Angiogenesis in Glioblastoma

Das, Sunit; Marsden, Philip A.

doi:10.1056/nejmcibr1309402

Cited by 228 publications

(196 citation statements)

References 5 publications

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“…Corresponding with elevated HOIL-1L levels, HIF1a expression correlates with the HOIL-1L expression in adenocarcinoma grade III patients (R 2 = 0.4313; P = 0.0203) ( Figure 6D). Tumors from patients with GBM have been reported to become severely hypoxic (1,7). In tumor tissue from patients with GBM, we found that HOIL-1L transcript levels were significantly increased in comparison with normal astrocytes (see Figure E8A).…”

Section: Hoil-1l Expression Is Elevated In Adenocarcinomasupporting

confidence: 51%

“…This is largely accomplished by a program activated in response to the stabilization of hypoxiainducible factors (HIFs), which act as transcription factors to induce metabolic changes and preserve cellular energy homeostasis (4)(5)(6). The importance of HIFs in tumorigenesis is experimentally well established and therapies directed at some HIF target genes are being clinically evaluated (3,7,8).…”

Section: Measurements and Main Resultsmentioning

confidence: 99%

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HOIL-1L Functions as the PKCζ Ubiquitin Ligase to Promote Lung Tumor Growth

Queisser

Dada

Deiss-Yehiely

et al. 2014

Am J Respir Crit Care Med

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Rationale: Protein kinase C zeta (PKCz) has been reported to act as a tumor suppressor. Deletion of PKCz in experimental cancer models has been shown to increase tumor growth. However, the mechanisms of PKCz down-regulation in cancerous cells have not been previously described.Objectives: To determine the molecular mechanisms that lead to decreased PKCz expression and thus increased survival in cancer cells and tumor growth.Methods: The levels of expression of heme-oxidized IRP2 ubiquitin ligase 1L (HOIL-1L), HOIL-1-interacting protein (HOIP), Shank-associated RH domain-interacting protein (SHARPIN), and PKCz were analyzed by Western blot and/or quantitative real-time polymerase chain reaction in different cell lines. Coimmunoprecipitation experiments were used to demonstrate the interaction between HOIL-1L and PKCz. Ubiquitination was measured in an in vitro ubiquitination assay and by Western blot with specific antibodies. The role of hypoxia-inducible factor (HIF) was determined by gain/loss-of-function experiments. The effect of HOIL-1L expression on cell death was investigated using RNA interference approaches in vitro and on tumor growth in mice models. Increased HOIL-1L and decreased PKCz expression was assessed in lung adenocarcinoma and glioblastoma multiforme and documented in several other cancer types by oncogenomic analysis. Measurements and Main Results:Hypoxia is a hallmark of rapidly growing solid tumors. We found that during hypoxia, PKCz is ubiquitinated and degraded via the ubiquitin ligase HOIL-1L, a component of the linear ubiquitin chain assembly complex (LUBAC). In vitro ubiquitination assays indicate that HOIL-1L ubiquitinates PKCz at Lys-48, targeting it for proteasomal degradation. In a xenograft tumor model and lung cancer model, we found that silencing of HOIL-1L increased the abundance of PKCz and decreased the size of tumors, suggesting that lower levels of HOIL-1L promote survival. Indeed, mRNA transcript levels of HOIL-1L were elevated in tumor of patients with lung adenocarcinoma, and in a lung adenocarcinoma tissue microarray the levels of HOIL-1L were associated with high-grade tumors. Moreover, we found that HOIL-1L expression was regulated by HIFs. Interestingly, the actions of HOIL-1L were independent of LUBAC.Conclusions: These data provide first evidence of a mechanism of cancer cell adaptation to hypoxia where HIFs regulate HOIL-1L, which targets PKCz for degradation to promote tumor survival. We provided a proof of concept that silencing of HOIL-1L impairs lung tumor growth and that HOIL-1L expression predicts survival rate in cancer patients suggesting that HOIL-1L is an attractive target for cancer therapy.

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Section: Hoil-1l Expression Is Elevated In Adenocarcinomasupporting

confidence: 51%

Section: Measurements and Main Resultsmentioning

confidence: 99%

HOIL-1L Functions as the PKCζ Ubiquitin Ligase to Promote Lung Tumor Growth

Queisser

Dada

Deiss-Yehiely

et al. 2014

Am J Respir Crit Care Med

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“…Vascular endothelial growth factor (VEGF) is highly expressed in glioma cells (22)(23)(24), and its expression is directly associated with the malignancy and prognosis of gliomas (25). Phosphoinositide-3-kinase (PI3K) is a lipid second messenger associated with intracellular signal transduction that can catalyze the formation of phosphoinositide-3 phosphate, which is the phosphorylated product of the third hydroxyl of inositol phosphate (26).…”

Section: Introductionmentioning

confidence: 99%

High expression of VEGF and PI3K in glioma stem cells provides new criteria for the grading of gliomas

