Current perspectives on antiangiogenesis strategies in the treatment of malignant gliomas

Jansen, Marnix; Hamer, Philip C. De Witt; Witmer, Antonella N.; Troost, Dirk; Noorden, C. J. F. Van

doi:10.1016/j.brainresrev.2004.03.001

Cited by 86 publications

(64 citation statements)

References 143 publications

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“…This will be of considerable importance, as common clinical interventions modulate tumor hypoxia. Examples include antiangiogenic therapies that increase tumor hypoxia, blood transfusions, erythropoietin application or oxygen delivery that decrease tumor hypoxia (Puduvalli and Sawaya, 2000;Jansen et al, 2004;Rieger et al, 2010). (ii) Interference with the adaptive responses towards starvation conditions by targeting key regulators of energy metabolism hold great promise as selective antitumor strategies.…”

Section: Sco2 Inhibits Hypoxia-induced Cell Deathmentioning

confidence: 99%

Synthesis of cytochrome c oxidase 2: a p53-dependent metabolic regulator that promotes respiratory function and protects glioma and colon cancer cells from hypoxia-induced cell death

et al. 2011

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P53 has an important role in the processing of starvation signals. P53-dependent molecular mediators of the Warburg effect reduce glucose consumption and promote mitochondrial function. We therefore hypothesized that the retention of wild-type p53 characteristic of primary glioblastomas limits metabolic demands induced by deregulated signal transduction in the presence of hypoxia and nutrient depletion. Here we report that short hairpin RNA-mediated gene suppression of wild-type p53 or ectopic expression of mutant temperature-sensitive dominant-negative p53 V135A increased glucose consumption and lactate production, decreased oxygen consumption and enhanced hypoxia-induced cell death in p53 wild-type human glioblastoma cells. Similarly, genetic knockout of p53 in HCT116 colon carcinoma cells resulted in reduced respiration and hypersensitivity towards hypoxia-induced cell death. Further, wild-type p53 gene silencing reduced the expression of synthesis of cytochrome c oxidase 2 (SCO2), an effector necessary for respiratory chain function. An SCO2 transgene reverted the metabolic phenotype and restored resistance towards hypoxia in p53-depleted and p53 mutant glioma cells in a rotenonesensitive manner, demonstrating that this effect was dependent on intact oxidative phosphorylation. Supplementation with methyl-pyruvate, a mitochondrial substrate, rescued p53 wild-type but not p53 mutant cells from hypoxic cell death, demonstrating a p53-mediated selective aptitude to metabolize mitochondrial substrates. Further, SCO2 gene silencing in p53 wild-type glioma cells sensitized these cells towards hypoxia. Finally, lentiviral gene suppression of SCO2 significantly enhanced tumor necrosis in a subcutaneous HCT116 xenograft tumor model, compatible with impaired energy metabolism in these cells. These findings demonstrate that glioma and colon cancer cells with p53 wild-type status can skew the Warburg effect and thereby reduce their vulnerability towards tumor hypoxia in an SCO2-dependent manner. Targeting SCO2 may therefore represent a valuable strategy to enhance sensitivity towards hypoxia and may complement strategies targeting glucose metabolism.

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Section: Sco2 Inhibits Hypoxia-induced Cell Deathmentioning

confidence: 99%

Synthesis of cytochrome c oxidase 2: a p53-dependent metabolic regulator that promotes respiratory function and protects glioma and colon cancer cells from hypoxia-induced cell death

et al. 2011

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“…The growth of new capillaries (angiogenesis) occurs in the central nervous system (CNS), not just during development (Marin-Padilla, 1985;Plate et al, 1994;Plate, 1999), but also in a number of conditions within the adult CNS, including brain tumors (Plate and Risau, 1995;Bello et al, 2004;Jansen et al, 2004), arterio-venous malformations (AVMs) (Rothbart et al, 1996;Uranashi et al, 2001), and cerebral ischemia (Garcia et al, 1971). Analysis of postmortem tissue of stroke patients has shown that cerebral ischemia stimulates the growth of new capillaries in areas surrounding the ischemic core, also known as the ischemic penumbra (Krupinski et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Increased expression of fibronectin and the α5β1 integrin in angiogenic cerebral blood vessels of mice subject to hypobaric hypoxia

Milner

Hung

Erokwu

et al. 2008

Molecular and Cellular Neuroscience

120

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The extracellular matrix (ECM) is an important regulator of angiogenesis and vascular remodeling. We showed previously that angiogenic capillaries in the developing CNS express high levels of fibronectin and its receptor α5β1 integrin, and that this expression is developmentally downregulated. As cerebral hypoxia leads to an angiogenic response, we sought to determine whether angiogenic vessels in the adult CNS re-express fibronectin and the α5β1 integrin. Ten-week old mice were subject to hypobaric hypoxia for 0, 4, 7 and 14 days, and fibronectin/integrin expression examined. Fibronectin and the α5 integrin subunit were strongly upregulated on capillaries in the hypoxic CNS, with the effect maximal at the earliest time point examined (4 days). Immunofluorescent studies demonstrated that the α5 integrin was expressed by angiogenic endothelial cells. In light of the defined angiogenic role for fibronectin in other systems, this work suggests that induction of fibronectin-α5β1 integrin expression may be an important molecular switch driving angiogenesis in the hypoxic CNS.

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“…Tumor angiogenesis is a complex process that involves several steps, including the breakdown of basement membrane, endothelial cell proliferation, cell to cell and cell to matrix interactions, and mobilization of circulating endothelial cells and hematopoietic progenitors (59). Each of these steps involves several molecular alterations that can be potentially targeted therapeutically.…”

Section: Vascular Endothelial Growth Factor Receptormentioning

confidence: 99%

“…Gliomas are highly vascularized tumors and have been shown to overexpress VEGF-A; such expression has been linked to a poorer prognosis (60,61). Other studies suggest that blocking VEGF pathways may normalize tumor vasculature and improve chemotherapy delivery, allowing higher drug concentrations (59). Several strategies for targeting VEGF have been proposed, such as anti-VEGF-A and VEGFR-2 monoclonal antibodies, antisense oligonucleotides, ribozymes, and VEGFR TKI.…”

Section: Vascular Endothelial Growth Factor Receptormentioning

confidence: 99%

Lessons learned in the development of targeted therapy for malignant gliomas

Omuro

Faivre

Raymond

2007

Molecular Cancer Therapeutics

177

137

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Current perspectives on antiangiogenesis strategies in the treatment of malignant gliomas

Cited by 86 publications

References 143 publications

Synthesis of cytochrome c oxidase 2: a p53-dependent metabolic regulator that promotes respiratory function and protects glioma and colon cancer cells from hypoxia-induced cell death

Synthesis of cytochrome c oxidase 2: a p53-dependent metabolic regulator that promotes respiratory function and protects glioma and colon cancer cells from hypoxia-induced cell death

Increased expression of fibronectin and the α5β1 integrin in angiogenic cerebral blood vessels of mice subject to hypobaric hypoxia

Lessons learned in the development of targeted therapy for malignant gliomas

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