald 1996;Portwine et al 2001) and p53 status is clearly linked to radiation responses in several other tumor types (Schmitt et al 2002). It has been suggested that increased p53 staining (implying p53 dysfunction) is associated with a poor prognosis, and is more common in anaplastic medulloblastoma, known to have a worse clinical outcome, and p53 inactivation is associated with decreased levels of radiation-induced apoptosis in medulloblastoma cell lines (Dee et al 1995;Woodburn et al 2001;Eberhart et al 2005). Therefore, preclinical trials that include radiation therapy using p53-deficient models of medulloblastoma may generate results inconsistent with the majority of these tumors in humans.…”

mentioning

confidence: 99%

PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo

Hambardzumyan¹,

Becher²,

Rosenblum³

et al. 2008

Genes Dev.

434

359

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Medulloblastomas are brain tumors that arise in the cerebellum of children and contain stem cells in a perivascular niche thought to give rise to recurrence following radiation. We used several mouse models of medulloblastomas in parallel to better understand how the critical cell types in these tumors respond to therapy. In our models, the proliferating cells in the tumor bulk undergo radiation-induced, p53-dependent apoptotic cell death. Activation of Akt signaling via PTEN loss transforms these cells to a nonproliferating extensive nodularity morphology. By contrast, the nestin-expressing perivascular stem cells survive radiation, activate PI3K/Akt pathway, undergo p53-dependent cell cycle arrest, and re-enter the cell cycle at 72 h. Furthermore, the ability of these cells to induce p53 is dependent on the presence of PTEN. These cellular characteristics are similar to human medulloblastomas. Finally, inhibition of Akt signaling sensitizes cells in the perivascular region to radiation-induced apoptosis.[Keywords: p53; PTEN; PI3K/Akt; medulloblastoma] Supplemental material is available at http://www.genesdev.org. Received October 17, 2007; revised version accepted December 17, 2007. Previous studies have shown the existence of a small subpopulation of cells in brain tumors that share key characteristics with neuronal stem/progenitor cells. These findings suggest that brain tumors contain "cancer stem cells" that may be critical for tumorigenesis (Ignatova et al. 2002;Hemmati et al. 2003;Singh et al. 2003). Brain tumor stem cells positive for nestin and CD133 occupy a perivascular niche (PVN) and a disruption of that microenvironment ablates the self-renewing cell population in brain tumors and arrests tumor growth (Calabrese et al. 2007). Nestin has been shown to be a strong prognostic factor for glioma malignancy (Strojnik et al. 2007). Furthermore, brain tumor cells expressing the stem cell marker CD133 have been shown to be relatively resistant to radiation by preferential activation of the DNA damage response (Bao et al. 2006). However, the molecular pathways governing such stem-like behavior remain largely elusive.Many critical questions surrounding the biology of therapeutic response in tumor stem-like cells remain to be answered. For example, are the stem-like cells in the niche the ones resistant to therapy, and does the niche provide additional protection for the stem-like cells that is independent of the DNA damage response? Does the relatively low cycling of stem-like cells contribute to their resistant character, or does radiation cause cell cycle arrest in the stem-like cells that are cycling at the time of treatment? Furthermore, what is the time interval between radiation treatment and the point when the stem-like cells re-enter the cell cycle? Do the mutations commonly found in some types of brain tumors, such as p53 or PTEN loss, affect the therapeutic response of either the resistant stem-like cells or the non-stem-like cell populations? Finally, are there signaling pathways that contribut...

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Increased p53 immunopositivity in anaplastic medulloblastoma and supratentorial PNET is not caused by JC virus

Cited by 35 publications

References 48 publications

p53 expression predicts dismal outcome for medulloblastoma patients with metastatic disease

p53 expression predicts dismal outcome for medulloblastoma patients with metastatic disease

c-Myc Overexpression Causes Anaplasia in Medulloblastoma

PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo

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