Wang

Zhang

Weigao

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. Glioma is a type of tumor derived from glial cells, which is associated with a high level of incidence and mortality. At present, the generation of a fast and efficient method to evaluate the malignancy grade of glioma is required. Cancer stem cells (CSCs) are currently attracting attention in oncological studies; therefore, the present study aimed to investigate novel biomarkers of glioma CSCs, in order to provide new criteria for the grading of glioma. The mRNA expression levels of CD133, (sex determining region Y)-box 2, nestin, vascular endothelial growth factor (VEGF) and phosphoinositide-3-kinase (PI3K) were detected in 15 human samples of high-malignancy glioma and 12 human samples of low-malignancy glioma in vitro. The mRNA expression levels of VEGF and PI3K were higher in the high-malignancy group, as compared with in the low-malignancy group. In conclusion, the mRNA expression levels of VEGF and PI3K in glioma CSCs may be considered a novel criteria for the grading of glioma.

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“…The expression of a v b 3 on tumors is related to its proliferative and metastatic properties (21,22). GBM cells can differentiate into endothelial cells and pericytes, thus providing a means of tumor vascularization (23). Angiogenesis (the formation of new blood vessels from existing ones) is a vital process in the progression of GBM and is responsible for the growth of tumors.…”

Section: Discussionmentioning

confidence: 99%

Can an ¹⁸F-ALF-NOTA-PRGD2 PET/CT Scan Predict Treatment Sensitivity to Concurrent Chemoradiotherapy in Patients with Newly Diagnosed Glioblastoma?

et al. 2015

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This study examined the value of a novel 1-step labeled integrin α v β 3 -targeting 18 F-AlF-NOTA-PRGD2 (denoted as 18 F-RGD) scan in assessing sensitivity to concurrent chemoradiotherapy (CCRT) in patients with newly diagnosed glioblastoma multiforme (GBM). Methods: Twenty-five patients with newly diagnosed GBM were enrolled in this study 3-5 wk after surgical resection. All participants were investigated with 18 F-RGD PET/CT on baseline (T1) and at the third week (T2) after the start of CCRT. Tumor volume, maximal and mean standardized uptake value of the tumor (SUV max , SUV mean ), and tumor-to-nontumor ratios of the tumor volume were obtained. The MRI treatment response was assessed at the 11th week (T3). The change in the lesion volume from T1 to T3 on MRI was used as an endpoint to evaluate the predictive ability of 18 F-RGD PET/CT. Results: With 18 F-RGD PET/CT imaging, we successfully visualized the residual lesions of GBM. Twenty-five and 23 18 F-RGD PET/CT scans at baseline and the third week, respectively, were available for analysis. We found that 18 F-RGD PET/CT parameters, both pretreatment SUV max on baseline (P , 0.05) and intratreatment SUV max at the third week (SUV maxT2 ) (P , 0.05) and tumor-to-nontumor ratios at the third week (P , 0.05), were predictive of treatment sensitivity to CCRT. Additionally, the change of volume from T1 to T2 on MRI was also predictive (P , 0.05). According to receiver-operating-characteristic curve analysis, the most significant parameter was SUV maxT2 (area under the curve, 0.846). The threshold of SUV maxT2 was 1.35, and its sensitivity, specificity, and accuracy were 84.6%, 90.0% and 87.0%, respectively. Conclusion: 18 F-RGD PET/CT allows for the noninvasive visualization of GBM lesions and the prediction of sensitivity to CCRT as early as 3 wk after treatment initiation.

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Angiogenesis in Glioblastoma

Cited by 228 publications

References 5 publications

HOIL-1L Functions as the PKCζ Ubiquitin Ligase to Promote Lung Tumor Growth

HOIL-1L Functions as the PKCζ Ubiquitin Ligase to Promote Lung Tumor Growth

High expression of VEGF and PI3K in glioma stem cells provides new criteria for the grading of gliomas

Can an ¹⁸F-ALF-NOTA-PRGD2 PET/CT Scan Predict Treatment Sensitivity to Concurrent Chemoradiotherapy in Patients with Newly Diagnosed Glioblastoma?

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Angiogenesis in Glioblastoma

Cited by 228 publications

References 5 publications

HOIL-1L Functions as the PKCζ Ubiquitin Ligase to Promote Lung Tumor Growth

HOIL-1L Functions as the PKCζ Ubiquitin Ligase to Promote Lung Tumor Growth

High expression of VEGF and PI3K in glioma stem cells provides new criteria for the grading of gliomas

Can an 18F-ALF-NOTA-PRGD2 PET/CT Scan Predict Treatment Sensitivity to Concurrent Chemoradiotherapy in Patients with Newly Diagnosed Glioblastoma?

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Can an ¹⁸F-ALF-NOTA-PRGD2 PET/CT Scan Predict Treatment Sensitivity to Concurrent Chemoradiotherapy in Patients with Newly Diagnosed Glioblastoma?