Tumour angiogenesis: Its mechanism and therapeutic implications in malignant gliomas

Wong, Michael L.; Prawira, Amy; Kaye, Andrew H.; Hovens, Christopher M.

doi:10.1016/j.jocn.2009.02.009

Cited by 101 publications

(95 citation statements)

References 256 publications

(241 reference statements)

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“…Such phenomena may be due to findings from the dataset demonstrating that loss of NPAS3 expression increases expression of angiogenesis-promoting factors including FGFR2 and VEGFA, which are well characterized in the progression of astrocytomas. 47,48 Increased levels of vascular endothelial growth factor A are prominently identified in high-grade astrocytomas, 47,48 which correlate well with absence of NPAS3 expression observed in these lesions.…”

Section: Discussionmentioning

confidence: 82%

NPAS3 Demonstrates Features of a Tumor Suppressive Role in Driving the Progression of Astrocytomas

Moreira

Kiehl

et al. 2011

The American Journal of Pathology

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Malignant astrocytomas, the most common primary brain tumors, are predominantly fatal. Improved treatments will require a better understanding of the biological features of high-grade astrocytomas. To better understand the role of neuronal PAS 3 (NPAS3) in diseases in human beings, it was investigated as a candidate for astrocytomagenesis based on the presence of aberrant protein expression in greater than 70% of a human astrocytoma panel (n ‫؍‬ 433) and most notably in surgically resected malignant lesions. In subsequent functional studies, it was concluded that NPAS3 exhibits features of a tumor-suppressor, which drives the progression of astrocytomas by modulating the cell cycle, proliferation, apoptosis, and cell migration/invasion and has a further influence on the viability of endothelial cells. Of clinical importance, absence of NPAS3 expression in glioblastomas was a significantly negative prognostic marker of survival. In addition, malignant astrocytomas lacking NPAS3 expression demonstrated loss of function mutations, which were associated with loss of heterozygosity. While overexpressed NPAS3 in malignant glioma cell lines significantly suppressed transformation, the converse decreased expression considerably induced more aggressive growth. In addition, knockdown NPAS3 expression in a human astrocyte cell line in concert with the human papillomavirus E6 and E7 oncogenes induced growth of malignant astrocytomas. In conclusion, NPAS3 drives the progression of human malignant astrocytomas as a tumor suppressor and is a negative prognostication marker for survival.

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Section: Discussionmentioning

confidence: 82%

NPAS3 Demonstrates Features of a Tumor Suppressive Role in Driving the Progression of Astrocytomas

Moreira

Kiehl

et al. 2011

The American Journal of Pathology

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“…Details are presented in Table 2. 17,24 Our data may find an important relevance in anti-angiogenic therapeutics of cancer, presently based on angiogenesis inhibitors targeting the VEGF signalling pathway. Such treatments have been proven to be efficacious in patient survival, associated with a chemotherapy.…”

Section: D133p53a Stimulates Angiogenesis H Bernard Et Almentioning

confidence: 93%

“…17 Such intense vascularization has a critical role in the pathological features of glioblastoma multiformes, including peritumoural oedema resulting from the defective blood-brain barrier in the newly formed vasculature. Thus, human glioblastoma U87, expressing WTp53, has been chosen here to address the role of D133p53 isoforms in angiogenesis and tumour progression.…”

Section: Introductionmentioning

confidence: 99%

The p53 isoform, Δ133p53α, stimulates angiogenesis and tumour progression

et al. 2012

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The tumour suppressor p53, involved in DNA repair, cell cycle arrest and apoptosis, also inhibits blood vessel formation, that is, angiogenesis, a process strongly contributing to tumour development. The p53 gene expresses 12 different proteins (isoforms), including TAp53 (p53 (or p53a), p53b and p53g) and D133p53 isoforms (D133p53a, D133p53b and D133p53g). The D133p53a isoform was shown to modulate p53 transcriptional activity and is overexpressed in various human tumours. However, its role in tumour progression is still unexplored. In the present study, we examined the involvement of D133p53 isoforms in tumoural angiogenesis and tumour growth in the highly angiogenic human glioblastoma U87. Our data show that conditioned media from U87 cells depleted for D133p53 isoforms block endothelial cell migration and tubulogenesis without affecting endothelial cell proliferation in vitro. The D133p53 depletion in U2OS osteosarcoma cells resulted in a similar angiogenesis blockade. Furthermore, using conditioned media from U87 cells ectopically expressing each D133p53 isoform, we determined that D133p53a and D133p53g but not D133p53b, stimulate angiogenesis. Our in vivo data using the chicken chorio-allantoic membrane and mice xenografts establish that angiogenesis and growth of glioblastoma U87 tumours are inhibited upon depletion of D133p53 isoforms. By TaqMan low-density array, we show that alteration of expression ratio of D133p53 and TAp53 isoforms differentially regulates angiogenic gene expression with D133p53 isoforms inducing pro-angiogenic gene expression and repressing anti-angiogenic gene expression.

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“…This vascular proliferation is often found in relation to hypoxia and is stimulated by proangiogenetic factors including hypoxia inducible factor 1 (HIF 1), vascular endothelial growth factors (VEGFs), IL 8, and platelet-derived growth factor (PDGF) [11,12,25]. In our series of glioblastomas microvascular proliferation was commonly seen (169/200, 84.5%), with endothelial proliferation more common (164/200, 82%) than glomeruloid tufts (131/200, 65.5%).…”

Section: Discussionmentioning

confidence: 99%

“…For instance, hypoxic pseudopalisading cells can induce glioma angiogenesis and serve as a link between necrosis and microvascular proliferation [10][11][12]. Further, the secondary features of Scherer have been related to the infiltrative properties of neoplastic astrocytes [13,14].…”

Section: Introductionmentioning

confidence: 99%

The Histopathological Spectrum of Primary Human Glioblastomas with Relations to Tumour Biology

Habberstad

Lind-Landström²,

Torp³

2012

J Clin Exp Pathol

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Glioblastoma is the most common primary brain tumour in humans. Diagnostic challenges can occur as glioblastomas are highly heterogeneous tumours. The aim of this study was to investigate the frequencies and correlations between several histological features in primary glioblastomas and describe any link to tumour biology. In conclusion, glioblastomas present a variety of cell types and histological features, important to know and be aware of for the diagnostic pathologist. Interestingly, microvascular proliferation and necroses were frequently found in co-existence. Further, several of these features are closely linked to tumour biology, making histopathology fundamental for increased understanding of gliomagenesis.

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Tumour angiogenesis: Its mechanism and therapeutic implications in malignant gliomas

Cited by 101 publications

References 256 publications

NPAS3 Demonstrates Features of a Tumor Suppressive Role in Driving the Progression of Astrocytomas

NPAS3 Demonstrates Features of a Tumor Suppressive Role in Driving the Progression of Astrocytomas

The p53 isoform, Δ133p53α, stimulates angiogenesis and tumour progression

The Histopathological Spectrum of Primary Human Glioblastomas with Relations to Tumour Biology

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